FULL PRESCRIBINGINFORMATION use Lamivudine andTenofovirDisoproxilFumarateTablets,Co-packagedwithNevirapineTabletsUSP,fororal lamivudine andtenofovirdisoproxilfumaratetablets,co-packagedwithnevirapinetablets. for information prescribing full See effectively. and safely tablets nevirapine with co-packaged tablets, These highlights do not include all the information needed to use lamivudine and tenofovir disoproxil fumarate HIGHLIGHTS OFPRESCRIBINGINFORMATION Pharma code:Front630Back631 Book Folding:50x70mm Size :500x700mm Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. (4.1, 5.10, 8.7) • ------CONTRAINDICATIONS------Tablets: 300mglamivudineandtenofovirdisoproxilfumarate,Co-packagedwith200nevirapine.(3) ------DOSAGE FORMSANDSTRENGTHS------daily once taken mg mg/300 300 Tablet Fumarate Disoproxil Tenofovir and Lamivudine One Maintenance: • with Tablet Fumarate Disoproxil Tenofovir and Lamivudine One dosing): of days 14 (Initial Period Lead-in • ------DOSAGE ANDADMINISTRATION------The14-daylead-inperiodwithnevirapinetabletsmustbestrictlyfollowed;ithasbeendemonstratedto • DRUGINTERACTIONS 7 ADVERSEREACTIONS 6 WARNINGSANDPRECAUTIONS 5 CONTRAINDICATIONS DOSAGEFORMSANDSTRENGTHS 4 3 DOSAGEANDADMINISTRATION INDICATIONSANDUSAGE 2 1 EXACERBATION OF HEPATITIS B, LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS ACUTE TREATMENT POST and STEATOSIS WITH HEPATOMEGALY ACIDOSIS/SEVERE LACTIC WARNINGS: FULL PRESCRIBINGINFORMATION:CONTENTS* Initiationoftreatmentisnotrecommendedinthefollowingpopulationsunlessbenefitsoutweigh • Important considerationswiththeuseofnevirapine-containingproducts: of ageandolderwithabodyweightatleast35kg.(1) combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and adolescents 16 years in or alone indicated are nevirapine, and fumarate disoproxil tenofovir lamivudine, of combination a mg, 200 Lamivudine and Tenofovir Disoproxil Fumarate Tablets, 300 mg/300 mg Co-packaged with Nevirapine Tablets USP ------INDICATIONS ANDUSAGE------[ Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings Patients withRash clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis. fixed-dose combination formulation, they are not recommended for patients with impaired renal function (creatinine a contain Tablets Nevirapine with Co-packaged Tablets, Fumarate Disoproxil Tenofovir and Lamivudine Because DoseAdjustment 2.2 food andoneNevirapine200mgTablettakentwicedailyorallywithorwithoutfood. One LamivudineandTenofovirDisoproxilFumarateTablet300 mg/300 mgtakenoncedailyorallywithorwithout If theinitial14daysofdosingistoleratedwithoutanyincidencerash,recommendedmaintenancedoseis: Maintenance without food. or with orally daily once taken nevirapine) of mg 200 (containing tablet nevirapine one with fumarate) disoproxil tenofovir of mg 300 lamivudine, of mg 300 (containing tablet fumarate disoproxil tenofovir and lamivudine One Lead-in Period(Initial14daysofdosing) RecommendedDoseinAdultsandAdolescents[16YearsofAgeOlderwithaBodyWeightat DOSAGEANDADMINISTRATION 2.1 Itshouldnotbeadministeredwithothernevirapine-containingproducts,includingVIRAMUNE(nevirapine). 2 • mg 200 The daily. twice mg 200 to escalate dose not do period, lead-in 14-day the beyond persists rash If • the rash has resolved until mg/day 200 of period lead-in 14-day the during symptoms constitutional without rash moderate to mild The14-daylead-inperiodwithnevirapinetabletsUSP,200mgdailydosingmustbestrictlyfollowed;ithas • Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine • infection: HIV-1 of treatment the for products nevirapine-containing of use the regarding information important Additional other antiretroviralagentsforthetreatmentofHIV-1infection. with combination in use for indicated inhibitor transcriptase reverse non-nucleoside a is Nevirapine Nevirapine: infection. HIV-1 of treatment the for antiretrovirals other with combination in indicated inhibitors transcriptase reverse nucleoside are Fumarate Disoproxil Tenofovir and Lamivudine Fumarate: Disoproxil Tenofovir and Lamivudine 16 yearsofageandolderwithabodyweightatleast35kg(77lb). adolescents and adults in infection HIV-1 of treatment the for antiretrovirals other with combination in or alone INDICATIONSANDUSAGE indicated are USP Tablets, Nevirapine with Co-packaged Tablets Fumarate Disoproxil Tenofovir and Lamivudine 1 and ‘H’onotherside. side one on ‘129’ with debossed tablets, coated film biconvex shaped, capsule blue, to blue light are tablets The of tenofovirdisoproxilfumarate,whichisequivalentto245mgand300lamivudine. mg 300 contains tablet film-coated Each tablets. as available are fumarate disoproxil Tenofovir and Lamivudine DOSAGEFORMSANDSTRENGTHS Lamivudine andTenofovirDisoproxilFumarate 3 despite discontinuationoftreatment. throughout nevirapine treatment post-dose escalation.Aftertheinitial18-weekperiod,frequentclinicalandlaboratorymonitoringshouldcontinue in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at two weeks and month, per once than often more monitoring laboratory and clinical recommend experts Some established. first 18weeksoftreatmentwithnevirapine.Theoptimalfrequencymonitoringduringthisperiodhasnotbeen the during and baseline at essential is tests, enzyme liver including monitoring, laboratory and clinical Intensive Nevirapine MonitoringofPatients 2.3 200 mgtabletdailyforthefirst14days(lead-in)followedbyonetwicedaily. one using dosing, recommended the restart days, 7 than more for dosing nevirapine interrupt who patients For Patients withDoseInterruption after recovery If a clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapine Patients withHepaticEvents period shouldnotexceed28daysatwhichpointanalternativeregimenbesought. see Boxed Warning, Warnings and Precautions (5.11) Monitoring during the first 18 weeks of therapy is essential. Extra vigilance is warranted during the first • • • • • Discontinue nevirapine-containingproductsimmediatelyifexperiencing: • • • • REACTIONS SKIN and HEPATOTOXICITY FATAL) (INCLUDING LIFE-THREATENING B, HEPATITIS OF EXACERBATONS ACUTE TREATMENT POST and STEATOSIS WITH HEPATOMEGALY ACIDOSIS/SEVERE LACTIC WARNINGS: at increased risk; women with CD4 with women risk; increased at CD4 all genders, both in occur can use nevirapine with associated hepatotoxicity However, risk. greatest the at are infection, HIV-1 of treatment the for antiretrovirals other with combination in nevirapine receiving despite discontinuationoftreatment. progressed has injury hepatic cases, some In reactions. hypersensitivity or rash skin severe following or symptoms, systemic other or rash with combined elevations transaminase or hepatitis, clinical following nevirapine restart not Do events. these of risk greatest of period the is which therapy, of weeks 6 first skin reactions.Extravigilanceiswarrantedduringthe detect potentiallylife-threateninghepatotoxicityor Monitoring: [see WarningsandPrecautions(5.11)] nevirapine 200mgdailydosinghasbeenobserved to decreasetheincidenceofrashandmustbefollowed with period lead-in 14-day The treatment. of weeks 18 first the in rash a develop who patients all for nevirapine and seek medical evaluation immediately. Transaminase levels should be checked immediately discontinue must reactions hypersensitivity or reactions skin severe of symptoms or signs developing and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients with nevirapine tablets. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, treated with nevirapine, one component of lamivudine and tenofovir disoproxil fumarate tablets co-packaged Reactions: Skin nevirapine andseekmedicalevaluationimmediately hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue contraindicated is PEP occupational non- and occupational for nevirapine of Use (PEP). prophylaxis post-exposure for nevirapine taking HIV often associated with rash. Female gender and higher CD4 non-specific prodromalsignsorsymptomsofhepatitisand progressed tohepaticfailure.Theseeventsare with presented patients cases, some In tablets. nevirapine with co-packaged tablets fumarate disoproxil weeks, hasbeenreportedinpatientstreatedwithnevirapine,onecomponentoflamivudineandtenofovir Hepatotoxicity: Severe,life-threatening,andinsomecasesfatalhepatotoxicity,particularlythefirst18 of anti-hepatitisBtherapymaybewarranted 1 and HBV and discontinue lamivudine and tenofovir disoproxil fumarate tablets. If appropriate, resumption both clinicalandlaboratoryfollow-upforatleastseveralmonthsinpatientswhoareco-infectedwithHIV- with closely monitored be should function Hepatic tablets. nevirapine with co-packaged tablets fumarate disoproxil tenofovir and lamivudine of components two fumarate, disoproxil tenofovir and lamivudine are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued Exacerbations ofHepatitisB:SevereacuteexacerbationshepatitisBhavebeenreportedinpatientswho (5.1)]. occur hepatotoxicity pronounced or acidosis lactic of suggestive findings with nevirapine tablets, in combination with other antiretrovirals. Suspend treatment if clinical or laboratory disoproxil fumarate,twocomponentsoflamivudineandtenofovirfumaratetabletsco-packaged tenofovir and lamivudine including analogs nucleoside of use the with reported been have cases, fatal Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including

MEDICATION GUIDE WARNINGS: LACTICACIDOSIS/SEVEREHEPATOMEGALYWITHSTEATOSISandPOSTTREATMENTACUTE EXACERBATONS OFHEPATITISB,LIFE-THREATENING(INCLUDINGFATAL)HEPATOTOXICITYandSKIN

Lamivudine and Tenofovir Disoproxil Fumarate Tablets, 300 mg/300 mg Co-packaged + orally andoneNevirapineTablet200mgtakentwicedailywithorwithoutfood.(2) mg ofnevirapine)takenoncedailyorallywithorwithoutfood(2). one NevirapineTablet(containing300mgoflamivudine,tenofovirdisoproxilfumarate,and200 reduce thefrequencyofrash(2.2,5.11). adultmaleswithCD4 • . Trimethoprim/Sulfamethoxazole(TMP/SMX) 7.2 Interferon-andRibavirin-BasedRegimens 7.1 PostmarketingExperience 6.2 AdverseReactionsfromClinicalTrialsExperience 6.1 DrugInteractions 5.13 Resistance 5.12 SkinReactions 5.11 HepatotoxicityandHepaticImpairment 5.10 EarlyVirologicFailure 5.9 FatRedistribution 5.8 ImmuneReconstitutionSyndrome 5.7 BoneEffects 5.6 NewOnsetorWorseningRenalImpairment 5.5 UsewithInterferon-andRibavirin-BasedRegimens 5.4 CoadministrationwithOtherProducts 5.3 PatientsCo-infectedwithHIV-1andHBV 5.2 LacticAcidosis/SevereHepatomegalywithSteatosis 5.1 Post-ExposureProphylaxis 4.2 HepaticImpairment 4.1 MonitoringofPatients 2.3 DosageAdjustment 2.2 RecommendedDoseinAdultsandAdolescents(Olderthan16YearsofAgeorWeighingGreater 2.1 adultfemaleswithCD4 • risks (1,5.10) 6 weeksoftherapy,whichistheperiodgreatestrisktheseevents.(5) Any rashwithsystemicsymptoms(5.11) Severe skinorhypersensitivityreactions(5.11) Increase transaminasescombinedwithrashorothersystemicsymptoms(5.11) Signs orsymptomsofhepatitis(5.10) Fatal andnon-fatalskinreactions(5.11) Fatal andnon-fatalhepatotoxicity(5.10) initiate anti-hepatitisBtreatment.(5.2) and tenofovir disoproxil fumarate. Monitor hepatic function closely in these patients and, if appropriate, hepatitis Bvirus(HBV)andhumanimmunodeficiency(HIV-1)havediscontinuedlamivudine with co-infected are who patients in reported been have B hepatitis of exacerbations acute Severe if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs. (5.1) use ofnucleosideanalogsincludinglamivudineandtenofovirdisoproxilfumarate.Suspendtreatment the with reported been have cases, fatal including steatosis, with hepatomegaly and acidosis Lactic Least 35kg(77lb)] should besought. which pointanalternativeregimen once-daily dosingregimenshouldnotbecontinuedbeyond28days,at Precautions (5.11) been demonstrated to reduce the frequency of rash [ Boxed WarningandWarningsPrecautions(5.10) in adult males with CD4 with males adult in tablets, USP should not be initiated in adult females with CD4 with females adult in initiated be not should USP tablets, with Nevirapine Tablets USP, 200 mg cell counts and at any time during treatment. Hepatic failure has also been reported in patients without

Read this Medication Guide before you start taking lamivudine and tenofovir disoproxil or Equalto35kg) Patients mustbemonitoredintensivelyduringthefirst18weeksoftherapywithnevirapineto

fumarate tablets, co-packaged with nevirapine tablets and each time you get a refill. [seeWarningsandPrecautions(5.10) There may be new information. This information does not take the place of talking to

your doctor about your medical condition or treatment. patients in occurred have cases, fatal including reactions, skin life-threatening Severe,

What is the Most Important Information I Should Know About Lamivudine and [ see Warnings and Precautions (5.11) Seefullprescribinginformationforcompleteboxedwarning. Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets? ]. Nevirapine, one component of Lamivudine and Tenofovir Disoproxil Fumarate + Tablets Co-packaged with Nevirapine Tablets, can cause serious side effects. cells/mm 400 than greater counts cell [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed +

These include severe liver and skin problems that can cause death. These problems cellcountsgreaterthan400cells/mm + can happen at any time during treatment, but your risk is higher during the first cellcountsgreaterthan250cells/mm +

18 weeks of treatment. cells/mm 250 than greater counts cell [see Contraindications (4.2)] Contraindications [see 1. Severe liver problems: Anyone who takes nevirapine may get severe liver . problems. In some cases these liver problems can lead to liver failure and the

need for a liver transplant, or death. [see WarningsandPrecautions(5.2)]. People who have a higher CD4+ cell count when they begin nevirapine treatment have REACTIONS ]. a higher risk of liver problems, especially: ]. Do not increase nevirapine dose if a

+ 3 [see WarningsandPrecautions(5.10)] • Women with CD4 counts higher than 250 cells/mm . This group has the highest see Dosage and Administration (2.1) and Warnings and ]. ].

risk. + cell counts at initiation of therapy place patients The total duration of the once daily lead-in dosing Note: PharmacodepositionandOrientationwill bechangebasedonfoldingsize Spec: Printedon40GSMBiblepaper,front& backsideprinting. Colour :Single(PantoneBlackC) • Men with CD4+ counts higher than 400 cells/mm3. If you are a woman with CD4+ counts higher than 250 cells/mm3 or a man with CD4+ + 3 3 cells/mm 250 than greater counts cell counts higher than 400 cells/mm , you and your doctor will decide whether starting [ risk the outweighs benefit the unless . Patients with signs or symptoms of symptoms or signs with Patients . nevirapine is right for you. 3 3 In general, women have a higher risk of liver problems compared to men. [see Warnings and Precautions and Warnings [see 3

People who have abnormal liver test results before starting nevirapine treatment and women pregnant including , people with hepatitis B or C also have a greater chance of getting liver problems. You may get a rash if you have liver problems. Stop taking nevirapine and call your doctor right away if you have any of the

following symptoms of liver problems: patient experiences

• dark (tea colored) urine . • yellowing of your skin or whites of your eyes Nevirapine • light-colored bowel movements (stools) • fever 3 see or • nausea (feeling sick to your stomach) • feel unwell or like you have the flu all pediatrictrials,skeletalgrowth(height)appearedtobeunaffected. In years. 18 than less to years 12 aged subjects adolescent infected B hepatitis chronic in observed were trends gain waslessinthetenofovir-treatedHIV-1infectedpediatricsubjectsascomparedtocontrolgroups.Similar BMD body Total turnover. bone increased suggest and subjects adult in observed those to similar were effects bone years, 18 than less to years 2 aged subjects infected HIV-1 In patients. pediatric in rapidly increases BMD Clinical trials evaluating tenofovir in pediatric and adolescent subjects were conducted. Under normal circumstances, receiving tenofovir relative tocomparators.Serumparathyroidhormonelevelsand1,25VitaminDwerealsohigherinsubjects turnover bone increased suggesting metabolism, bone of markers biochemical in increases and (BMD) density In clinicaltrialsinHIV-1infectedadults,tenofovirwasassociatedwithslightlygreaterdecreasesbonemineral Bone MineralDensity: BoneEffects 5.6 manifestations ofproximalrenaltubulopathyandshouldpromptanevaluationfunctioninat-riskpatients. be may weakness or pain muscular and/or fractures extremities, in pain pain, bone worsening or Persistent replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. renal and hospitalization required patients Some DF. tenofovir on stable appeared who dysfunction renal for failure afterinitiationofhighdoseormultipleNSAIDshavebeenreportedinHIV-infectedpatientswithriskfactors with HEPSERA tenofovir disoproxil fumarate), and VIRAMUNE (nevirapine). Also, they should not be administered in combination (rilpivirine, emtricitabine,andtenofovirdisoproxilfumarate),STRIBILD(cobicistat,elvitegravir, VIREAD (tenofovirdisoproxilfumarate),TRUVADA(emtricitabineandtenofovirCOMPLERA and zidovudine),ATRIPLA(efavirenz,emtricitabine,tenofovirdisoproxilfumarate),EMTRIVA(emtricitabine), (lamivudine andzidovudine),EPZICOM(abacavirsulfatelamivudine),TRIZIVIRsulfate,lamivudine, fumarate-containing, ornevirapine-containingproductsincludingEPIVIREPIVIR-HBV(lamivudine),COMBIVIR disoproxil tenofovir emtricitabine-containing, lamivudine-containing, other with concomitantly administered be not should Tablets Nevirapine with Co-packaged Tablets, Fumarate Disoproxil Tenofovir and Lamivudine CoadministrationwithOtherProducts 5.3 virus. B hepatitis with infection concurrent of presence the in regimens antiretroviral lamivudine-containing received virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have B hepatitis of Emergence information). additional for EPIVIR-HBV for information prescribing full (see response B, emergenceoflamivudine-resistantHBVhasbeendetectedandassociatedwithdiminishedtreatment Emergence of Lamivudine-Resistant In HBV: non-HIV-l-infected patients treated with lamivudine for chronic hepatitis *Sections orsubsectionsomittedfromthefullprescribinginformationarenotlisted. PATIENTCOUNSELINGINFORMATION 17 HOWSUPPLIED/STORAGEANDHANDLING 16 CLINICALSTUDIES 14 NONCLINICALTOXICOLOGY 13 CLINICALPHARMACOLOGY 12 DESCRIPTION 11 OVERDOSAGE 10 USEINSPECIFICPOPULATIONS 8 NursingMothers:WomeninfectedwithHIVshouldbeinstructednottobreastfeed.(8.3) See 17forPATIENTCOUNSELINGINFORMATIONandMedicationGuide. • ------USE INSPECIFICPOPULATIONS------lamivudine of component one nevirapine, of concentrations the alter may drugs other of Coadministration • lopinavir/ritonavir or ritonavir, and darunavir ritonavir, and atazanavir with tenofovir of Coadministration • tenofovir increases and concentrations atazanavir decreases Coadministration inhibitors: protease HIV-1 • Didanosine: Coadministration increases didanosine concentrations. Use with caution and monitor for evidence • ------DRUG INTERACTIONS------experienced renal events while receiving HEPSERA previously have who patients including dysfunction, renal of risk at patients In tablets. fumarate disoproxil as clinically appropriate during therapy with tenofovir disoproxil fumarate, a component of lamivudine, and tenofovir and therapy initiating to prior patients all in assessed be clearance creatinine estimated that recommended is It disoproxil fumarate,acomponentoflamivudineandtenofovirfumarate Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir and failure renal acute of cases including impairment, Renal kidney. the by eliminated principally is Tenofovir NewOnsetorWorseningRenalImpairment 5.5 See thecompleteprescribinginformationforinterferonandribavirin. considered ifworseningclinicaltoxicitiesareobserved,includinghepaticdecompensation(e.g.,Child-Pugh>6). be also should both or ribavirin, alfa, interferon of discontinuation or reduction Dose appropriate. medically of lamivudineshouldbeconsideredas associated toxicities,especiallyhepaticdecompensation.Discontinuation Patients receiving interferon alfa with or without ribavirin and lamivudine should be closely monitored for treatment- infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. patients co-infected HIV-1/HCV in lamivudine with coadministered was ribavirin when seen was suppression) virologic HIV-1/HCV of loss (e.g., interaction pharmacodynamic or pharmacokinetic a of evidence no Although tablets. lamivudine, onecomponentoflamivudineandtenofovirdisoproxilfumaratetabletsco-packagedwithnevirapine as such analogs nucleoside pyrimidine of phosphorylation the reduce can ribavirin shown have studies vitro In UseWithInterferon-andRibavirin-BasedRegimens 5.4 be warranted. up foratleastseveralmonthsafterstoppingtreatment.Ifappropriate,resumptionofanti-hepatitisBtherapymay lamivudine andtenofovirdisoproxilfumarate should becloselymonitoredwithbothclinicalandlaboratoryfollow- Fumarate may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue initiating antiretroviral therapy. Discontinuation of anti-HBV therapy, including Lamivudine and Tenofovir Disoproxil It isrecommendedthatallpatientswithHIV-1betestedforthepresenceofchronichepatitisBvirus(HBV)before PatientsCo-infectedwithHIV-1andHBV 5.2 and steatosisevenintheabsenceofmarkedtransaminaseelevations) laboratory findingssuggestiveoflacticacidosisorpronouncedhepatotoxicity(whichmayincludehepatomegaly or clinical develops who patient any in suspended be should fumarate disoproxil tenofovir and lamivudine with factors forliverdisease;however,caseshavealsobeen reported inpatientswithnoknownrisk factors. Treatment risk known with patient any to analogs nucleoside administering when exercised be should caution Particular factors. risk be may exposure nucleoside prolonged and Obesity women. in been have cases these of majority A tenofovir disoproxil fumarate tablets co-packaged with nevirapine tablets, in combination with other antiretrovirals. of nucleosideanalogs,includinglamivudineandtenofovirdisoproxilfumarate,twocomponents use the with reported been have cases, fatal including steatosis, with hepatomegaly severe and acidosis Lactic LacticAcidosis/SevereHepatomegalywithSteatosis 5.1 of rash[seeDosageandAdministration(2.1)] frequency the reduce to demonstrated been has dosing daily mg 200 nevirapine with period lead-in 14-day the period, frequentclinicalandlaboratorymonitoringshouldcontinuethroughoutnevirapinetreatment.Inaddition, enzyme testsatbaseline,priortodoseescalationandtwoweekspost-doseescalation.Aftertheinitial18-week liver of monitoring include particular, in and month, per once than often more monitoring laboratory and clinical recommend experts Some established. been not has period time this during monitoring of frequency optimal monitoring ofpatientsisrequiredtodetectpotentiallylife-threateninghepaticeventsandskinreactions. The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory lymphadenopathy, orrenaldysfunction. granulocytopenia, eosinophilia, edema, facial conjunctivitis, lesions, oral blisters, aches, joint or muscle with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, syndrome, toxicepidermalnecrolysis,andhypersensitivityreactions.Hepatitis/hepaticfailuremaybeassociated Stevens-Johnson failure, hepatitis/hepatic are tablets, nevirapine with co-packaged tablets fumarate disoproxil tenofovir and lamivudine of component one nevirapine, with associated reactions adverse serious most The WARNINGSANDPRECAUTIONS Nevirapine 5 and Precautions(5.10)]. regimens (PEP) prophylaxis post-exposure non-occupational and occupational of part as use for Lamivudine andTenofovirDisoproxilFumarateTablets,Co-packagedwithNevirapineTabletsarecontraindicated Post-ExposureProphylaxis 4.2 Precautions (5.10)andUseinSpecificPopulations(8.7)] in patientswithmoderateorsevere(Child-PughClassBC,respectively)hepaticimpairment Lamivudine andTenofovirDisoproxilFumarateTablets,Co-packagedwithNevirapineTabletsarecontraindicated HepaticImpairment CONTRAINDICATIONS 4.1 4 one sideand‘7’onotherwithabreaklinebothsides. on ‘H’ with debossed tablets, biconvex shaped, capsule yellow, pale to off-white are mg 200 Tablets, Nevirapine Nevirapine and whichmaycontributetofractures),havebeenreportedinassociationwiththeuseoftenofovir Cases ofosteomalacia(associatedwithproximalrenaltubulopathy,manifestedasbone pain orinextremities Mineralization Defects: be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. may supplementation such studied, not was D vitamin and calcium with supplementation of effect the Although of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. years 12 patients pediatric and adults for considered be should BMD of Assessment unknown. are risk fracture The effects of tenofovir -associated changes in BMD and biochemical markers on long-term bone health and future or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) drugs anti-inflammatory non-steroidal multiple or high-dose (e.g., agent nephrotoxic a of use recent or concurrent with avoided be should tablets, nevirapine with Tenofovir disoproxil fumarate, one component of lamivudine, and tenofovir disoproxil fumarate tablets co-packaged periodically duringtenofovirtherapy. and tenofovir, of initiation to prior assessed be protein urine and glucose, urine phosphorus, serum clearance, • pain or tenderness on your right side below your ribs FDA-1088 or 1-800- at FDA or 866-495-1995 at Limited Labs Hetero contact REACTIONS, ADVERSE SUSPECTED report To with 6% vs. 15% is rash of incidence the adults In rash. is reaction adverse reported common most The • and malaise nausea, pain, headache, are reactions adverse common Most subjects: adult HIV-infected In • ------ADVERSE REACTIONS------Rash:Fatalandnon-fatalskinreactions,includingStevens-Johnsonsyndrome,toxicepidermalnecrolysis, HepatotoxicityandHepaticImpairment.(5.10) • • TripleNucleoside-onlyRegimens:EarlyvirologicfailurehasbeenreportedinHIV-infectedpatients.Monitor • Immune Reconstitution Syndrome (5.7) and Redistribution/Accumulation of Body Fat (5.8) has been reported • DecreasesinBoneMineralDensity(BMD):ObservedHIV-infectedpatients.ConsiderassessmentofBMD • NewOnsetorWorseningRenalImpairment:CanincludeacuterenalfailureandFanconisyndrome.Assess • or tenofovir-, emtricitabine-, lamivudine-, other with use not Do Products: Other with Coadministration • virus B hepatitis with co-infected are who patients in Reported B: Hepatitis of Exacerbations Acute Severe • Suspend analogs. nucleoside of use the with Reported Steatosis: with Hepatomegaly and Acidosis Lactic • PRECAUTIONS------AND ------WARNINGS Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved • • tiredness 75Methadone 17.5 Contraceptives 17.4 DrugInteractions 17.3 HepatotoxicityandSkinReactions 17.2 AdviceforthePatient 17.1 ClinicalEfficacyinPatientswithHIV-1Infection 14.1 ReproductiveToxicologyStudiesandAnimaland/orPharmacology 13.2 Carcinogenesis,Mutagenesis,ImpairmentofFertility 13.1 Microbiology 12.4 Pharmacokinetics 12.3 MechanismofAction 12.1 PatientswithHepaticImpairment 8.7 PatientswithRenalImpairment 8.6 GeriatricUse 8.5 PediatricUse 8.4 NursingMothers 8.3 Pregnancy 8.1 DrugsMetabolizedbyHepaticCytochromeP450Isoenzymes,3A,and2B6 7.7 DrugsAffectingRenalFunction 7.6 HIV-1ProteaseInhibitors 7.5 Didanosine 7.4 DrugswithNoObservedInteractionsLamivudine 7.3 must beconsideredbeforeandduringtherapy.(5.13,7.7,12.3) interactions drug-drug for potential The nevirapine. with co-packaged fumarate, disoproxil tenofovir and increases tenofovirconcentrations.Monitorforevidenceoftoxicity.(7.5) (7.5) ritonavir. with given atazanavir use tenofovir, with coadministered When concentrations. didanosine ifwarranted.(7.4) of discontinuations or reductions dose Consider neuropathy). pancreatitis, (e.g., toxicity didanosine of placebo. Withgrade3/4rashoccurringin2%ofsubjects.(6.1) fatigue, nasalsignsandsymptoms,diarrhea,rash,depression,asthenia,cough.(6.1) of treatment.(5.11) weeks 18 first the in rash a develop who patients all for immediately transaminase Check occur. reactions disoproxil fumaratetablets,co-packagedwithnevirapinetabletsifsevereskinreactionsorhypersensitivity tenofovir and lamivudine discontinue Permanently reported. been have reactions, hypersensitivity and carefully andconsidertreatmentmodification.(5.9) in HIV-infectedpatientsreceivingantiretroviralcombinationtherapy. (5.6) loss. bone or osteoporosis for factors risk other or fracture pathologic of history a with patients in packaged withnevirapineconcurrentorrecentuseofnephrotoxicdrugs.(5.5) periodically duringtreatment.Avoidadministeringlamivudineandtenofovirdisoproxilfumaratetablets,co- and treatment initiating before protein urine and glucose urine phosphorus, serum clearance, creatinine risk at patients In tablets. nevirapine with co-packaged tablets estimated creatinineclearancebeforeinitiatingtreatmentwithlamivudineandtenofovirdisoproxilfumarate nevirapine-containing products.DonotadministerincombinationwithHEPSERA(adefovirdipivoxil).(5.3) closely inthesepatientsand,ifappropriate,initiateanti-hepatitisBtreatment.(5.2) function hepatic Monitor fumarate. disoproxil tenofovir or lamivudine discontinued have and HIV-1 and (5.1) treatment ifclinicalorlaboratoryfindingssuggestiveoflacticacidosispronouncedhepatotoxicityoccur. use. (4.2,5.10)

• loss of appetite [see ClinicalPharmacology(12.3)] Your doctor should see you and do blood tests often to check your liver function www.fda.gov/medwatch

during the first 18 weeks of treatment with nevirapine. You should continue to have ®

your liver checked regularly during your treatment with nevirapine. It is important for (adefovir dipivoxil)

you to keep all of your doctor appointments. [See AdverseReactions(6.1)] 2. Severe rash and skin reactions: Skin rash is the most common side effect of nevirapine. Most rashes happen in the first 6 weeks of taking nevirapine. Rashes and skin reactions may be severe, life-threatening, and in some people, may lead to death. Stop using nevirapine and call your doctor right away if you get a rash with any of the following symptoms:

• blisters [see DrugInteractions(7.6)]. • mouth sores • red or inflamed eyes, like “pink eye” (conjunctivitis) , hepaticdecompensation(somefatal)hasoccurredinHIV-1/HCVco- .

• liver problems (see symptoms of liver problems above) ® .

• swelling of your face (adefovir dipivoxil), it is recommended that estimated creatinine Page 1of4 • fever . • feel unwell or like you have the flu • tiredness (7.6)] Interactions Drug [See • muscle or joint aches . [See AdverseReactions(6.1)]

If your doctor tells you to stop treatment with nevirapine because you have had any of the serious liver or skin problems described above, you should never take estimated assess dysfunction, renal for nevirapine again. See the section "What are the possible side effects of Lamivudine and Tenofovir

Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets?" for more [see AdverseReactions(6.2)]. information. Patients taking lamivudine and tenofovir disoproxil fumarate, two components of

lamivudine and tenofovir disoproxil fumarate tablets co-packaged with nevirapine renal acute of Cases . Issued: March2014

tablets, may develop: [see Warningsand

3. Build-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen Warnings [see [See Adverse in some people who take lamivudine, tenofovir disoproxil fumarate, or similar . (nucleoside analog) medicines. Lactic acidosis is a serious medical emergency that can lead to death.

Lactic acidosis can be hard to identify early, because the symptoms could seem like The symptoms of other health problems. Call your healthcare provider right away if you get the following symptoms which could be signs of lactic acidosis: • feeling very weak or tired See Table7forlistingsofestablishedandpotentialdruginteractions DrugInteractions 5.13 [see ClinicalPharmacology(12.4)] concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop plasma low concurrently, stopped are nevirapine than half-lives shorter with antiretrovirals if account; into When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken thepotentialforcrossresistance. agents tobeusedincombinationwithnevirapineshouldtakeintoconsideration Resistant virusemergesrapidlywhennevirapineisadministeredasmonotherapy.Thechoiceofnewantiretroviral regimen. failing a to agent sole a as on added or HIV-1 treat to agent single a as used be not must Nevirapine Resistance 5.12 Therefore, useofprednisonetopreventnevirapine-associatedrashisnotrecommended. therapy. nevirapine of weeks 6 first the during rash of severity and incidence in increase an with associated was administration) nevirapine of days 14 first the for mg/day (40 use prednisone concomitant trial, clinical a In Women appeartobeathigherriskthanmenofdevelopingrashwithnevirapine. reaction. serious more a in result may rash of onset the after treatment nevirapine stopping in Delay occurs. severity any sought be should total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen without constitutionalsymptomsduringthe14-daylead-inperiodof200mg/dayuntilrashhasresolved rash moderate to mild a experiencing patient a to dose nevirapine increase not Do findings. constitutional by reduce the frequency of rash. Discontinue nevirapine if a patient experiences severe rash or any rash accompanied to shown been has which mg/day, 200 of period lead-in 14-day a with initiated be must nevirapine with Therapy (5.10)] elevations transaminase rash-associated with patients in nevirapine discontinue If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently rash combinedwithincreasedtransaminasesorothersymptoms,hypersensitivityreaction. (17.2)] Information Counseling Patient and Warning dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately evaluation medical seek and nevirapine discontinue permanently must dysfunction) lesions, conjunctivitis,facialedema,and/orhepatitis,eosinophilia,granulocytopenia,lymphadenopathy,andrenal limited to,severerashoraccompaniedbyfever,generalmalaise,fatigue,musclejointaches,blisters,oral not but (including, reactions hypersensitivity or reactions skin severe of symptoms or signs developing Patients the first6weeksin2%ofnevirapinerecipientscomparedtolessthan1%placebosubjects. during reported were rashes 4 and 3 Grade trials, clinical controlled In use. nevirapine with associated reactions liver and/or skin experiencing patients some in observed been has Rhabdomyolysis failure. hepatic including dysfunction organ and findings, constitutional rash, by characterized reactions hypersensitivity and necrolysis, epidermal toxic syndrome, Stevens-Johnson of cases included have These therapy. of weeks 6 first the during frequently most occurring reported, been have cases, fatal including reactions, skin life-threatening and Severe SkinReactions 5.11 impairment Do notadministernevirapinetopatientswithmoderateorsevere(Child-PughClassBC,respectively)hepatic Therefore, carefullymonitorpatientswith either hepaticfibrosisorcirrhosisforevidenceofdrug-inducedtoxicity. Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. [see Contraindications(4.2)]. prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated post-exposure of setting the in nevirapine of doses multiple receiving individuals uninfected HIV-1 in reported been has instance) one in transplantation requiring failure liver (including hepatotoxicity serious addition, In more afterstartingnevirapine)andasymptomaticincreasesinASTorALT. or weeks (6 events symptomatic later of risk greater a with associated are nevirapine with therapy of start the events compared to women with CD4 with women to compared events reported at all CD4 all at reported been have events adverse hepatic symptomatic since hepatotoxicity for monitored be should history, treatment The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 high with women are events, fatal potentially including events, hepatic of risk greatest at patients The discontinuation oftreatment. discontinue nevirapine.Donotrestartnevirapineafterrecovery.Insomecases,hepaticinjuryprogressesdespite If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently Dosage andAdministration(2.3),PatientCounselingInformation(17.2)] setting, eveniftransaminasesareinitiallynormaloralternativediagnosespossible acholic stools,livertendernessorhepatomegaly.Thediagnosisofhepatotoxicityshouldbeconsideredinthis appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, the for vigilant be should patients and Physicians treatment. of weeks 18 first the in rash a develop who hepatitis and/orhypersensitivityreaction.Transaminasesshouldalsobecheckedimmediatelyforallpatients of suggestive symptoms or signs experiences patient a if immediately checked be should Transaminases tests. enzyme liver include should which evaluation, medical seek immediately and nevirapine discontinue to and/or liver reactions associated with nevirapine use. Patients with signs or symptoms of hepatitis must be advised skin experiencing patients some in observed been has Rhabdomyolysis eosinophilia. or time, thromboplastin partial prolonged encephalopathy, hepatic hyperbilirubinemia, without or with elevation, transaminase with hepatic events.Someevents,particularlythosewithrashandothersymptoms,haveprogressedtofailure these of some accompanied symptoms flu-like and Fever events. adverse hepatic symptomatic with subjects the of half approximately in observed was Rash levels. transaminase serum abnormal initially without or with tenderness orhepatomegaly, prodromal signsorsymptomsoffatigue,malaise,anorexia,nausea,jaundice,liver non-specific, with presented subjects cases, some In treatment. during time any at occur may events hepatic risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, The therapy. of weeks 6 first the in greatest was severity of regardless events hepatic symptomatic of risk The received nevirapineand1%ofsubjectsincontrolgroups. who subjects of 11%) to 0% (range 4% in occurred severity of regardless events hepatic symptomatic trials, clinical controlled In tablets. nevirapine with co-packaged tablets fumarate disoproxil tenofovir and lamivudine of component one nevirapine, with treated patients in reported been have failure, hepatic and necrosis hepatic hepatitis, cholestatic and fulminant including hepatotoxicity, fatal cases some in and life-threatening, Severe, HepatotoxicityandHepaticImpairment 5.10 should becarefullymonitoredandconsideredfortreatmentmodification. regimen nucleoside-only triple a utilizing therapy a on Patients caution. with used be therefore should regimens particular, earlyvirologicalfailureandhighratesofresistancesubstitutionshavebeenreported.Triplenucleoside In inhibitor. protease HIV-1 a or inhibitor transcriptase reverse non-nucleoside a either with combination in reverse transcriptaseinhibitors(NRTI)aregenerallylesseffectivethantripledrugregimenscontainingtwoNRTIs Clinical studies in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside EarlyVirologicFailure 5.9 established. been not has relationship causal A unknown. currently are events these of consequences long-term and mechanism The therapy. antiretroviral combination receiving patients in observed been have enlargement (buffalohump),peripheralwasting,facial wasting, breastenlargement,and“cushingoidappearance” fat dorsocervical obesity, central including fat body of redistribution/accumulation patients, HIV-infected In FatRedistribution 5.8 occur manymonthsafterinitiationoftreatment. can and variable, more is onset to time the however, reconstitution, immune of setting the in occur to reported been also have syndrome) Guillain-Barré and polymyositis, disease, Graves’ as (such disorders Autoimmune jirovecii indolent or residual opportunistic infections (such as to response inflammatory an develop may responds system immune whose patients treatment, antiretroviral therapy, including lamivudine, tenofovir disoproxil fumarate, and nevirapine. During the initial phase of combination Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral ImmuneReconstitutionSyndrome 5.7 receiving productscontainingtenofovirDF in patientsatriskofrenaldysfunctionwhopresentwithpersistentorworseningbonemusclesymptomswhile tubulopathy. Hypophosphatemiaandosteomalaciasecondaryto proximal renaltubulopathyshouldbeconsidered (6.2)] Reactions provided inTable2. is abnormalities laboratory 4 and 3 Grade of summary A arms. treatment stavudine and fumarate disoproxil tenofovir the in frequency similar with occurred study this in observed abnormalities laboratory respectively, more commoninthestavudinegroup(40%and9%)comparedwithtenofovirdisoproxilfumarate(19%1%) Abnormalities: Laboratory d c b a 1. Table in summarized are reactions adverse severe to moderate treatment-emergent Selected nausea. and Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, (Study 903)weremildtomoderategastrointestinaleventsanddizziness. weeks 144 for efavirenz and lamivudine with combination in (N=301) stavudine or (N=299) fumarate disoproxil tenofovir received subjects treatment-naïve 600 which in study controlled comparative double-blind a in seen Treatment-Naïve Patients Study 903 - Treatment-Emergent Adverse Reactions: of the3largecontrolledclinicaltrialsincluderash,diarrhea,headache,pain,depression,asthenia,andnausea. The mostcommonadversereactions(incidencegreaterthanorequalto10%,Grades24)identifiedfromany 11,000 subjectshavereceivedtenofovirdisoproxilfumarateinexpandedaccessprograms. over trials; clinical in daily once mg 300 fumarate disoproxil tenofovir received have subjects 1,544 of total A antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. More than 12,000 subjects have been treated with tenofovir disoproxil fumarate alone or in combination with other Clinical TrialsinAdultPatientswithHIV-1Infection Tenofovir DisoproxilFumarate clinical trials. Pancreatitis: and cough. The mostcommonadversereactionsareheadache,nausea,malaise,fatigue,nasalsignsandsymptoms,diarrhea on 3,568HIV-1-infectedpatientsin7clinicaltrials. based primarily is adults in lamivudine of profile safety The Infection: HIV-1 with Patients Adult in Trials Clinical women with CD4 review, retrospective a In nevirapine. with events hepatic symptomatic for risk higher at are therapy nevirapine often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4 higher with patients and 2%), versus (6% events hepatic rash-associated, often counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, Table 1.SelectedTreatment-EmergentAdverseReactions counts less than 400 cells/mm 400 than less counts was observed in men with CD4 with men in observed was Lamivudine rates observedinpractice. NewOnsetorWorseningRenalImpairment • Hepaticdecompensationinpatientsco-infectedwithHIV-1andHepatitisC[seeWarningsPrecautions SevereAcuteExacerbationsofHepatitisB • LacticAcidosis/SevereHepatomegalywithSteatosis • • ADVERSEREACTIONS The followingadversereactionsarediscussedinothersectionsofthelabeling: 6 associated withanincreaseinadversereactionsandnoimprovementefficacy. class ofNNRTIs.Co-administrationnevirapineandefavirenzisnotrecommended as thiscombinationhasbeen optimal levelsofnevirapineandleadtolossvirologicresponsepossibleresistanceorthe (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub- inhibitors transcriptase reverse non-nucleoside with wort John’s St. of Co-administration recommended. not is Concomitant use of St. John's wort (Hypericum perforatum ) or St. John's wort-containing products and nevirapine trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the reflect not may and drug another of trials clinical the in rates to compared directly be cannot drug a of trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical AdversereactionsfromClinicalTrialsExperience SkinReaction 6.1 HepaticReaction • ImmuneReconstitutionSyndrome • BoneEffects • • Metabolic Disorders Digestive System Body asaWhole Musculoskeletal Skin andAppendages Respiratory Nervous System

• have unusual (not normal) muscle pain Rash eventincludesrash,pruritus,maculopapularurticaria,vesiculobullousandpustularrash. Peripheral neuropathyincludesperipheralneuritisandneuropathy. Lipodystrophy representsavarietyofinvestigator-describedadverseeventsnotprotocol-definedsyndrome. to studydrug. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship oiig %9% 5% 9% 13% 7% 8% 7% 12% 5% 12% 4% 8% 17% 11% 6% 9% 8% 13% Lipodystrophy 7% Vomiting 14% Dyspepsia Nausea Diarrhea Asthenia Back pain Abdominal pain Fever Pain Headache Myalgia Arthralgia Rash event Pneumonia Anxiety Depression Peripheral neuropathy Dizziness Insomnia (5.4)].

• have trouble breathing . pneumonia [PCP],ortuberculosis),whichmaynecessitatefurtherevaluationandtreatment. • have stomach pain with Group inStudy903(0to144Weeks) [see Contraindications (4.1), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)] Pharmacology Clinical and (8.7), Populations Specific in Use (4.1), Contraindications [see • nausea (feel sick to your stomach) Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received EPIVIR in the controlled d

. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal proximal of cases in reported been also have weakness or pain muscle and Arthralgias . + cell counts greater than 250 cells/mm • vomiting b . Patients must be monitored closely if isolated rash of rash isolated if closely monitored be must Patients (2.2)]. Administration and Dosage [see [see WarningsandPrecautions(5.6)]

+

[see WarningsandPrecautions(5.11)]. • feel cold, especially in your arms and legs cell [see WarningsandPrecautions(5.10)] counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at elevations transaminase increased and/or C or B hepatitis with Co-infection counts.

• feel dizzy or lightheaded c 1 With the exception of fasting cholesterol and fasting triglyceride elevations that were that elevations triglyceride fasting and cholesterol fasting of exception the With • have a fast or irregular heartbeat 3 + ). However, all patients, regardless of gender, CD4 gender, of regardless patients, all However, ). 4. Worsening of your Hepatitis B infection. If you have hepatitis B Virus (HBV) cell

infection it may become worse (flare-up) if you take lamivudine and tenofovir . counts greater than 400 cells/mm 400 than greater counts

disoproxil fumarate tablets, two components of lamivudine and tenofovir +

cell counts less than 250 cells/mm 250 than less counts cell Lamivudine and Tenofovir Disoproxil

disoproxil fumarate tablets co-packaged with nevirapine tablets, and then stop Tenofovir DisoproxilFumarate [see WarningsandPrecautions(5.7)] Fumarate Tablets Co-packaged with

them. A “flare-up” is when your HBV infection suddenly returns in a worse way [See WarningsandPrecautions(5.5)]. than before. Nevirapine Tablets USP

+ 3TCEfavirenz 2024867 • Do not let your lamivudine and tenofovir disoproxil fumarate tablets co-packaged [see BoxedWarning,WarningsandPrecautions(5.2)] [see WarningsandPrecautions(5.5)] with nevirapine run out. Mycobacterium avium N=299 . Do not restart nevirapine following severe skin rash, skin rash, skin severe following nevirapine restart not Do . 11% 18% 5% 6% 3% 5% 3% 5% 1% 5 % Refill your prescription or talk to your healthcare provider before your lamivudine 3 had a 12-fold higher risk of symptomatic hepatic adverse .

and tenofovir disoproxil fumarate tablets co-packaged with nevirapine are all [see BoxedWarning,WarningsandPrecautions(5.1)] a

gone. (Grades2to4)Reportedin • Do not stop taking lamivudine and tenofovir disoproxil fumarate tablets co- . packaged with nevirapine without first talking to your doctor.

• If you stop taking lamivudine and tenofovir disoproxil fumarate tablets co- [see DrugInteractions(7)] 3 (6% versus 1% for men with CD4 with men for 1% versus (6% packaged with nevirapine, your doctor will need to check your health often and infection, cytomegalovirus, 3

do regular blood tests to check your HBV infection. Tell your doctor about any risk increased An 1%). versus (11% new or unusual symptoms you may have after you stop taking lamivudine and The most common adverse reactions . .

tenofovir disoproxil fumarate tablets co-packaged with nevirapine. Precautions and Warnings [see d4T +3TCEfavirenz +

What are Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged antiretroviral or count, cell + with Nevirapine Tablets? of initiation at counts cell . ³ N=301 10% 12% [see BoxedWarning,

• Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with 5% inAnyTreatment 7% 6% 5% 5% 6% 8% 8%

Nevirapine Tablets can be used alone or in combination with other antiviral %

medicines to treat Human Immunodeficiency Virus (HIV) in patients 16 years .

of age and older with a body weight of at least 35 kg (77 pounds). HIV is the Pneumocystis

virus that causes AIDS (Acquired Immune Deficiency Syndrome). Boxed [see . Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with + + Nevirapine Tablets are prescription antiviral medicines. Lamivudine and tenofovir . The cell disoproxil fumarate are a type of medicines called nucleoside analog reverse cell . transcriptase inhibitors (NRTIs) and nevirapine is a non-nucleoside analog . reverse transcriptase inhibitor (NNRTI). Table 2. Grade 3/4 Laboratory Abnormalities Reported in Reported Abnormalities Laboratory 3/4 Grade Table 2. Musculoskeletal and Connective Tissue Disorders: Tissue Connective and Musculoskeletal Respiratory, Thoracic,andMediastinalDisorders: Metabolism andNutritionDisorders: Immune SystemDisorders: Tenofovir DisoproxilFumarate Skin: Alopecia,pruritus. Musculoskeletal: Hypersensitivity: Warning, WarningsandPrecautions(5.1,5.2)] Table 4.PercentageofAdultSubjectswithLaboratoryAbnormalities receiving nevirapineinplacebo-controlledtrialsareshownTable3. Treatment-related, adverseexperiencesofmoderateorsevereintensityobservedingreaterthan2%subjects Boxed WarningandWarningsPrecautions(5.11)] of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine-associated rash 6 weeksoftherapy.Grade3and4rasheswerereportedin2%nevirapinerecipientscomparedtolessthan1% first the during placebo receiving 6% to compared nevirapine receiving subjects of 13% in reported were rashes on thetrunk,faceandextremities.Incontrolledclinicaltrials(Trials1037,1038,1046,1090),Grade12 are usuallymildtomoderate,maculopapularerythematouscutaneouseruptions,withorwithoutpruritus,located Hepatic and Pancreatic: Hemic andLymphatic: General: Endocrine andMetabolic: Body asaWhole: Lamivudine and nevirapine. fumarate, disoproxil tenofovir lamivudine, to connection causal potential or reporting, of frequency seriousness, their of combination a to due inclusion for chosen been have reactions These made. be cannot frequency of fumarate, nevirapine. Because these reactions are reported voluntarily from a population of unknown size, estimates The followingadversereactionshavebeenreportedduringpostmarketinguseoflamivudine,tenofovirdisoproxil Skin andSubcutaneousTissueDisorders: GT) Hepatobiliary Disorders: Gastrointestinal Disorders: 1 1 2 CD4 higher and gender Female groups. control in subjects of 1% and nevirapine received who subjects of In controlledclinicaltrials,symptomatichepaticeventsregardlessofseverityoccurredin4%(range0%to11%) Hepatic Reaction dysfunction renal or lymphadenopathy, malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, general fever, by accompanied rash or rash severe include may which hypersensitivity of signs with associated syndrome, toxicepidermalnecrolysis,andhypersensitivityreactions.Hepatitis/hepaticfailuremaybeisolatedor Stevens-Johnson failure, hepatic hepatitis, are nevirapine with associated reactions adverse serious most The rates observedinclinicalpractice. the reflect not may and drug another of trials clinical the in rates to compared directly be cannot drug a of trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical Clinical TrialsinAdults Nevirapine remained withinthenormalrange that values in resulted changes these phosphatase, alkaline bone-specific for except however, group; stavudine the to relative group tenofovir the in levels D Vitamin 1,25 and levels hormone parathyroid serum higher and telopeptide) N urinary and telopeptide, C serum osteocalcin, serum phosphatase, alkaline bone-specific (serum metabolism bone of markers biochemical in increases significant were there addition, In group. stavudine the in subjects 6 and group tenofovir the in subjects 4 in reported were toes) and fingers (excluding fractures relevant Clinically hip. the at BMD of 7% or spine the at BMD of 5% least at lost subjects stavudine-treated the of 21% vs. subjects tenofovir-treated of percent Twenty-eight 144. Week through sustained was reduction this and trial stavudine group).Inbothgroups,themajorityofreductioninBMDoccurredfirst24to48weeks the in 4.5 ± -2.4% vs. group tenofovir the in 3.5 ± (-2.8% groups treatment two the between similar were hip with subjectsreceivingstavudine+lamivudineefavirenz(1%±4.6)through144weeks.ChangesinBMDatthe baseline in BMD at the lumbar spine in subjects receiving tenofovir + lamivudine + efavirenz (-2.2% ± 3.9) compared from decrease percentage mean greater significantly a was there 903, Study in subjects adult infected HIV-1 In Changes inBoneMineralDensity: of bodyfat[seeWarningsandPrecautions Whole: a as Body Nevirapine hypophosphatemia. myopathy, weakness, muscular hypokalemia, osteomalacia, rhabdomyolysis, tubulopathy: renal proximal of consequence a as occur may above, headings system body the under listed reactions, adverse following The General DisordersandAdministrationSiteConditions: increased creatinine,proteinuria,polyuria renal tubulopathy,interstitialnephritis(including Renal andUrinaryDisorders: which maycontributetofractures),muscularweakness,myopathy 2 and Warnings and Precautions (5.11)]. Precautions and Warnings and The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening Skin Reaction in controlsseeTable4. Liver enzymeabnormalities(AST,ALT, GGT) wereobservedmorefrequentlyinsubjectsreceivingnevirapinethan symptomatic events(6weeksormoreafterstartingnevirapine)andasymptomaticincreasesinASTALT. increased transaminaseelevationsatthestartoftherapywithnevirapineareassociatedagreaterrisklater of subjects who received nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or Asymptomatic transaminaseelevations(ASTor ALT greaterthan5xULN)wereobservedin6%(range0%to9%) risk oftheseevents counts (greaterthan250cells/mm³inwomenandgreater400men)placepatientsatincreased 100 mg.Tenofovirshouldnotbecoadministeredwithatazanavirwithoutritonavir. coadministered with tenofovir disoproxil fumarate, it is recommended that atazanavir 300 mg is given with ritonavir Table 3. Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Adult in Events Drug-Related Severe or Moderate with Subjects of Percentage Table 3. adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4 of Suppression neuropathy. and pancreatitis, including reactions, adverse mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated significantly increased formulation) enteric-coated or buffered the Tenofovir Disoproxil Fumarate decreases the AUC and C HIV-1ProteaseInhibitors 7.5 information fordidanosine. fat). For additional information on coadministration of tenofovir DF and didanosine, please refer to the full prescribing 20% kcal, 400 than (less meal light a with or conditions fasted under taken be may EC didanosine and fumarate disoproxil tenofovir coadministered, When DF. tenofovir with coadminstered is it when daily once mg 200 to reduced be should dose didanosine the kg, 60 than less weighing patients In DF. tenofovir with coadministered is it when daily once mg 250 to reduced be should dose didanosine the kg, 60 than greater weighing patients In in patientsreceivingtenofovirdisoproxilfumarate(tenofovirDF)withdidanosine400mgdaily. Table 4.PercentageofAdultSubjectswithLaboratoryAbnormalities nevirapine andcontrolregimensseeTable4. comparing trials clinical in frequencies similar with observed were thrombocytopenia) neutropenia, anemia, nevirapine therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, in controls(Table4).AsymptomaticelevationsGGToccurfrequentlybutarenotacontraindicationtocontinue Liver enzymetestabnormalities(AST,ALT)wereobservedmorefrequentlyinsubjectsreceivingnevirapinethan Laboratory Abnormalities When administered with tenofovir disoproxil fumarate, the C the fumarate, disoproxil tenofovir with administered When should bediscontinuedinpatientswhodevelopdidanosine-associatedadversereactions. receiving thiscombinationshouldbemonitoredcloselyfordidanosine-associatedadversereactions.Didanosine Coadministration oftenofovirdisoproxilfumarateanddidanosineshouldbeundertakenwithcautionpatients Didanosine 7.4 Tenofovir DisoproxilFumarate A druginteractionstudyshowednoclinicallysignificantbetweenlamivudineandzidovudine. DrugswithNoObservedInteractionsLamivudine 7.3 pharmacokinetics ofhigherdosesTMP/SMXsuchasthoseusedtotreatPCP. lamivudine on effect the regarding information no is There recommended. is drug either of dose in change No Trimethoprim/Sulfamethoxazole(TMP/SMX) 7.2 Clinical Pharmacology(12.3)]. antiretroviral therapyforHIV-1andinterferonalfawithorwithoutribavirin combination receiving patients co-infected HIV-1/HCV in occurred has fatal) (some decompensation hepatic patients, co-infected HIV-1/HCV in lamivudine with coadministered was ribavirin when seen was suppression) virologic HIV-1/HCV of loss (e.g., interaction pharmacodynamic or pharmacokinetic a of evidence no Although Interferon-andRibavirin-BasedRegimens 7.1 available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. of eliminationisactiverenalsecretionviatheorganiccationictransportsystem(e.g.,trimethoprim).Nodataare interactions withotherdrugsadministeredconcurrentlyshouldbeconsidered,particularlywhentheirmainroute of possibility The secretion. cationic organic active by urine the in eliminated predominantly is Lamivudine Lamivudine lamivudine, tenofovirdisoproxilfumarate,andnevirapine packaged withnevirapinetablets.Druginteractionstudieshavebeenconductedtheindividualcomponents: DRUGINTERACTIONS No druginteractionstudieshavebeenconductedusinglamivudineandtenofovirdisoproxilfumaratetablets,co- 7 hepatitis, eosinophilia,granulocytopenia,lymphadenopathy,and/orrenaldysfunctionhavebeenreported. and systemic symptoms (DRESS) symptoms systemic and muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia edema, facial conjunctivitis, lesions, oral blistering, fever, as such findings constitutional with associated rash with reactions hypersensitivity and syndrome hypersensitivity addition, In reported. been all have urticaria and Skin and Appendages: Neurologic: paraesthesia Musculoskeletal: Investigations: Hematology: anemia,eosinophilia,neutropenia Liver andBiliary: Gastrointestinal: • When used with alone or in combination with other HIV medicines, Lamivudine PostmarketingExperience 6.2 Any Fasting Cholesterol(>240mg/dL) Fasting Triglycerides(>750mg/dL) Neutrophils (<750/mm³) Hematuria (>100RBC/HPF) ALT (M:>215U/L;F:>170U/L) AST (M:>180U/L;F:>170U/L) Serum Amylase(>175U/L) Creatine Kinase(M:>990U/L;F:>845U/L) Laboratory Abnormality iiui 25m/L2222 2 4 2 8 14 2 3 4 2 4 5 Bilirubin >2.5mg/dL SGOT (AST)>250U/L SGPT (ALT)>250U/L Blood Chemistry Laboratory Abnormality einepsr wes 58 Median exposure(weeks) Fatigue Headache Granulocytopenia Nausea Rash Any adverseevent Diarrhea Abdominal pain Myalgia Subjects hadCD4 Background therapyincludedZDVandZDV+ddI;nevirapinemonotherapywasadministeredinsomesubjects. CD4 had Subjects PIs. and NRTIs of combinations and subjects all for 3TC included therapy Background and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets counts lessthan200cells/mm Platelets <50,000/mm Hemoglobin <8g/dL Hematology Neutrophils <750/mm counts lessthan200cells/mm may: Subjects hadCD4 Background therapyincludedZDVandZDV+ddI;nevirapine monotherapy was administeredinsomesubjects. Background therapyincluded3TCforallsubjectsandcombinationsofNRTIsPIs.SubjectshadCD4 ³ Grade3LaboratoryAbnormality

1. Reduce the amount of HIV in your blood (called “viral load”) Weakness. Subjects inStudy903(0to144Weeks) Trials 2. Help increase the number of CD4 (T) cells in your blood which help fight

off other infections. decreased serumphosphorus Anaphylaxis,urticaria. vomiting Muscle weakness,CPKelevation,rhabdomyolysis. Redistribution/accumulationofbodyfat arthralgia, rhabdomyolysisassociatedwithskinand/orliverreactions jaundice, fulminantandcholestatichepatitis,hepaticnecrosis,failure

Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your withdrawal drug somnolence, fever, [see BoxedWarningandWarningsPrecautions(5.10)]. + cellcountgreaterthanorequalto200cells/mm immune system. This may reduce your risk of death or infections that can happen + cellcountgreaterthanorequalto200cells/mm allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis Anemia(includingpureredcellaplasiaandsevereanemiasprogressingontherapy). when your immune system is weak (opportunistic infections). Lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B Hepatic steatosis,hepatitis,increasedliverenzymes(mostcommonlyAST,ALTgamma 3 3 Hyperglycemia. Pancreatitis, increasedamylase,abdominalpain

Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Allergic reaction,includingangioedema Tablets do not cure HIV-1 infection or AIDS and you may continue to experience Acute renalfailure, acute tubularnecrosis,Fanconisyndrome,proximal

illnesses associated with HIV-1 infection, including opportunistic infections. You 3 . Nevirapine Nevirapine Nevirapine 3 [See WarningsandPrecautions(5.6)] . (n=1121) should remain under the care of a doctor while taking lamivudine and tenofovir (n=1121) (n=1121) [see Warnings and Precautions (5.10)] Precautions and Warnings [see Lactic acidosis,hypokalemia,hypophosphatemia disoproxil fumarate tablets, co-packaged with nevirapine tablets. 15% <1 <1 <1 <1 2 1 1 5

Rash occurs most frequently within the first 6 weeks of therapy. Rashes therapy. of weeks 6 first the within frequently most occurs Rash 13 3 You must stay on continuous HIV therapy to control HIV infection and decrease HIV- 11< [see WarningsandPrecautions(5.5)] Rash [see Boxed Warning and Warnings and Precautions (5.10, 5.11)]. (5.10, Precautions and Warnings and Warning Boxed [see (5.8)] Trial 1090 related illnesses. Trial 1090 Trial 1090 .

Avoid doing things that can spread HIV-1 infection to others: Tenofovir Disoproxil Fumarate acute cases),nephrogenicdiabetes insipidus, renalinsufficiency, Dyspnea

• Do not share needles or other injection equipment. Rhabdomyolysis, + 3TCEfavirenz . Asthenia 1 1 1 • Do not share personal items that can have blood or body fluids on them, like min [see Drug Interactions (7)], Interactions Drug [see (n=1128) (n=1128) (n=1128) Placebo Placebo Placebo [seeClinicalPharmacology(12.3)]. of atazanavir

toothbrushes or razor blades. [see WarningsandPrecautions(5.8)]. 11% 52 <1 <1 <1 N=299 3 1 0 1 2 19% 12% 36% 3% 1% 7% 9% 5% 4% max • Do not have any kind of sex without protection. Always practice safer sex by 14 4 ³ 1% of Tenofovir Disoproxil Fumarate-Treated Disoproxil Tenofovir of 1%

using a latex or polyurethane condom or other barrier to reduce the chance of either as (administered didanosine of AUC and sexual contact with semen, vaginal secretions, or blood. osteomalacia (manifested as bone pain and pain bone as (manifested osteomalacia 3 [see Clinical Pharmacology (12.3)] Pharmacology Clinical [see .

Ask your doctor if you have any questions on how to prevent passing HIV to other 3 [see Clinical Pharmacology (12.3)] . people. . [seeWarningsandPrecautions(5.4), Nevirapine Nevirapine Nevirapine

Who Should Not Take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co- following: the of more or one plus (n=253) (n=253) (n=253) Trials 1037,1038,1046 Trials 1037,1038,1046 Trials 1037,1038,1046 32%

packaged with Nevirapine Tablets? . + 28 <1 2 5 2 1 4 9 7 cell counts has been observed been has counts cell 0 4

Tell your doctor if you have or have had liver or kidney problems. Your doctor may 12 redistribution/accumulation tell you not to take nevirapine, one component of Lamivudine and Tenofovir Disoproxil d4T +3TCEfavirenz Fumarate Tablets, Co-packaged with Nevirapine Tablets, if you have certain liver problems. [see Boxed Warning N=301 40% 12% Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine 42% 1% 9% 7% 8% 7% Tablets are only for people diagnosed with HIV. If you have not been diagnosed as 5% Placebo Placebo Placebo (n=203) HIV positive, then do not take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, (n=203) (n=203) 13% 28 [see Boxed 0 0 4 1 2 Co-packaged with Nevirapine Tablets. 1 4 2 0 1 2 2 2

What Should I Tell My Doctor Before Taking Lamivudine And Tenofovir Disoproxil . When . The . + + + [see cell cell Fumarate Tablets, Co-packaged with Nevirapine Tablets? cell Before you take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets, tell your doctor if you: for MagnitudeofInteraction. Be NeededDuetoDrugInteractionEstablishedInteractions:SeeClinicalPharmacology(12.3),Table8 Table 5EstablishedandPotentialDrugInteractions:UseWithCaution,AlterationinDoseorRegimenMay time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently. monitored be should levels anticoagulation nevirapine, with co-administered is warfarin When time. giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation The in Table5,additionalclinicalmonitoringmaybewarrantedwhenco-administeringthesedrugs. listed drugs of classes some for conducted been not have subjects seropositive HIV-1 in trials interaction drug specific Although 5. Table in listed also are interactions drug potential These system. P450 cytochrome the by there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized conducted inHIV-1seropositivesubjectsunlessotherwiseindicated.Inadditiontoestablisheddruginteractions, drug interactionsarelistedinTable5.ThedataTables5and8basedontheresultsofinteractiontrials in listed are drugs other and nevirapine of co-administration with occur that changes pharmacokinetic specific The may havelowerthanexpectedplasmalevelswhenco-administeredwithnevirapine. systems enzyme these by metabolized are that drugs result, a As enzymes. these of inducer an be to known is Nevirapine 2B6. and 3A isoenzymes, P450 cytochrome the via liver the by metabolized principally is Nevirapine DrugsMetabolizedbyHepaticCytochromeP450Isoenzymes,3A,and2B6 7.7 Nevirapine (5.5)]. valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs ganciclovir, valacyclovir, dipivoxil, adefovir acyclovir, cidofovir, to limited not are but include, examples Some drugs. eliminated renally other of concentrations the increase and/or tenofovir of concentrations serum increase may secretion tubular active for compete or function renal reduce that drugs with fumarate disoproxil tenofovir kidneys the by eliminated primarily is tenofovir Since DrugsAffectingRenalFunction 7.6 associated adversereactions. fumarate- disoproxil tenofovir develop who patients in discontinued be should Fumarate Disoproxil Tenofovir reactions. adverse fumarate-associated disoproxil tenofovir for monitored be should darunavir ritonavir-boosted or atazanavir, ritonavir-boosted lopinavir/ritonavir, with concomitantly tenofovir receiving Patients observed. be may absorption in increase an transporters, these of inhibitor an with co-administered is fumarate disoproxil is asubstrateofP-glycoprotein(Pgp)andbreastcancerresistanceprotein(BCRP)transporters.Whentenofovir been shown to increase tenofovir concentrations have ritonavir with coadministered darunavir and ritonavir, with coadministered atazanavir Lopinavir/ritonavir, serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural following collected were specimens fluid amniotic lamivudine subjects, of subset a In samples. serum cord umbilical and neonatal, maternal, in similar generally were concentrations Lamivudine women. postpartum in and adults non-pregnant in seen those to similar were women pregnant in pharmacokinetics Lamivudine studies werenotdesignedorpoweredtoprovideefficacyinformation. These antiretrovirals. other without daily twice mg 300 lamivudine using gestation weeks 38 at women 10 and twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, in South Africa. The study assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine Lamivudine: potential risktothefetus. the justifies benefit potential the if only pregnancy during used be should tablets nevirapine with co-packaged fumarate co-packagedwithnevirapineinpregnantwomen.Lamivudineandtenofovirdisoproxiltablets disoproxil tenofovir and lamivudine of combination the of studies well-controlled and adequate no are There B. category under classified are nevirapine and disoproxil Tenofovir C. category under classified is Lamivudine Lamivudine, TenofovirDisoproxilFumarateandNevirapine Pregnancy: USEINSPECIFICPOPULATIONS 8.1 8 • Have or have had hepatitis (inflammation of your liver) or problems with your shown arepredicted. interactions drug other All study. clinical a in evaluated was drug the and nevirapine between interaction The * Nelfinavir* Lopinavir/Ritonavir* Indinavir* Fosamprenavir/Ritonavir* Fosamprenavir* HIV AntiviralAgents:ProteaseInhibitors(PIs) Drug Name Atazanavir/Ritonavir* Diltiazem, nifedipine,verapamil Calcium channelblockers: oervrNe these of doses appropriate The Boceprevir Rilpivirine Etravirine Delavirdine Efavirenz* ethosuximide Carbamazepine, clonazepam, Anticonvulsants: Rifampin* Rifabutin* Amiodarone, disopyramide, lidocaine Antiarrhythmics: Telaprevir the of doses appropriate The Hepatitis CAntiviralAgents HIV AntiviralAgents:Non-NucleosideReverseTranscriptaseInhibitors(NNRTIs) Saquinavir/ritonavir HIV AntiviralAgents:ProteaseInhibitors(PIs) Warfarin Antithrombotics: Itraconazole Ketoconazole* Fluconazole* Antifungals: Clarithromycin* Antibiotics: Methadone* Analgesics: Other Agents Ethinyl estradiol and Norethindrone* Oral contraceptives: Fentanyl Opiate agonists: Cisapride Motility agents: Cyclosporine, tacrolimus,sirolimus Immunosuppressants: Ergotamine Ergot alkaloids: Cyclophosphamide Cancer chemotherapy:

liver. See “What is the most important information I should know about Pharmacology, Clinical

Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with vitro in Nevirapine Tablets?” and “Who should not take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets?” interaction between nevirapine and the antithrombotic agent warfarin is complex. As a result, when result, a As complex. is warfarin agent antithrombotic the and nevirapine between interaction

• Receive dialysis Lamivudine pharmacokineticswerestudiedinpregnantwomenduring2clinicalstudiesconducted • Have skin problems, such as rash Teratogenic Effects • Have any medical conditions • Are pregnant or planning to become pregnant. It is not known if Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets established on based modifications dosage possible about comments Clinical 8. Table will harm your unborn baby. • Are breastfeeding or plan to breast-feed. Lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets can pass into your breast i Indinavir hNevirapine iAmprenavir hNevirapine iAmprenavir iNelfinavir C iNelfinavir M8Metabolite h Nevirapine i Atazanavir iLopinavir decreased. be may concentrations Plasma increased. be may concentrations Plasma i Itraconazole i Ketoconazole i Methadone decreased. be may concentrations Plasma decreased. be may concentrations Plasma decreased. be may concentrations Plasma hNevirapine f Y345 y nevirapine. by CYP3A4/5 of induction to due decreased be may Plasma concentrations of boceprevir i Efavirenz decreased. be may anticonvulsant the and Plasma concentrations of nevirapine i Nevirapine hRifabutin h 14-OHclarithromycin i Clarithromycin decreased. be may concentrations Plasma CYP3A4 bytelaprevir. of inhibition to due increased concentrations of nevirapine may be of CYP3A4 by nevirapine and plasma induction to due decreased be may Plasma concentrationsoftelaprevir evaluated and saquinavir/ritonavir has not been nevirapine between interaction The i Norethindrone i Ethinylestradiol decreased. be may concentrations Plasma decreased. be may concentrations Plasma milk and may harm your baby. You should not breastfeed if you have HIV or ConcomitantDrug Effect on Concentration of Nevirapine because of the risk of passing HIV to your baby. Do not breast-feed during treatment with Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co- packaged with Nevirapine Tablets. Talk to your doctor about the best way to

feed your baby. [see Clinical Pharmacology (12.3)]. Tenofovir disoproxil fumarate

Tell your doctor and pharmacist about all the medicines you take, including min

prescription and non-prescription medicines, vitamins and herbal supplements. (12.3)] Pharmacology Clinical [see Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets may affect the way other medicines work, and other medicines may affect how Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets works. You should not take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co- packaged with Nevirapine Tablets if you also take: • St. John’s Wort. St. John’s Wort can lower the amount of Lamivudine and The The and safety have not been established. efficacy to respect with nevirapine and indinavir of combination this of doses appropriate The has notbeenstudied. daily once fosamprenavir/ritonavir with administered nevirapine of ritonavir twice daily. The combination with 700/100mgoffosamprenavir/ when nevirapineisco-administered No dosing adjustments are required not recommended. is ritonavir without fosamprenavir Co-administration of nevirapine and efficacy have not been established. been not have efficacy nelfinavir withrespecttosafetyand and nevirapine of combination in combination withnevirapine. daily once administered be should solution oral nor tablets nevirapine. Neither lopinavir/ritonavir with combination in used when solution twice daily is recommended oral mL) (6.5 mg 533/133 or daily ritonavir to 500/125 mg tablets twice lopinavir/ of adjustment dose A to increased nevirapine exposures. nevirapine increased to for nevirapine-associated toxicity due exposure and there is a potential risk atazanavir decreases substantially nevirapine because atazanavir Do not co-administer nevirapine with Clinical Comment Dosing inadultpatients: established. been not have combinations these for doses Appropriate reduction inefficacy. a in result may concentrations plasma boceprevir in decreases because coadministered be not shown tobebeneficial. been not has combination this as coadministered with another NNRTI be not should Nevirapine altered. be may concentrations Plasma been established. not have efficacy and combinations withrespecttosafety anticonvulsants. of levels and response virologic monitor and caution with Use established. been not have this combination for doses Appropriate events. adverse associated efficacy or an increase in nevirapine- telaprevir in reduction a in result may both or telaprevir, nevirapine, of concentrations plasma in be coadministered because changes Nevirapine and telaprevir should not established. been not have efficacy and safety to respect with saquinavir/ritonavir and nevirapine of combination is recommended. Monitoring of anticoagulation levels anticoagulation. on effect Potential that may reduce efficacy of the drug. itraconazole plasmaconcentrations in decreases potential to due concomitantly administered be not should itraconazole and Nevirapine the efficacyofdrug. reduce may concentrations plasma ketoconazole in decreases because concomitantly administered be not Nevirapine and ketoconazole should events. adverse associated be monitored closely for nevirapine- administration, andpatientsshould concomitant in used be should caution nevirapine, to exposure increased of risk the of Because use rifabutininstead. nevirapine-containing regimenmay a using and tuberculosis with needing to treat patients co-infected the efficacyofdrug.Physicians reduce may concentrations plasma nevirapine in decreases because concomitantly administered be Nevirapine andrifampinshouldnot administration. concomitant in used be should caution Therefore, toxicity. rifabutin for risk higher at be may and exposure rifabutin in increases large experience may patients some however, variability, increased. Duetohighintersubject moderately were concentrations metabolite its and Rifabutin considered. be should azithromycin, as Alternatives toclarithromycin,such against this pathogen may be altered. intracellulare complex, overall activity against activity reduced has metabolite active clarithromycin Because increased. were concentrations metabolite 14-OH however, significantly decreased by nevirapine; was exposure Clarithromycin accordingly. adjusted be should dose methadone and withdrawal should be monitored for evidence of patients beginning nevirapine therapy withdrawal. Methadone-maintained opiate of symptoms prevent to increased dosagesmayberequired decreased; were levels Methadone is recommended. contraception of method additional or alternative An medications. may lower the plasma levels of these nevirapine since nevirapine, taking method ofcontraceptioninwomen sole the as used be not should control birth of methods hormonal other and contraceptives Oral established. been not have this combination for doses Appropriate established. been not have this combination for doses Appropriate established. been not have combinations these for doses Appropriate established. been not have this combination for doses Appropriate Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets in established. been not have this combination for doses Appropriate your body. should boceprevir and virapine prpit dss f the of doses appropriate • efavirenz (Sustiva®), etravirine (Intelence®), rilpivirine (Edurant®), or delavirdine [See Warnings and Precautions (Rescriptor®). avium- Mycobacterium • atazanavir (Reyataz®) , coadministration of coadministration , • boceprevir (Victrelis®) • telaprevir (Incivek®) • tipranavir (Aptivus®) • darunavir (Prezista®) • lopinavir and ritonavir (Kaletra®) once daily rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal Elimination: The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. In Table 7. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence Tenofovir Disoproxil Fumarate: Tenofovir Disoproxil Fumarate is an acyclic nucleoside phosphonate diester analog Nevirapine: Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice 9 healthy subjects given a single 300 mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min of Tenofovir Disoproxil Fumarate of adenosine monophosphate. Tenofovir Disoproxil Fumarate requires initial diester hydrolysis for conversion to the blood-brain barrier. daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women (mean ± SD). In 20 HIV-l-infected patients given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate, an obligate chain 14 CLINICAL STUDIES ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. % Change of Coadministered Drug terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV polymerase by compared with other HIV-1-infected patients. Dose of Coadministered a Coadministered Drug N Pharmacokinetic Parameters competing with the natural substrate deoxyadenosine 5’-triphosphate and, after incorporation into DNA, by DNA 14.1 Clinical Efficacy in Patients with HIV-1 Infection Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, In most single-dose studies in HIV-1-infected patients, HBV-infected patients, or healthy subjects with serum Drug (mg) (90% CI) chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases a, b, and mitochondrial sampling for 24 hours after dosing, the observed mean elimination half-life (t ) ranged from 5 to 7 hours. In HIV- Lamivudine and Tenofovir Disoproxil Fumarate respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred 1/2 DNA polymerase g. 1-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half- Cmax AUC Cmin in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at Treatment-Naïve Adult Patients life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg. Abacavir 300 once 8h 12 NA Nevirapine: Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities Study 903 Tenofovir Disoproxil Fumarate (i 1 to h 26) is transferred to the fetus [see Nonclinical Toxicology (13.2)]. by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing Atazanavirb 400 once daily × 14 days 34 i 21 i 25 i 40 or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases a, Tenofovir Disoproxil Fumarate: Animal Data: Reproduction studies have been performed in rats and rabbits at The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected tenofovir disoproxil fumarate (300 mg once daily) administered in combination with lamivudine and efavirenz individuals. Tenofovir pharmacokinetics are similar between these populations. (i 27 to i 14) (i 30 to i 19) (i 48 to i 32) b, g, or d) are not inhibited by nevirapine. versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence + Atazanavirb Atazanavir/Ritonavir 10 i 28 i 25c i 23c Antiviral Activity of 36 years (range 18 to 64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 of impaired fertility or harm to the fetus due to tenofovir. Absorption: Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The cell count was 279 cells/mm3 (range 3 to 956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted subjects is approximately 25%. Following 300/100 once daily × 42 (i 50 to h 5) (i 42 to i 3) (i 46 to h 10) Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines (including + Nevirapine: Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic (range 417 to 5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4 cell count. Forty-three percent days + 3 oral administration of a single dose of tenofovir disoproxil fumarate 300 mg to HIV-1 infected subjects in the fasted monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility assays. EC50 values of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4 cell counts <200 cells/mm . Treatment nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women state, maximum serum concentrations (C ) are achieved in 1 ± 0.4 hrs. C and AUC values are 0.30 ± 0.09 (50% effective concentrations) were in the range of 0.003 to 15 µM (1 µM = 0.23 mcg/mL). HIV-1 from therapy- + 3 max max Darunavird Darunavir/Ritonavir 12 h 16 h 21 h 24 outcomes through 48 and 144 weeks are presented in Table 10. with CD4 cell counts greater than 250 cells/mm should not initiate nevirapine unless the benefit outweighs the mcg/mL and 2.29 ± 0.69 mcg•hr/mL, respectively. naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.429 µM 300/100 mg once daily (i 6 to h 42) (i 5 to h 54) (i 10 to h 69) (range: 0.2 to 2.007 µM) from Virco (n = 92 baseline samples from COLA40263) and 2.35 µM (1.37 to 3.68 µM) Table 10. Outcomes of Randomized Treatment at Week 48 and 144 (Study 903) risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see Boxed Warning]. The pharmacokinetics of tenofovir are dose proportional over a tenofovir disoproxil fumarate dose range of 75 from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of lamivudine against Animal Data: No observable teratogenicity was detected in reproductive studies performed in pregnant rats and to 600 mg and are not affected by repeated dosing. 250 once, different HIV-1 clades (A to G) ranged from 0.001 to 0.12 µM, and against HIV-2 isolates from 0.003 to 0.12 µM At Week 48 At Week 144 simultaneously with rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures Distribution: In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, i 20g in peripheral blood mononuclear cells. Ribavirin (50 µM) decreased the anti-HIV-1 activity of lamivudine by 3.5 Tenofovir d4T+3TC+EFV Tenofovir d4T+3TC+EFV Didanosinee tenofovir disoproxil 33 NA approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the over the tenofovir concentration range 0.01 to 25 mcg/mL. The volume of distribution at steady-state is (i 32 to i 7) fold in MT-4 cells. In HIV-1-infected MT-4 cells, lamivudine in combination with zidovudine at various ratios Disoproxil (N=301) Disoproxil (N=301) fumarate and a light Outcomes recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1 mg/kg and 3 mg/kg. exhibited synergistic antiretroviral activity. Please see the full prescribing information for EPIVIR-HBV (lamivudine) Fumarate+ Fumarate+ mealf for information regarding the inhibitory activity of lamivudine against HBV. administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended Metabolism and Elimination: In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates 3TC+EFV 3TC+EFV human clinical dose). of CYP enzymes. Emtricitabine 200 once daily 17 h 20 Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV- (N=299) (N=299) 1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. 8.3 Nursing Mothers × 7 days (h 12 to h 29) Responder* 79% 82% 68% 62% Following IV administration of tenofovir, approximately 70 to 80% of the dose is recovered in the urine as unchanged The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 µM to 8.5 µM. In drug Lamivudine and Tenofovir Disoproxil Fumarate Co-packaged with Nevirapine: The Centers for Disease Control tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir disoproxil fumarate, Entecavir 1 mg once daily 28 h 13 combination studies, tenofovir was not antagonistic with nucleoside reverse transcriptase inhibitors (abacavir, Virologic failure† 6% 4% 10% 8% and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir x 10 days (h 11 to h 15) didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors disoproxil fumarate 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir). Rebound 5% 3% 8% 7% transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and serious adverse reactions Indinavir 800 three times daily × 12 i 11 in urine over 24 hours. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values Never suppressed 0% 1% 0% 0% in nursing infants, mothers should be instructed not to breastfeed if they are receiving lamivudine and tenofovir 7 days (i 30 to h 12) ranged from 0.5 µM to 2.2 µM) and strain specific activity against HIV-2 (EC values ranged from 1.6 µM to 5.5 Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be 50 disoproxil fumarate tablets, co-packaged with nevirapine tablets. µM). Added an antiretroviral agent 1% 1% 2% 1% competition for elimination with other compounds that are also renally eliminated. Lamivudine 150 twice daily 15 i 24 Lamivudine: Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving × 7 days (i 34 to i 12) Nevirapine: The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral Death <1% 1% <1% 2% lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 Effects of Food on Oral Absorption: Administration of tenofovir disoproxil fumarate following a high-fat meal (~700 blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC of Lopinavir Lopinavir/Ritonavir 24 Discontinued due to adverse event 6% 6% 8% 13% mg zidovudine twice daily) had measurable concentrations of lamivudine. 0 to ¥ embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against approximately 40% and an increase in C of approximately 14%. However, administration of tenofovir disoproxil 400/100 twice daily ‡ max a panel of 2923 isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The Discontinued for other reasons 8% 7% 14% 15% Tenofovir Disoproxil Fumarate: Samples of breast milk obtained from five HIV-1 infected mothers in the first fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared Ritonavir × 14 days th 99 percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14 to 302 nM, n=29) post-partum week show that tenofovir is excreted in human milk at low levels. The impact of this exposure in to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC Saquinavir Saquinavir/Ritonavir 32 h 22 h 29h h 47h against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, * Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. breastfed infants is unknown. of tenofovir are 0.33 ± 0.12 mcg/mL and 3.32 ± 1.37 mcg•hr/mL following multiple doses of tenofovir disoproxil 1000/100 twice daily × (h 6 to h 41) (h 12 to h 48) (h 23 to h 76) CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) † Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144. fumarate 300 mg once daily in the fed state, when meal content was not controlled. or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz 8.4 Pediatric Use 14 days ‡ Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons. exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease Nevirapine Ritonavir i 23 Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets should only be (i 3 to i 46) inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between Absorption and Bioavailability: Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or administered to HIV-1 patients 16 years of age and older with a body weight of at least 35 kg (77 lb). Because + £100,000 copies/mL) and CD4 cell count (< or ³200 cells/mm3). Through 144 weeks of therapy, 62% and 58% this co-packaged product contains a fixed-dose combination formulation, it cannot be adjusted for patients of volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose Tacrolimus 0.05 mg/kg twice daily x 21 tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma 7 days anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin of subjects in the tenofovir disoproxil fumarate and stavudine arms, respectively achieved and maintained confirmed lower age and weight. Safety and efficacy have not been established in pediatric patients less than 16 years of age + nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 in cell culture. HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 263 cells/mm3 for the tenofovir with a body weight less than 35 kg. i disoproxil fumarate arm and 283 cells/mm3 for the stavudine arm. mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range Tipranavir Tipranavir/ 22 i 17 i 18 i 21 Resistance 8.5 Geriatric Use of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar, Ritonavir 500/100 twice (i 26 to i 6) (i 25 to i 9) (i 30 to i 10) Through 144 weeks, 11 subjects in the tenofovir disoproxil fumarate group and 9 subjects in the stavudine group (n=242) were attained at 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably daily Lamivudine: Lamivudine-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed experienced a new CDC Class C event. Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets: Clinical studies bioavailable and interchangeable at doses up to 200 mg. When nevirapine (200 mg) was administered to 24 healthy that the resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 Tipranavir/ 20 i 11 i 9 i 12 Nevirapine with the individual components: lamivudine, tenofovir disoproxil fumarate, and nevirapine did not include sufficient adults (12 female, 12 male), with either a high-fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid changing the methionine to either isoleucine or valine (Ml84V/I). numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting Ritonavir 750/200 twice (i 16 to i 4) (i 15 to i 3) (i 22 to 0) HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less daily (23 doses) than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with nevirapine + lamivudine general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased conditions. In a separate trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic exposure (AUCô) isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may a be administered with or without food, antacid or didanosine. Increase = h; Decrease = i; No Effect = ; NA = Not Applicable phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine- nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice 8.6 Patients with Renal Impairment b Reyataz (atazanavir) Prescribing Information resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) Distribution: Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The c lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets are not recommended administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC mutations conferring resistance to zidovudine. subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline for patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir + 3 CD4 cell count of 96 cells/mm and a baseline HIV-1 RNA of 4.58 log10 copies/mL (38,291 copies/mL). Prior to renal disease (ESRD) requiring hemodialysis because they contain a fixed-dose combination formulation that found in breast milk [see Use in Specific Populations (8.3)]. Nevirapine is about 60% bound to plasma proteins 400 mg when given alone. Lamivudine-resistant HBV isolates develop substitutions (rtM204V/I) in the YMDD motif of the catalytic domain entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions cannot be adjusted. in the plasma concentration range of 1 to 10 mcg/mL. Nevirapine concentrations in human cerebrospinal fluid d Prezista (darunavir) Prescribing Information antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior (n=6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory mutations improving e to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 8.7 Patients with Hepatic Impairment to plasma protein. Videx EC (didanosine) Prescribing Information. Subjects received didanosine enteric-coated capsules. replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include: rtL80I and rtAl81T. copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 11. f Similar HBV mutants have been reported in HIV-1-infected patients who received lamivudine-containing antiretroviral Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets are not recommended Metabolism/Elimination: In vivo trials in humans and in vitro studies with human liver microsomes have shown 373 kcal, 8.2 regimens in the presence of concurrent infection with hepatitis B virus [see Warnings and Precautions (5.2)]. Table 11. BI 1090 Outcomes Through 48 Weeks g for patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell Outcome Nevirapine Placebo metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is h (4.1), Warnings and Precautions (5.10), and Clinical Pharmacology (12.3)]. Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required culture. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2 to 4 fold reduction (N=1121) (N=1128) mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other when tenofovir DF and ritonavir-boosted saquinavir are coadministered. in susceptibility to tenofovir. % 10 OVERDOSAGE isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to % 14 i Aptivus (tipranavir) Prescribing Information In Study 903 of treatment-naïve subjects (tenofovir disoproxil fumarate + lamivudine + efavirenz versus stavudine If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of C-nevirapine, Responders at 48 weeks: HIV-1 RNA <50 copies/mL 18 2 approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the + lamivudine + efavirenz) [see Clinical Studies (14.1)], genotypic analyses of isolates from subjects with virologic applied as necessary. Coadministration of tenofovir disoproxil fumarate and didanosine should be undertaken with caution [See Drug failure through Week 144 showed development of efavirenz and lamivudine resistance-associated substitutions Treatment Failure 82 98 primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was Interactions (7.4)]. When administered with multiple doses of tenofovir disoproxil fumarate, the C and AUC of max to occur most frequently and with no difference between the treatment arms. The K65R substitution occurred in Lamivudine: There is no known antidote for lamivudine. One case of an adult ingesting 6 grams of lamivudine made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 Never suppressed viral load 45 66 conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine 8/47 (17%) analyzed patient isolates on the tenofovir disoproxil fumarate arm and in 2/49 (4%) analyzed patient was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Because mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures to didanosine isolates on the stavudine arm. Of the 8 subjects whose virus developed K65R in the tenofovir disoproxil fumarate Virologic failure after response 7 4 a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other CDC category C event or death 10 11 dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays Nevirapine: Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration substitutions resulting in resistance to tenofovir disoproxil fumarate were not identified in this trial. a minor role in elimination of the parent compound. Added antiretroviral therapy1 while <50 copies/mL 5 1 in a lamivudine overdose event. of nevirapine and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations In Study 934 of treatment-naïve subjects (tenofovir disoproxil fumarate + emtricitabine + efavirenz versus zidovudine Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces of these drugs and attenuate their therapeutic effects. (AZT)/lamivudine (3TC) + efavirenz) [see Clinical Studies (14.1)], genotypic analysis performed on HIV-1 isolates Discontinued trial therapy due to AE 7 6 Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of tenofovir CYP3A and CYP2B6 by approximately 20 to 25%, as indicated by erythromycin breath test results and urine disoproxil fumarate 300 mg is available. In Study 901, 600 mg tenofovir disoproxil fumarate was administered While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early Discontinued trial <48 weeks2 910 metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2-fold Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of discontinuation showed development of efavirenz resistance-associated substitutions occurred most frequently to 8 subjects orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four 1 including change to open-label nevirapine (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 µM, a concentration that is unlikely and was similar between the two treatment arms. The M184V substitution, associated with resistance to emtricitabine known. weeks of dosing with 200 to 400 mg/day. Autoinduction also results in a corresponding decrease in the terminal to be achieved in patients as the therapeutic range is less than 25 µM. Therefore, nevirapine may have minimal and lamivudine, was observed in 2/19 analyzed subject isolates in the tenofovir disoproxil fumarate + emtricitabine 2 includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25 to 30 hours inhibitory effect on other substrates of CYP3A. group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study + Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following The change from baseline in CD4 cell count through one year of therapy was significantly greater for the nevirapine following multiple dosing with 200 to 400 mg/day. 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard 3 3 a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour hemodialysis session removed approximately Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 group compared to the placebo group for the overall trial population (64 cells/mm vs. 22 cells/mm , respectively), genotypic analysis. 3 10% of the administered tenofovir dose. Effect of Food on Absorption of Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19. as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm vs. 25 Tablets: Lamivudine and tenofovir disoproxil fumarate combination tablets (300 mg/300 mg) were bioequivalent Nevirapine: HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. cells/mm3, respectively). Nevirapine: There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging Table 8 (see below) contains the results of drug interaction trials performed with nevirapine and other drugs likely to EPIVIR (lamivudine) Tablets and VIREAD (tenofovir disoproxil fumarate) Tablets and Nevirapine tablets (200 to be co-administered. The effects of nevirapine on the AUC, C , and C of co-administered drugs are summarized. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending At two years into the trial, 16% of subjects on nevirapine had experienced class C CDC events as compared to from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including mg) were bioequivalent to VIRAMUNE (nevirapine) Tablets, when administered to healthy volunteers under the max min upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not 21% of subjects on the control arm. edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, fasted and fed condition states. Therefore, this co-packaged product can be administered with or without food. Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence altered when selection included nevirapine in combination with several other NNRTIs. of Nevirapine (All interactions trials were conducted in HIV-1 positive subjects) Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected vomiting, and weight decrease. All events subsided following discontinuation of nevirapine. Special Populations Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine subjects with CD4+ cell counts of 200 to 600 cells/mm3 at baseline. BI 1046 compared treatment with (n=24) or nevirapine and ZDV (n=14) were monitored in Phase 1 and 2 trials over 1 to ³12 weeks. After 1 week nevirapine+zidovudine+didanosine to nevirapine+zidovudine and zidovudine+didanosine. Treatment doses were 11 DESCRIPTION Race Co-administered Dose of Dose Regimen of n Co-administered % Change of Co-administered Drug of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. nevirapine at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three Lamivudine and Tenofovir disoproxil fumarate Tablets are fixed dose combination tablets containing lamivudine Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics. Drug Nevirapine Pharmacokinetic Parameters (90% CI) One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean Drug + and tenofovir disoproxil fumarate. Lamivudine, USP (Epivir, also known as 3TC) belongs to the synthetic nucleoside G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week baseline HIV-1 RNA of 4.41 log10 copies/mL (25, 704 copies/mL) and mean baseline CD4 cell count of 376 Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100- 3 analogue class of antiretroviral drugs. Tenofovir disoproxil fumarate (Viread, also known as tenofovir DF) is Antiretrovirals AUC Cmax Cmin cells/mm . The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and to adequately determine potential pharmacokinetic differences among these populations. fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Nevirapine: An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV- Atazanavir/ 300/100 mg QD 200 mg BID day 1 23 Atazanavir Atazanavir Atazanavir nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C nevirapine+zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects Both lamivudine and tenofovir DF exhibit inhibitory activity against HIV-1 reverse transcriptase. 1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady- Ritonavira,d day 4 to 13, then to 23. Subjects 300/100 mg 300/100 mg 300/100 mg substitutions regardless of dose. treated with nevirapine+zidovudine. 400/ 100 mg QD, were treated with Lamivudine and Tenofovir disoproxil fumarate Tablets are for oral administration. Each tablet contains 300 mg state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) i42 i28 i72 Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving CD4+ cell counts in the nevirapine+ZDV+ddI group increased above baseline by a mean of 139 cells/mm3 at one of lamivudine, USP and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been day 14 to 23 nevirapine prior to (i52 to i29) (i40 to i14) (i80 to i60) nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for year, significantly greater than the increase of 87 cells/mm3 in the ZDV+ddI subjects. The nevirapine+ZDV group disoproxil), as active ingredients. The tablets also have the following inactive ingredients colloidal silicon dioxide, evaluated specifically for the effects of ethnicity. trial entry. 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following mean decreased by 6 cells/mm3 below baseline. NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, corn starch, croscarmellose sodium, crospovidone, FD&C Blue #2/ indigo caramine aluminum lake, lactose Pediatric Patients Atazanavir Atazanavir Atazanavir 16 HOW SUPPLIED/STORAGE AND HANDLING 400/100 mg 400/100 mg 400/100 mg F227L, and M230L. monohydrate, magnesium stearate, microcrystalline cellulose and povidone. The tablets are coated with opadry Lamivudine and Tenofovir Disoproxil Fumarate tablets co-packaged with Nevirapine tablets should not be administered Cross-Resistance Lamivudine and Tenofovir Disoproxil Fumarate Tablets, 300 mg/300 mg Co-packaged with Nevirapine Tablets II light blue which contains FD&C blue #2/ indigo carmine aluminum lake, hypromellose, lactose monohydrate, to HIV-1 infected pediatric patients less than 16 years of age with a body weight of less than 35 kg (77 lb). i19 h2 i59 USP, 200 mg. titanium dioxide, and triacetin. (i35 to h2) (i15 to h24) (i73 to i40) Lamivudine: Lamivudine-resistant HIV-1 mutants were cross-resistant to didanosine (ddI). In some patients treated Geriatric Patients: Lamivudine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of lamivudine and Lamivudine and Tenofovir Disoproxil Fumarate tablets are light blue to blue, capsule shaped, biconvex film coated with zidovudine plus didanosine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, tablets, debossed with ‘129’ on one side and ‘H’ on other side. Lamivudine, USP tenofovir disoproxil fumarate have not been studied in patients over 65 years of age have not been studied [see Darunavir/Ritona 400/100 mg BID 200 mg BID 8 h24 h40 h2 have emerged. Use in Specific Populations (8.5)]. vire (i3 to h57) (h14 to h73) (i21 to h32) Nevirapine Tablets USP, 200 mg are off-white to pale yellow, capsule shaped, biconvex tablets, debossed with Lamivudine, USP (also known as 3TC), a synthetic nucleoside analogue with activity against HIV-1 and HBV. The Genotypic and Phenotypic Analysis of On-Therapy HIV-1 Isolates From Patients With Virologic Failure: Study Nevirapine: Nevirapine pharmacokinetics in HIV-1-infected adults do not appear with age (range 18 to 68); however, ‘H’ on one side and ‘7’ on other side with a break line on both sides. chemical name of lamivudine, USP is 2(1H) - Pyrimidinone, 4-amino-1- [2- (hydroxyl methyl)-1,3-oxathio-lan-5- Didanosine 100 to 150 mg BID 200 mg QD x 14 18 § EPV20001: Fifty-three of 554 (10%) subjects enrolled in EPV20001 were identified as virological failures (plasma nevirapine has not been extensively evaluated in subjects beyond the age of 55 years [see Use in Specific Populations yl], (2R-cis)-. Lamivudine, USP is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also days; 200 mg BID HIV-l RNA level ³400 copies/mL) by Week 48. Of the 53 failures, 28 subjects were randomized to the lamivudine Each blister card contains: (8.5)]. once-daily treatment group and 25 to the lamivudine twice-daily treatment group. The median baseline plasma been referred to as (-)-2’-deoxy-3’-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight x 14 days One film-coated tablet of tenofovir disoproxil fumarate 300 mg (equivalent to tenofovir disoproxil 245 mg or Gender HIV-l RNA levels of subjects in the lamivudine once-daily group and lamivudine twice-daily group were 4.9 log10 tenofovir 136 mg) co-formulated with lamivudine, USP 300 mg of 229.26. It has the following structural formula: a Efavirenz 600 mg QD 200 mg QD x 14 17 i28 i12 i32 copies/mL and 4.6 log10 copies/mL, respectively. Genotypic analysis of on-therapy isolates from 22 subjects Lamivudine: There are no significant gender differences in lamivudine pharmacokinetics. days; (i34 to i14) (i23 to h1) (i35 to i19) identified as virologic failures in the lamivudine once-daily group showed: Two uncoated tablets, each containing nevirapine, USP 200 mg Tenofovir Disoproxil Fumarate: Tenofovir pharmacokinetics are similar in male and female subjects. 400 mg QD x 14 • isolates from 0/22 subjects contained treatment-emergent zidovudine resistance-associated amino acid Lamivudine and Tenofovir Disoproxil Fumarate Tablets 300 mg/300 mg Co-packaged with Nevirapine Tablets USP, days 200 mg are supplied in: Nevirapine: In the multinational 2NN trial, a population pharmacokinetic substudy of 1077 subjects was performed substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E) that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since Fosamprenavir 1400 mg BID 200 mg BID. 17 i33 i25 i35 • isolates from 10/22 subjects contained treatment-emergent efavirenz resistance-associated amino acid Blister card of 3 tablets (Alu Desiccant Blister) neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of Subjects were (i45 to i20) (i37 to i10) (i50 to i15) substitutions (L100I, K101E, K103N, V108I, or Y181C) Store at room temperature below 30ºC (86°F). gender cannot solely be explained by body size. treated with • isolates from 8/22 subjects contained a treatment-emergent lamivudine resistance-associated amino acid Throw away medicines that are no longer needed or out-of-date. Patients with Renal Impairment nevirapine prior to substitution (M184I or M184V) trial entry. Keep all medicines out of the reach of children. See Use in Specific Populations (8.6). Phenotypic analysis of baseline-matched on-therapy HIV-l isolates from subjects (n =13) receiving lamivudine Fosamprenavir/ 700/100 mg BID 200 mg BID. 17 i11 i19 once daily showed: 17 PATIENT COUNSELING INFORMATION Lamivudine and Tenofovir Disoproxil Fumarate Co-packaged with Nevirapine are not recommended for patients Ritonavir Subjects were (i23 to i3) (i32 to i4) • isolates from 12/13 subjects were susceptible to zidovudine • “See FDA-approved patient labeling (Medication Guide)” with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease treated with 17.1 Advice for the Patient (ESRD) requiring hemodialysis because they contain a fixed-dose combination formulation that cannot be adjusted. nevirapine prior to • isolates from 8/13 subjects exhibited a 25- to 295-fold decrease in susceptibility to efavirenz isolates from Patients with Hepatic Impairment trial entry 7/13 subjects showed an 85- to 299-fold decrease in susceptibility to lamivudine Patients should be advised that: Lamivudine, USP is a white or almost white powder which is soluble in water, sparingly soluble in methanol and Tenofovir Disoproxil Fumarate: Cross-resistance among certain reverse transcriptase inhibitors has been recognized. Lamivudine and Tenofovir Disoproxil Fumarate Co-packaged with Nevirapine is contraindicated for patients Indinavira 800 mg q8H 200 mg QD x 14 19 i31 i15 i44 • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets are not a cure slightly soluble in ethanol. with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications (4), The K65R substitution selected by tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, days; (i39 to i22) (i24 to i4) (i53 to i33) didanosine, or zalcitabine. HIV-1 isolates with this mutation also show reduced susceptibility to emtricitabine and Warnings and Precautions (5.10), and Use in Specific Populations (8.7)]. including opportunistic infections. Patients should remain under the care of a physician when using lamivudine Tenofovir Disoproxil Fumarate 200 mg BID x 14 lamivudine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors the K65R and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets. days Tenofovir disoproxil fumarate which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative Nevirapine: In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak substitution. HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated Score 1 to 2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to- reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold • Patients should avoid doing things that can spread HIV-1 infection to others. of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic nucleoside phosphonate a, b 2 Lopinavir 300/75 mg/m 7 mg/kg or 4 12, i22 i14 i55 decrease in the susceptibility to tenofovir. • Do not share needles or other injection equipment. central bridging; Ishak Score 3 to 4), or severe (n=9; marked bridging with occasional cirrhosis without c (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase. decompensation indicating Child-Pugh A; Ishak Score 5 to 6) fibrosis as a measure of hepatic impairment, the (lopinavir/ mg/kg QD x 2 15 (i44 to h9) (i36 to h16) (i75 to i19) ritonavir)b weeks; In Studies 902 and 907 conducted in treatment-experienced subjects (tenofovir disoproxil fumarate + Standard • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy] multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, BID x 1 week Background Therapy (SBT) compared to Placebo + SBT), 14/304 (5%) of the tenofovir disoproxil fumarate-treated blades. methoxy]phosphinyl]methoxy]propyl] adenine fumarate (1:1). It has a molecular formula of C H N O P • C H O approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 subjects with virologic failure through Week 96 had greater than 1.4-fold (median 2.7-fold) reduced susceptibility 19 30 5 10 4 4 4 • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane mcg/mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully a to tenofovir. Genotypic analysis of the baseline and failure isolates showed the development of the K65R substitution and a molecular weight of 635.51. It has the following structural formula: Lopinavir 400/100 mg BID 200 mg QD x 14 22, i27 i19 i51 condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. for evidence of drug-induced toxicity [see Warnings and Precautions (5.10)]. The subjects studied were receiving (lopinavir/ days; 200 mg BID 19c (i47 to i2) (i38 to h5) (i72 to i26) in the HIV-1 reverse transcriptase gene. antiretroviral therapy containing nevirapine 200 mg twice daily for at least 6 weeks prior to pharmacokinetic ritonavir) >1 year • Do not breastfeed. Lamivudine, tenofovir disoproxil fumarate, and nevirapine are excreted in human sampling, with a median duration of therapy of 3.4 years. The virologic response to tenofovir disoproxil fumarate therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-experienced subjects participating in Studies 902 and 907. In these clinical trials, breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the f breast milk. In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate Maraviroc 300 mg SD 200 mg BID 8 h1 h54 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation. Virologic (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of nevirapine, a significant increase in the (i35 to h55) (i6 to h151) responses for subjects in the genotype substudy were similar to the overall trial results. • The long term effects of lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with tablets are unknown. a Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Nelfinavir 750 mg TID 200 mg QD x 14 23 h32 days; 200 mg BID (i50 to h5) patterns on virologic outcome. Because of the large number of potential comparisons, statistical testing was not • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets are for oral Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the conducted. Varying degrees of cross-resistance of tenofovir disoproxil fumarate to pre-existing zidovudine ingestion only. impact of hepatic impairment on multiple-dose pharmacokinetics. Nelfinavir-M8 x 14 days resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) were observed and metabolite • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets should not be Assessment of Drug Interactions i62 i59 i66 appeared to depend on the type and number of specific substitutions. Tenofovir disoproxil fumarate-treated subjects discontinued without first informing their physician. (i70 to i53) (i68 to i48) (i74 to i55) whose HIV-1 expressed 3 or more zidovudine resistance-associated substitutions that included either the M41L See Drug Interactions (7). or L210W reverse transcriptase substitution showed reduced responses to tenofovir disoproxil fumarate therapy; • It is important to take lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine No drug interaction studies have been conducted using lamivudine and tenofovir disoproxil fumarate tablets co- Ritonavir 600 mg BID 200 mg QD x 14 18 however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F, tablets on a regular dosing schedule and to avoid missing doses. days; 200 mg BID or K219Q/E/N substitution did not appear to affect responses to tenofovir disoproxil fumarate therapy. Subjects Tenofovir disoproxil fumarate is a white to an off-white crystalline powder which is sparingly soluble in methanol packaged with nevirapine tablets. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment x 14 days whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had with lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets should be and in ethanol. Lamivudine: Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon reduced response to tenofovir disoproxil fumarate. Limited data are available for subjects whose virus expressed suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced alfa in a study of 19 healthy male subjects [see Warnings and Precautions (5.4)]. Stavudine 30 to 40 mg BID 200 mg QD x 14 22 § a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response. hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see In this insert, all dosages are expressed in terms of Tenofovir disoproxil fumarate except where otherwise noted. days; 200 mg BID Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, In the protocol defined analyses, virologic response to tenofovir disoproxil fumarate was not reduced in subjects Warnings and Precautions (5.1)]. Nevirapine USP x 14 days no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) with HIV-1 that expressed the abacavir/emtricitabine/lamivudine resistance-associated M184V substitution. HIV- • Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or co-

Nevirapine Tablets, USP are for oral administration. Each tablet contains 200 mg of Nevirapine, USP and the or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and Zalcitabine 0.125 to 0.25 mg 200 mg QD x 14 6 § 1 RNA responses among these subjects were durable through Week 48. infected with HBV and HIV-1 and have discontinued lamivudine and tenofovir disoproxil fumarate tablets, TID days; 200 mg BID inactive ingredients colloidal silicon dioxide, corn starch, croscarmellose sodium, magnesium stearate, microcrystalline lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen Studies 902 and 907 Phenotypic Analyses co-packaged with nevirapine tablets [see Warnings and Precautions (5.2)]. to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.4)]. x 14 days cellulose, povidone and sodium starch glycolate. Phenotypic analysis of baseline HIV-1 from treatment-experienced subjects (N=100) demonstrated a correlation • Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has Trimethoprim/Sulfamethoxazole: Lamivudine and TMP/SMX were coadministered to 14 HIV-1-positive patients Zidovudine 100 to 200 mg TID 200 mg QD x 14 11 i28 i30 § occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and Nevirapine, USP is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human between baseline susceptibility to tenofovir disoproxil fumarate and response to tenofovir disoproxil fumarate in a single-center, open-label, randomized, crossover study. Each patient received treatment with a single 300 mg days; (i40 to i4) (i51 to h14) therapy. Table 9 summarizes the HIV-1 RNA response by baseline tenofovir disoproxil fumarate susceptibility. interferon alfa with or without ribavirin [see Warnings and Precautions (5.4)]. Immunodeficiency Virus Type 1 (HIV-1). Nevirapine, USP is structurally a member of the dipyridodiazepinone dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of 200 mg BID x 14 • Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Lamivudine chemical class of compounds. lamivudine 300 mg with the fifth dose in a crossover design. days Table 9. HIV-1 RNA Response at Week 24 by Baseline Tenofovir Disoproxil Fumarate Susceptibility (Intent- To-Treat)a and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets should be avoided with The chemical name of nevirapine, USP is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] Coadministration of TMP/SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine Other Medications AUC C C concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs). Lamivudine and max min Baseline Tenofovir Disoproxil Fumarate Susceptibilityb Change in HIV-1 RNAc (N) Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets are not recommended for diazepin-6-one. Its molecular weight is 266.3 and it has the molecular formula C15H14N4O. Nevirapine, USP has AUC¥, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal a clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine Clarithromycin 500 mg BID 200 mg QD x 14 15 i31 i23 i56 patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end- the following structural formula: <1 -0.74 (35) [see Drug Interactions (7.2)]. days; (i38 to i24) (i31 to i14) (i70 to i36) stage renal disease (ESRD) requiring hemodialysis [see Dosage and Administration (2.2)]. >1 and £3 -0.56 (49) • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets should not be Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in Metabolite 14-OH- 200 mg BID x 14 12 asymptomatic HIV-l-infected adult patients given a single dose of zidovudine (200 mg) in combination with h42 h47 >3 and £4 -0.3 (7) administered in combination with HEPSERA (adefovir dipivoxil) [see Warnings and Precautions (5.3)]. clarithromycin days (h16 to h73) (h21 to h80) multiple doses of lamivudine (300 mg q 12 hr) [see Drug Interactions (7.3)]. >4 -0.12 (9) • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets should not be a coadministered with other lamivudine-containing, emtricitabine-containing, nevirapine-containing drugs or Tenofovir Disoproxil Fumarate: At concentrations substantially higher (~300-fold) than those observed in vivo, Ethinyl estradiol 0.035 mg 200 mg QD x 14 i20 § a. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco). tenofovir-containing, including COMBIVIR (lamivudine and zidovudine), EPIVIR or EPIVIR-HBV (lamivudine), tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, (as Ortho- days; (i33 to i3) b. Fold change in susceptibility from wild-type. EPZICOM (abacavir sulfate amd lamivudine), or TRIZIVIR (abacavir sulfate, lamivudine and zidovudine), CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A and Novum® 1/35) 200 mg BID x 14 EMTRIVA (emtricitabine), STRIBILD (cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate), 10 c. substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of days Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/mL. VIREAD (tenofovir disoproxil fumarate), VIRAMUNE (nevirapine), TRUVADA® (emtricitabine and tenofovir tenofovir, the potential for CYP mediated interactions involving tenofovir disoproxil fumarate with other medicinal Norethindronea 1 mg i19 i16 Nevirapine: Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell disoproxil fumarate), COMPLERA (emtricitabine, rilpivirine and tenofovir) or ATRIPLA (emtricitabine, efavirenz § products is low. (as Ortho- (i30 to i7) (i27 to i3) culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine, efavirenz, and etravirine. and tenofovir disoproxil fumarate) [see Warnings and Precautions (5.3)] ® Tenofovir Disoproxil Fumarate has been evaluated in healthy volunteers in combination with other antiretroviral Novum 1/35) The Y188N conferred 22- and 7-fold reductions in susceptibility to delavirdine and efavirenz, respectively, but • Decreases in bone mineral density have been observed with the use of lamivudine and tenofovir disoproxil and potential concomitant drugs. Tables 6 and 7 summarize pharmacokinetic effects of coadministered drug on showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to fumarate tablets, co-packaged with nevirapine tablets in patients with HIV. Bone mineral density monitoring delavirdine and etravirine 3- and 8-fold, respectively, but did not reduce susceptibility to efavirenz. However, Nevirapine, USP is a white to off-white crystalline powder that is practically insoluble in water, freely soluble in tenofovir pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of coadministered Depomedroxy- 150 mg every 3 200 mg QD x 14 32 should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia drug. Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics progesterone months days; nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were [see Warnings and Precautions (5.6)]. methanol and in dichloromethane. susceptible to nevirapine in cell culture. of didanosine that may be of clinical significance. Concomitant dosing of coadministration of tenofovir disoproxil acetate 200 mg BID x 14 • Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving 12 CLINICAL PHARMACOLOGY fumarate with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric- days 13 NONCLINICAL TOXICOLOGY antiretroviral therapy, including lamivudine, nevirapine and tenofovir disoproxil fumarate, and that the cause For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility and long-term health effects of these conditions are not known at this time [see Warnings and Precautions similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 7). The Fluconazole 200 mg QD 200 mg QD x 14 19 consult the lamivudine, tenofovir disoproxil fumarate, and nevirapine prescribing information. (5.8)]. mechanism of this interaction is unknown. days; Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic 12.1 Mechanism of Action 200 mg BID x 14 potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended 17.2 Hepatotoxicity and Skin Reactions No clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and efavirenz, therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro methadone, nelfinavir, oral contraceptives, or ribavirin. days Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine-containing Lamivudine and Tenofovir Disoproxil Fumarate tablets, Co-packaged with Nevirapine Tablets are a combination cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human products that may result in death. Instruct patients developing signs or symptoms of liver disease or severe of antiviral drugs: lamivudine, tenofovir disoproxil fumarate, and nevirapine [see Microbiology (12.4)]. Ketoconazolea 400 mg QD 200 mg QD x 14 lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of Table 6. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the i72 i44 activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans 12.3 Pharmacokinetics days; 21 § laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic Coadministered Drug 200 mg BID x 14 (i80 to i60) (i58 to i27) at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash Pharmacokinetics in Adults days to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, % Change of Tenofovir Pharmacokinetic evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring. facial edema, and/or hepatitis. Lamivudine and Tenofovir Disoproxil Fumarate: Lamivudine and tenofovir disoproxil fumarate from the combination Parametersb Antiretrovirals Dose of Coadministered Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice tablets (300 mg/300 mg) were bioequivalent to that from EPIVIR (lamivudine) Tablets and VIREAD (tenofovir Coadministered Drug N (90% CI) Methadonea Individual Subject 200 mg QD x 14 9 In a controlled pharmacokinetic trial with 9 Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of Drug (mg) and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disoproxil fumarate) Tablets respectively, when administered to healthy volunteers under fasted and fed conditions. Dosing days; 200 mg BID subjects receiving chronic methadone to humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased Cmax AUC Cmin disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine Nevirapine: Nevirapine tablets (200 mg) were bioequivalent to VIRAMUNE (nevirapine) Tablets, when administered ³7 days whom steady-state nevirapine therapy was at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of Abacavir 300 once 8 NC added, the clearance of methadone was to healthy volunteers under fasted and fed conditions. to 5 times that observed in humans at the therapeutic dose. hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine Atazanavirc 400 once daily × 14 days 33 h 14 h 24 h 22 increased by 3-fold, resulting in symptoms Tenofovir Disoproxil Fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Lamivudine (h 8 to h 20) (h 21 to h 28) (h 15 to h 30) of withdrawal, requiring dose adjustments in bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 10 mg segments, in 7 of the 9 subjects. cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of The steady-state pharmacokinetics properties of the lamivudine 300 mg tablet once daily for 7 days compared c was negative when administered to male mice. Atazanavir/ Ritonavir 300/100 once daily 12 h 34 h 37 h 29 Methadone did not have any effect on symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C with the lamivudine 150 mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. (h 20 to h 51) (h 30 to h 45) (h 21 to h 36) nevirapine clearance. There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil and/or increased transaminases at the start of therapy with nevirapine are associated with a greater risk of later Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT [see d a daily with respect to plasma AUC ; however, C was 66% higher and the trough value was 53% lower Darunavir/Ritonavir 300/100 twice daily 12 h 24 h 22 h 37 Rifabutin 150 or 300 mg QD 200 mg QD x 14 19 h17 h28 area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven Boxed Warning and Warnings and Precautions (5.10)]. 24,.ss max,ss (h 8 to h 42) (h 10 to h 35) (h 19 to h 57) days; (i2 to h40) (h9 to h51) of gestation. There was, however, an alteration of the estrous cycle in female rats. compared with the 150 mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct e Metabolite blood mononuclear cells were also similar with respect to AUC and C ; however, trough values were Didanosine 250 or 400 once daily × 14 Nevirapine: Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed 24,.ss max24,ss 25-O-desacetyl- 200 mg BID x 14 patients that if any rash occurs during the two-week lead-in period, do not escalate the nevirapine dose until the lower compared with the 150 mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine 7 days h24 h29 h22 with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all rash resolves. The total duration of the once-daily lead-in dosing period should not exceed 28 days, at which point rifabutin days (i16 to h84) (i2 to h68) (i14 to h74) triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes Emtricitabine 200 once daily × 7 days 17 doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations Rifampina 600 mg QD 200 mg QD x 14 14 h11 § at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal nevirapine immediately and consult a physician. Nevirapine should not be restarted following severe skin rash or is not known. Entecavir 1 mg once daily x 10 28 days; (i4 to h28) studies was lower than that measured in humans at the 200 mg twice daily dose. The mechanism of the carcinogenic hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash [see Absorption and Bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-1-infected patients. days 200 mg BID x 14 potential is unknown. However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or Boxed Warning and Warnings and Precautions (5.11)]. days clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150 mg tablet and 87% ± 13% Indinavir 800 three times daily × 13 h 14 17.3 Drug Interactions § = Cmin below detectable level of the assay (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays for the oral solution. After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum 7 days (i 3 to h 33) using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Nevirapine, one component of Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine lamivudine concentration (C ) was 1.5 0.5 mcg/mL (mean ± SD). The area under the plasma concentration h = Increase, i = Decrease, = No Effect max Lamivudine 150 twice daily × 7 days 15 Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine- Tablets, may interact with some drugs; therefore, patients should be advised to report to their doctor the use of versus a For information regarding clinical recommendations, see Drug Interactions (7). treated mice and rats is not known. In reproductive toxicology studies, evidence of impaired fertility was seen in any other prescription, non-prescription medication, or herbal products, particularly St. John’s wort. time curve (AUC) and C increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. Lopinavir/Ritonavir 400/100 twice daily × 14 24 h 32 h 51 female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with max b Pediatric subjects ranging in age from 6 months to 12 years. 17.4 Contraceptives days (h 25 to h 38) (h 37 to h 66) the recommended clinical dose of nevirapine. The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.5 c Parallel group design; n for nevirapine+lopinavir/ritonavir, n for lopinavir/ritonavir alone. Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used h 23 13.2 Reproductive Toxicology Studies and Animal Toxicology and/or Pharmacology following 15 days of oral administration of 2 mg/kg twice daily. Saquinavir/Ritonavir 1000/100 twice daily × 35 d as the sole method of contraception in women taking nevirapine, since nevirapine, one component of lamivudine 14 days (h 16 to h 30) Parallel group design; n=23 for atazanavir/ritonavir + nevirapine, n=22 for atazanavir/ritonavir without nevirapine. and tenofovir disoproxil fumarate tablets co-packaged with nevirapine tablets, may lower the plasma levels of these Effects of Food on Oral Absorption: An investigational 25 mg dosage form of lamivudine was administered orally Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. Reproductive Toxicology Studies medications. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine therapy, to 12 asymptomatic, HIV-1-infected patients on 2 occasions, once in the fasted state and once with food (1,099 Tacrolimus 0.05 mg/kg twice daily x 21 h 13 e Based on between-trial comparison. Lamivudine: Reproduction studies have been performed in rats and rabbits at orally administered doses up to the therapeutic effect of the hormonal therapy should be monitored [see Drug Interactions (7)]. kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed 7 days (h 1 to h 27) 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that f Based on historical controls. for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality 17.5 Methadone state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was i 23 i 2 h 7 500/100 twice daily 22 Because of the design of the drug interaction trials (addition of 28 days of nevirapine therapy to existing HIV-1 was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (i 32 to i 13) (i 9 to h 5) (i 2 to h 17) Nevirapine, one component of lamivudine and tenofovir disoproxil fumarate tablets co-packaged with nevirapine Tipranavir/ Ritonavirf therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed tablets, may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal (AUC¥) in the fed and fasted states; therefore, lamivudine tablets may be administered with or without food. that lamivudine is transferred to the fetus through the placenta. 750/200 twice daily i 38 h 2 h 14 comparison to historical controls. syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Monitor methadone- 20 Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was (23 doses) (i 46 to i 29) (i 6 to h 10) (h 1 to h 27) Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Animal Toxicology and/or Pharmacology maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly [see Drug Interactions (7)]. 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine Tenofovir Disoproxil Fumarate: Tenofovir and Tenofovir Disoproxil Fumarate administered in toxicology studies independent of dose and did not correlate with body weight. exposure, based on a comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans All brand names listed are the registered trademarks of their respective owners and are not trademarks of Hetero a Subjects received tenofovir disoproxil fumarate 300 mg once daily. Table 8 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that over the concentration caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in Labs Limited. b was co-administered with low-dose ritonavir and nevirapine. Increase = h; Decrease = i; No Effect = ; NC = Not Calculated monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% 12.4 Microbiology toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown. and was independent of concentration. c Reyataz (atazanavir) Prescribing Information Mechanism of Action Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, Manufactured by: d HETEROTM Metabolism: Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of Prezista (darunavir) Prescribing Information Lamivudine: Intracellularly, lamivudine is phosphorylated to its active 5’-triphosphate metabolite, lamivudine phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-l- e Subjects received didanosine buffered tablets. triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA animals. These toxicities were noted at exposures (based on AUCs) 2 to 20 times higher than those observed in HETERO LABS LIMITED infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. chain termination after incorporation of the nucleotide analogue. 3TC-TP is a weak inhibitor of cellular DNA humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not 22-110, I.D.A., Jeedimetla, f Serum concentrations of this metabolite have not been determined. Aptivus (tipranavir) Prescribing Information polymerases a, b, and g. known. Hyderabad–500055, India. Issued: March 2014 indinavir sulfate (Crixivan • rifampin (Rifadin • fluconazole (Diflucan • Issued: March 2014 are not trademarks of Hetero Labs Limited. and owners respective their of trademarks registered the are listed names brand All Rx only magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. sodium, croscarmellose starch, corn dioxide, silicon colloidal Ingredients: Inactive Active Ingredient: Nevirapine Tablets, USP hypromellose, lactose monohydrate, titanium dioxide and triacetin. with opadry II light blue which contains FD&C blue #2/ indigo carmine aluminum lake, magnesium stearate, microcrystalline cellulose and povidone. The tablets are coated crospovidone, FD & C Blue #2/ indigo caramine aluminum lake, lactose monohydrate, sodium, croscarmellose starch, corn dioxide, silicon colloidal Ingredients: Inactive Active Ingredient: Lamivudine and tenofovir Disoproxil Fumarate Tablets Co-packaged With Nevirapine tablets? fosamprenavir calcium (Lexiva • ketoconazole (Nizoral • clarithromycin (Biaxin • interferon alfa and ribavirin Also tell your doctor if you take: didanosine (VIDEC, VIDEX EC) • adefovir (HEPSERA) • • other medicines that contain lamivudine or emtricitabine such as: • other medicines that contain tenofovir disoproxil fumarate such as: • and contraceptives) (oral mouth by taken pills control Birth pills. control Birth • nelfinavir mesylate (Viracept methadone • • amiodarone, disopyramide (Norpace • rifabutin (Mycobutin • cisapride (Propulsid • cyclosporine, tacrolimus, sirolimus (Rapamune ergotamine • cyclophosphamide • diltiazem, nifedipine, verapamil • • saquinavir mesylate (Invirase • carbamazepine, clonazepam (Klonopin • • Medicines are sometimes prescribed for purposes other than those listed in a in listed those than other purposes for prescribed sometimes are Medicines • co-packaged with Nevirapine Tablets: General Information about Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Do not keep medicine that is out of date or that you no longer need. If you throw • with co-packaged tablets, fumarate disoproxil tenofovir and lamivudine Keep • Store lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with • • with Nevirapine Tablets? How Do I Store Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged or 1-800-FDA-1088 at FDA or 866-495-1995 www.fda.gov/medwatch. at Limited Labs Hetero to Call your doctor for medical advice about side effects. You may also report side effects your doctor or pharmacist. ask information more For Tablets. Nevirapine with Co-packaged Tablets Fumarate Disoproxil Tenofovir and Lamivudine of effects side possible the all not are These nevirapine tablets. with co-packaged tablets, fumarate disoproxil tenofovir and lamivudine taking while Tell your doctor if you have any side effects that bothers you or that does not go away rash. is tablets, nevirapine with co-packaged tablets fumarate disoproxil tenofovir and lamivudine of component one nevirapine, of effect side common most The healthcare provider if you start having new symptoms after starting your HIV medicine. begin to fight infections that have been hidden in your body for a long time. Tell and stronger get may system immune Your medicines. HIV taking start you when Syndrome) Reconstitution (Immune system immune your in Changes conditions are not known. legs, arms, and face may also happen. The cause and long-term health effects of these hump”), breast, and around the main part of your body (trunk). Loss fat from (“buffalo neck and back upper the in fat of amount increased include may changes Changes in body fat Tablets may cause other serious side effects, including: Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine are: The most common side effects of lamivudine and tenofovir disoproxil fumarate tablets check your bones. to tests additional do to need may provider healthcare Your fractures). to lead may disoproxil fumarate. Bone problems include bone pain, softening or thinning (which problems Bone and tenofovir disoproxil fumarate tablets. may need to do blood tests to check your kidneys during your treatment with lamivudine provider healthcare your problems, kidney cause can that medicine another take to need or past the in problems kidney had have you If fumarate. disoproxil tenofovir New or worse kidney problems other serious side effects, including: tenofovir disoproxil fumarate tablets co-packaged with nevirapine tablets, may cause and lamivudine of components two Fumarate, Disoproxil Tenofovir and Lamivudine at the beginning of this Medication Guide). and Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets? (Also see Tablets, Co-packaged with Nevirapine Tablets? What are the Possible Side Effects of Day 15, you will take 1 nevirapine tablet two times a day. 2. of chance your lower to day each dose 1 with you start should doctor Your 1. Starting nevirapine tablets: doctor your ask days, 7 than more for tablets nevirapine taking stop you If • Co- Tablets, Fumarate Disoproxil Tenofovir and Lamivudine your let not Do • With Co-packaged Tablets, Fumarate Disoproxil Tenofovir and Lamivudine • Take each dose with a full glass of water. • Tablets Fumarate Disoproxil Tenofovir and Lamivudine the of dose usual The • 35 kg (77 pounds) least at of weight body a with older and age of years 16 Adolescents and Adults If doctor. your by directed as exactly co-packaged this in medicines the Take • packaged With Nevirapine Tablets? Co- Tablets, Fumarate Disoproxil Tenofovir and Lamivudine Take I Should How when you get a new medicine. Know the medicines you take. Keep a list of them to show your doctor or pharmacist fentanyl pharmacist. or doctor your ask above, medicine a take you if sure not are you If • warfarin (Coumadin • itraconazole (Sporanox • What are the Ingredients of Do not use lamivudine and tenofovir disoproxil fumarate tablets, co-packaged • about information important most the summarizes Guide Medication This • Manufactured by: emtricitabine (EMTRIVA) abacavir sulfate, lamivudine, and zidovudine (TRIZIVIR) • abacavir sulfate and lamivudine (EPZICOM) • lamivudine and zidovudine (COMBIVIR) • lamivudine (EPIVIR, EPIVIR-HBV) • • fumarate disoproxil tenofovir emtricitabine, elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (TRUVADA) • rilpivirine, emtricitabine, and tenofovir disoproxil fumarate (COMPLERA) • efavirenz, emtricitabine, and tenofovir disoproxil fumarate (ATRIPLA) • tenofovir disoproxil fumarate (VIREAD) • • Tablets, Co-packaged with Nevirapine Tablets. pregnancy during treatment with Lamivudine and Tenofovir Disoproxil Fumarate with your doctor about other types of birth control that you can use to prevent other hormone types of birth control may not work to prevent pregnancy. Talk Medication any medicines away make sure that children will not find them. nevirapine tablets in the original blister cards. nevirapine tablets at room temperature below 30°C (86°F). children. of reach of out medicines other all and tablets nevirapine Keep lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with weakness • depression cough pain • • • nasal signs and symptoms • fatigue headache • diarrhea • rash • nausea • • Your doctor may want you to have blood tests or other medical evaluations • three the all of use the requires always almost HIV/AIDS of Treatment • You should never take your starting dose for longer than 28 days. If after • • • each day for the first 14 days. getting a serious rash. starting dose again, which is taken 1 time each day for 14 days. nevirapine taking begin to need may You again. them taking start you before packaged with Nevirapine Tablets run out. with a body weight less than 35 kg (77 pounds). Nevirapine Tablets are not recommended in patients less than 16 years of age These medications are taken with or without food. Follow your doctor's instructions. to strictly follow the once daily dose of nevirapine tablets for first 14 days. days lowers the chance of rash, which could be serious. Therefore, it is important twice daily thereafter. Starting with one Nevirapine Tablet a day for the first 14 tablets for adults is one tablet daily the first 14 days followed by nevirapine co-packaged the of dose usual The day. a once taken tablet one is (both the medications are present in one single tablet) for adult and adolescents to explain them you you do not understand these directions, ask your pharmacist, nurse, or doctor with nevirapine tablets if the seal over bottle opening is broken or missing. for health professionals. disoproxil fumarate tablets, co-packaged with nevirapine tablets that are written tenofovir and lamivudine about information for pharmacist or doctor your tablets. If you would like more information, talk with your doctor. You can ask lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine symptoms you have. It may harm them. co-packaged with nevirapine tablets to other people, even if they have the same tablets, fumarate disoproxil tenofovir and lamivudine give not Do prescribed. tablets, co-packaged with nevirapine tablets for a condition for which it was not Hyderabad–500055, India. 22-110, I.D.A., Jeedimetla, HETERO LABS LIMITED HETERO "What is the most important information I should know about Lamivudine (STRIBILD) during treatment with this medication to monitor progress and side effects. doctor. your to talk can you until them of all stop should you HIV, drugs. If you need to stop taking one of the medicines are for for you instead of nevirapine. you and your doctor should talk about prescribing another HIV medicine 28 days you are still receiving this starting dose because you have a rash, Do not increase your dose to 2 times a day if you have rash. days of nevirapine 14 first the during rash skin a get you if away right doctor your Call can happen in some people who take lamivudine and tenofovir and lamivudine take who people some in happen can Guide. TM nevirapine, USP lamivudine, USP and tenofovir disoproxil fumarate can happen in some people who take antiviral medicines. These ® , Rifamate Do not use lamivudine and tenofovir disoproxil fumarate disoproxil tenofovir and lamivudine use not Do ® ® ® ® , Jantoven

® ) ) ® Lamivudine and Tenofovir Disoproxil Fumarate Tablets, ) ) It is important that you only take 1 dose of nevirapine ® ) ) treatment . ® can happen in some people who take lamivudine and ) ® ® ® ) , Rifater ) ® Lamivudine and Tenofovir Disoproxil Fumarate ® ) without ritonavir (Norvir ) ® ® ), lidocaine ® ) ), ethosuximide (Zarontin ® ) ® ) ® ) can happen can "

Page 2 of 4 MEDICATION GUIDE Lamivudine and Tenofovir Disoproxil Fumarate Tablets, 300 mg/300 mg Co-packaged with Nevirapine Tablets USP, 200 mg

Read this Medication Guide before you start taking lamivudine and • If you stop taking lamivudine and tenofovir disoproxil fumarate tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets tablets co-packaged with nevirapine, your doctor will need to check and each time you get a refill. There may be new information. This your health often and do regular blood tests to check your HBV information does not take the place of talking to your doctor about your infection. Tell your doctor about any new or unusual symptoms you medical condition or treatment. may have after you stop taking lamivudine and tenofovir disoproxil What is the Most Important Information I Should Know About fumarate tablets co-packaged with nevirapine. Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged What are Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co- with Nevirapine Tablets? packaged with Nevirapine Tablets? Nevirapine, one component of Lamivudine and Tenofovir Disoproxil • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged Fumarate Tablets Co-packaged with Nevirapine Tablets, can cause with Nevirapine Tablets can be used alone or in combination with serious side effects. These include severe liver and skin problems other antiviral medicines to treat Human Immunodeficiency Virus that can cause death. These problems can happen at any time during (HIV) in patients 16 years of age and older with a body weight of at treatment, but your risk is higher during the first 18 weeks of treatment. least 35 kg (77 pounds). HIV is the virus that causes AIDS (Acquired 1. Severe liver problems: Anyone who takes nevirapine may get severe Immune Deficiency Syndrome). liver problems. In some cases these liver problems can lead to liver Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged failure and the need for a liver transplant, or death. with Nevirapine Tablets are prescription antiviral medicines. People who have a higher CD4+ cell count when they begin nevirapine Lamivudine and tenofovir disoproxil fumarate are a type of medicines treatment have a higher risk of liver problems, especially: called nucleoside analog reverse transcriptase inhibitors (NRTIs) • Women with CD4+ counts higher than 250 cells/mm3. This group and nevirapine is a non-nucleoside analog reverse transcriptase has the highest risk. inhibitor (NNRTI). • Men with CD4+ counts higher than 400 cells/mm3. • When used with alone or in combination with other HIV medicines, + Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged If you are a woman with CD4 counts higher than 250 cells/mm3 or a with Nevirapine Tablets may: man with CD4+ counts higher than 400 cells/mm3, you and your doctor will decide whether starting nevirapine is right for you. 1. Reduce the amount of HIV in your blood (called “viral load”) In general, women have a higher risk of liver problems compared to 2. Help increase the number of CD4 (T) cells in your blood which men. help fight off other infections. People who have abnormal liver test results before starting nevirapine Reducing the amount of HIV and increasing the CD4 (T) cell count may treatment and people with hepatitis B or C also have a greater chance improve your immune system. This may reduce your risk of death or of getting liver problems. infections that can happen when your immune system is weak (opportunistic infections). You may get a rash if you have liver problems. Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged Stop taking nevirapine and call your doctor right away if you have with Nevirapine Tablets do not cure HIV-1 infection or AIDS and you any of the following symptoms of liver problems: may continue to experience illnesses associated with HIV-1 infection, • dark (tea colored) urine including opportunistic infections. You should remain under the care • yellowing of your skin or whites of your eyes of a doctor while taking lamivudine and tenofovir disoproxil fumarate • light-colored bowel movements (stools) tablets, co-packaged with nevirapine tablets. • fever You must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses. • nausea (feeling sick to your stomach) Avoid doing things that can spread HIV-1 infection to others: • feel unwell or like you have the flu • Do not share needles or other injection equipment. • pain or tenderness on your right side below your ribs • Do not share personal items that can have blood or body fluids • tiredness on them, like toothbrushes or razor blades. • loss of appetite • Do not have any kind of sex without protection. Always practice Your doctor should see you and do blood tests often to check your liver safer sex by using a latex or polyurethane condom or other barrier function during the first 18 weeks of treatment with nevirapine. You to reduce the chance of sexual contact with semen, vaginal secretions, should continue to have your liver checked regularly during your treatment or blood. with nevirapine. It is important for you to keep all of your doctor Ask your doctor if you have any questions on how to prevent passing appointments. HIV to other people. 2. Severe rash and skin reactions: Skin rash is the most common Who Should Not Take Lamivudine and Tenofovir Disoproxil Fumarate side effect of nevirapine. Most rashes happen in the first 6 weeks Tablets, Co-packaged with Nevirapine Tablets? of taking nevirapine. Rashes and skin reactions may be severe, life-threatening, and in some people, may lead to death. Stop Tell your doctor if you have or have had liver or kidney problems. Your using nevirapine and call your doctor right away if you get a rash doctor may tell you not to take nevirapine, one component of Lamivudine with any of the following symptoms: and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets, if you have certain liver problems. • blisters Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged • mouth sores with Nevirapine Tablets are only for people diagnosed with HIV. If you • red or inflamed eyes, like “pink eye” (conjunctivitis) have not been diagnosed as HIV positive, then do not take Lamivudine • liver problems (see symptoms of liver problems above) and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine • swelling of your face Tablets. • fever What Should I Tell My Doctor Before Taking Lamivudine And Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets? • feel unwell or like you have the flu Before you take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, • tiredness Co-packaged with Nevirapine Tablets, tell your doctor if you: • muscle or joint aches • Have or have had hepatitis (inflammation of your liver) or problems If your doctor tells you to stop treatment with nevirapine because you with your liver. See “What is the most important information I have had any of the serious liver or skin problems described above, should know about Lamivudine and Tenofovir Disoproxil Fumarate you should never take nevirapine again. Tablets, Co-packaged with Nevirapine Tablets?” and “Who should See the section "What are the possible side effects of Lamivudine and not take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine Co-packaged with Nevirapine Tablets?” Tablets?" for more information. • Receive dialysis Patients taking lamivudine and tenofovir disoproxil fumarate, two • Have skin problems, such as rash components of lamivudine and tenofovir disoproxil fumarate tablets co- • Have any medical conditions packaged with nevirapine tablets, may develop: • Are pregnant or planning to become pregnant. It is not known if 3. Build-up of an acid in your blood (lactic acidosis). Lactic acidosis Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged can happen in some people who take lamivudine, tenofovir disoproxil with Nevirapine Tablets will harm your unborn baby. fumarate, or similar (nucleoside analog) medicines. Lactic acidosis is a serious medical emergency that can lead to death. • Are breastfeeding or plan to breast-feed. Lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets can Lactic acidosis can be hard to identify early, because the symptoms pass into your breast milk and may harm your baby. You should not could seem like symptoms of other health problems. Call your healthcare breastfeed if you have HIV because of the risk of passing HIV to provider right away if you get the following symptoms which could your baby. Do not breast-feed during treatment with Lamivudine be signs of lactic acidosis: and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with • feeling very weak or tired Nevirapine Tablets. Talk to your doctor about the best way to feed • have unusual (not normal) muscle pain your baby. • have trouble breathing Tell your doctor and pharmacist about all the medicines you take, • have stomach pain with including prescription and non-prescription medicines, vitamins and herbal supplements. Lamivudine and Tenofovir Disoproxil Fumarate • nausea (feel sick to your stomach) Tablets, Co-packaged with Nevirapine Tablets may affect the way other • vomiting medicines work, and other medicines may affect how Lamivudine and • feel cold, especially in your arms and legs Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine • feel dizzy or lightheaded Tablets works. • have a fast or irregular heartbeat You should not take Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets if you also take: 4. Worsening of your Hepatitis B infection. If you have hepatitis B Virus (HBV) infection it may become worse (flare-up) if you take • St. John’s Wort. St. John’s Wort can lower the amount of Lamivudine lamivudine and tenofovir disoproxil fumarate tablets, two components and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with of lamivudine and tenofovir disoproxil fumarate tablets co-packaged Nevirapine Tablets in your body. with nevirapine tablets, and then stop them. A “flare-up” is when • efavirenz (Sustiva®), etravirine (Intelence®), rilpivirine (Edurant®), your HBV infection suddenly returns in a worse way than before. or delavirdine (Rescriptor®). • Do not let your lamivudine and tenofovir disoproxil fumarate tablets • atazanavir (Reyataz®) co-packaged with nevirapine run out. • boceprevir (Victrelis®) Refill your prescription or talk to your healthcare provider before • telaprevir (Incivek®) your lamivudine and tenofovir disoproxil fumarate tablets co-packaged • tipranavir (Aptivus®) with nevirapine are all gone. • darunavir (Prezista®) • Do not stop taking lamivudine and tenofovir disoproxil fumarate ® tablets co-packaged with nevirapine without first talking to your • lopinavir and ritonavir (Kaletra ) once daily doctor. • fosamprenavir calcium (Lexiva®) without ritonavir (Norvir®)

Size : 220 x 450 mm Pharma code : Front 632 Back 633 Colours : Sigle (Pantone Black C) Spec: Printed on 40 GSM Bible paper, front & back side printing. Page 1 of 4 • itraconazole (Sporanox®) New or worse kidney problems can happen in some people who take • ketoconazole (Nizoral®) lamivudine and tenofovir disoproxil fumarate. If you have had kidney ® ® ® problems in the past or need to take another medicine that can cause • rifampin (Rifadin , Rifamate , Rifater ) kidney problems, your healthcare provider may need to do blood tests • Birth control pills. Birth control pills taken by mouth (oral to check your kidneys during your treatment with lamivudine and contraceptives) and other hormone types of birth control may not tenofovir disoproxil fumarate tablets. work to prevent pregnancy. Talk with your doctor about other types Bone problems can happen in some people who take lamivudine and of birth control that you can use to prevent pregnancy during tenofovir disoproxil fumarate. Bone problems include bone pain, softening treatment with Lamivudine and Tenofovir Disoproxil Fumarate Tablets, or thinning (which may lead to fractures). Your healthcare provider may Co-packaged with Nevirapine Tablets. need to do additional tests to check your bones. • other medicines that contain tenofovir disoproxil fumarate such as: The most common side effects of lamivudine and tenofovir disoproxil • tenofovir disoproxil fumarate (VIREAD) fumarate tablets are: • efavirenz, emtricitabine, and tenofovir disoproxil fumarate • nausea • nasal signs and symptoms (ATRIPLA) • rash • cough • rilpivirine, emtricitabine, and tenofovir disoproxil fumarate • diarrhea • pain (COMPLERA) • headache • depression • emtricitabine and tenofovir disoproxil fumarate (TRUVADA) • fatigue • weakness • cobicistat, elvitegravir, emtricitabine, tenofovir disoproxil fumarate (STRIBILD) Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged • other medicines that contain lamivudine or emtricitabine such as: with Nevirapine Tablets may cause other serious side effects, including: • lamivudine (EPIVIR, EPIVIR-HBV) Changes in body fat can happen in some people who take antiviral medicines. These changes may include increased amount of fat in the • lamivudine and zidovudine (COMBIVIR) upper back and neck (“buffalo hump”), breast, and around the main • abacavir sulfate and lamivudine (EPZICOM) part of your body (trunk). Loss of fat from the legs, arms, and face may • abacavir sulfate, lamivudine, and zidovudine (TRIZIVIR) also happen. The cause and long-term health effects of these conditions • emtricitabine (EMTRIVA) are not known. • adefovir (HEPSERA) Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system • didanosine (VIDEC, VIDEX EC) may get stronger and begin to fight infections that have been hidden in • interferon alfa and ribavirin your body for a long time. Tell your healthcare provider if you start Also tell your doctor if you take: having new symptoms after starting your HIV medicine. • clarithromycin (Biaxin®) The most common side effect of nevirapine, one component of lamivudine ® and tenofovir disoproxil fumarate tablets co-packaged with nevirapine • fluconazole (Diflucan ) tablets, is rash. ® • indinavir sulfate (Crixivan ) Tell your doctor if you have any side effects that bothers you or that • methadone does not go away while taking lamivudine and tenofovir disoproxil • nelfinavir mesylate (Viracept®) fumarate tablets, co-packaged with nevirapine tablets. • rifabutin (Mycobutin®) These are not all the possible side effects of Lamivudine and Tenofovir • warfarin (Coumadin®, Jantoven®) Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets. For more information ask your doctor or pharmacist. • saquinavir mesylate (Invirase®) ® Call your doctor for medical advice about side effects. You may also • amiodarone, disopyramide (Norpace ), lidocaine report side effects to Hetero Labs Limited at 866-495-1995 or FDA at • carbamazepine, clonazepam (Klonopin®), ethosuximide (Zarontin®) 1-800-FDA-1088 or www.fda.gov/medwatch. • diltiazem, nifedipine, verapamil How Do I Store Lamivudine and Tenofovir Disoproxil Fumarate Tablets, • cyclophosphamide Co-packaged with Nevirapine Tablets? • ergotamine • Keep lamivudine and tenofovir disoproxil fumarate tablets, co- ® packaged with nevirapine tablets and all other medicines out of • cyclosporine, tacrolimus, sirolimus (Rapamune ) reach of children. ® • cisapride (Propulsid ) • Store lamivudine and tenofovir disoproxil fumarate tablets, co- • fentanyl packaged with nevirapine tablets at room temperature below 30°C If you are not sure if you take a medicine above, ask your doctor or (86°F). pharmacist. • Keep lamivudine and tenofovir disoproxil fumarate tablets, co- Know the medicines you take. Keep a list of them to show your doctor packaged with nevirapine tablets in the original blister cards. or pharmacist when you get a new medicine. • Do not keep medicine that is out of date or that you no longer need. How Should I Take Lamivudine and Tenofovir Disoproxil Fumarate If you throw any medicines away make sure that children will not Tablets, Co-packaged With Nevirapine Tablets? find them. • Take the medicines in this co-packaged exactly as directed by your General Information about Lamivudine and Tenofovir Disoproxil doctor. If you do not understand these directions, ask your pharmacist, Fumarate Tablets, co-packaged with Nevirapine Tablets: nurse, or doctor to explain them to you • Medicines are sometimes prescribed for purposes other than those Adults and Adolescents 16 years of age and older with a body weight listed in a Medication Guide. Do not use lamivudine and tenofovir of at least 35 kg (77 pounds) disoproxil fumarate tablets, co-packaged with nevirapine tablets for a condition for which it was not prescribed. Do not give lamivudine • The usual dose of the Lamivudine and Tenofovir Disoproxil Fumarate and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine Tablets (both the medications are present in one single tablet) for tablets to other people, even if they have the same symptoms you adult and adolescents is one tablet taken once a day. The usual dose have. It may harm them. of the co-packaged nevirapine tablets for adults is one tablet daily for the first 14 days followed by one tablet twice daily thereafter. • This Medication Guide summarizes the most important information Starting with one Nevirapine Tablet a day for the first 14 days lowers about lamivudine and tenofovir disoproxil fumarate tablets, co- the chance of rash, which could be serious. Therefore, it is important packaged with nevirapine tablets. If you would like more information, to strictly follow the once daily dose of nevirapine tablets for the talk with your doctor. You can ask your doctor or pharmacist for first 14 days. Follow your doctor's instructions. information about lamivudine and tenofovir disoproxil fumarate tablets, co-packaged with nevirapine tablets that are written for health • Take each dose with a full glass of water. professionals. These medications are taken with or without food. • Do not use lamivudine and tenofovir disoproxil fumarate tablets, co- • Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged packaged with nevirapine tablets if the seal over bottle opening is With Nevirapine Tablets are not recommended in patients less than broken or missing. 16 years of age with a body weight less than 35 kg (77 pounds). What are the Ingredients of Lamivudine and Tenofovir Disoproxil • Do not let your Lamivudine and Tenofovir Disoproxil Fumarate Fumarate Tablets, Co-packaged With Nevirapine tablets? Tablets, Co-packaged with Nevirapine Tablets run out. Lamivudine and tenofovir Disoproxil Fumarate Tablets • If you stop taking nevirapine tablets for more than 7 days, ask your Active Ingredient: lamivudine, USP and tenofovir disoproxil fumarate doctor before you start taking them again. You may need to begin taking nevirapine starting dose again, which is taken 1 time each Inactive Ingredients: colloidal silicon dioxide, corn starch, croscarmellose day for 14 days. sodium, crospovidone, FD & C Blue #2/ indigo caramine aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose Starting nevirapine tablets: and povidone. The tablets are coated with opadry II light blue which 1. Your doctor should start you with 1 dose each day to lower your contains FD&C blue #2/ indigo carmine aluminum lake, hypromellose, chance of getting a serious rash. It is important that you only take lactose monohydrate, titanium dioxide and triacetin. 1 dose of nevirapine each day for the first 14 days. Nevirapine Tablets, USP • Call your doctor right away if you get a skin rash during the Active Ingredient: nevirapine, USP first 14 days of nevirapine treatment. Inactive Ingredients: colloidal silicon dioxide, corn starch, croscarmellose • Do not increase your dose to 2 times a day if you have a rash. sodium, magnesium stearate, microcrystalline cellulose, povidone and • You should never take your starting dose for longer than 28 sodium starch glycolate. days. If after 28 days you are still receiving this starting dose Rx only because you have a rash, you and your doctor should talk about All brand names listed are the registered trademarks of their respective prescribing another HIV medicine for you instead of nevirapine. owners and are not trademarks of Hetero Labs Limited. 2. Day 15, you will take 1 nevirapine tablet two times a day. • Treatment of HIV/AIDS almost always requires the use of all the three drugs. If you need to stop taking one of the medicines you Manufactured by: 2024901 are taking for HIV, you should stop all of them until you can talk HETEROTM to your doctor. HETERO LABS LIMITED • Your doctor may want you to have blood tests or other medical 22-110, I.D.A., Jeedimetla, evaluations during treatment with this medication to monitor Hyderabad–500055, India. progress and side effects. Issued: March 2014 What are the Possible Side Effects of Lamivudine and Tenofovir Disoproxil Fumarate Tablets, Co-packaged with Nevirapine Tablets? (Also see "What is the most important information I should know about Lamivudine and Tenofovir Disoproxil Fumarate Tablets Co-packaged with Nevirapine Tablets?" at the beginning of this Medication Guide). Lamivudine and Tenofovir Disoproxil Fumarate, two components of lamivudine and tenofovir disoproxil fumarate tablets co-packaged with nevirapine tablets, may cause other serious side effects, including:

Page 2 of 4