DRUGS & SUPPLEMENTS
WARNING: LIFE-THREATENING HEPATOTOXICITY and SKINREACTIONSHEPATOTOXICITY:
Severe, life-threatening,and in some cases fatal hepatotoxicity, particularly in the first18 weeks, has been reported in patients treated with Auro-Nevirapine. Insome cases, patients presented with non-specific prodromal signs orsymptoms of hepatitis and progressed to hepatic failure. These eventsare often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patientsat increased risk; women with CD4+ cellcounts greater than 250 cells/mm3, includingpregnant women receiving Auro-Nevirapine in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Auro-Nevirapine use can occur in both genders,all CD4+ cell counts and at any time duringtreatment. Hepatic failure has also been reported in patients withoutHIV taking Auro-Nevirapine for post-exposure prophylaxis (PEP). Use of VIRAMUNEfor occupational and non-occupational PEP is contraindicated . Patients with signs or symptoms of hepatitis, or with increasedtransaminases combined with rash or other systemic symptoms, mustdiscontinue Auro-Nevirapine and seek medical evaluation immediately .
Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Auro-Nevirapine. These have included cases of Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionscharacterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions orhypersensitivity reactions must discontinue Auro-Nevirapine and seek medicalevaluation immediately. Transaminase levels should be checked immediatelyfor all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with Auro-Nevirapine 200 mg daily dosing has beenobserved to decrease the incidence of rash and must be followed .
MONITORINGFOR HEPATOTOXICITY AND SKIN REACTIONS:
Patients must be monitored intensively during thefirst 18 weeks of therapy with Auro-Nevirapine to detect potentially life-threateninghepatotoxicity or skin reactions. Extra vigilance is warranted duringthe first 6 weeks of therapy, which is the period of greatest riskof these events. Do not restart Auro-Nevirapine following clinical hepatitis,or transaminase elevations combined with rash or other systemic symptoms,or following severe skin rash or hypersensitivity reactions. In somecases, hepatic injury has progressed despite discontinuation of treatment.
WARNING: LIFE-THREATENING (INCLUDING FATAL)HEPATOTOXICITY and SKIN REACTIONS
See full prescribing informationfor complete boxed warning.
1 INDICATIONS AND USAGEAuro-Nevirapine is indicated in combination withother antiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients 15 days andolder .
Limitations of Use:
Based onserious and life-threatening hepatotoxicity observed in controlledand uncontrolled trials, Auro-Nevirapine is not recommended to be initiated,unless the benefit outweighs the risk, in:
2 DOSAGE AND ADMINISTRATION
2.1 Adult PatientsThe recommended dose for Auro-Nevirapine is one200 mg tablet daily for the first 14 days, followed by one 200 mgtablet twice daily, in combination with other antiretroviral agents. The 14-day lead-in period with Auro-Nevirapine 200 mg daily dosing must bestrictly followed as the lead-in period has been observed to decreasethe incidence of rash . If rash persists beyondthe 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond28 days, at which point, an alternative regimen should be sought. For concomitantly administered antiretroviral therapy, the manufacturer’srecommended dosage and monitoring should be followed.
2.2 Pediatric PatientsThe recommended oral dose for pediatricpatients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400mg for any patient.
2.3 Monitoring ofPatientsIntensive clinicaland laboratory monitoring, including liver enzyme tests, is essentialat baseline and during the first 18 weeks of treatment with Auro-Nevirapine. The optimal frequency of monitoring during this period has not beenestablished. Some experts recommend clinical and laboratory monitoringmore often than once per month, and in particular, would include monitoringof liver enzyme tests at baseline, prior to dose escalation, and attwo weeks post-dose escalation. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE treatment . In some cases, hepatic injuryhas progressed despite discontinuation of treatment.
2.4 Dosage AdjustmentPatients with Rash
DiscontinueVIRAMUNE if a patient experiences severe rash or any rash accompaniedby constitutional findings . Do not increase VIRAMUNEdose if a patient experiences mild to moderate rash without constitutionalsymptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved . The total duration of the once daily lead-in dosing periodshould not exceed 28 days at which point an alternative regimen shouldbe sought.
Patients with HepaticEvents
If a clinical (symptomatic)hepatic event occurs, permanently discontinue Auro-Nevirapine. Do not restartVIRAMUNE after recovery .
Patients with Dose Interruption
For patients who interrupt Auro-Nevirapine dosing for morethan 7 days, restart the recommended dosing, using one 200 mg tabletdaily (150 mg/m2/day in pediatric patients)for the first 14 days (lead-in) followed by one 200 mg tablet twicedaily (150 mg/m2 twice daily for pediatricpatients).
Patients with RenalImpairment
Patients with CrCLgreater than or equal to 20 mL per min do not require an adjustmentin Auro-Nevirapine dosing. The pharmacokinetics of Auro-Nevirapine have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Auro-Nevirapine following each dialysis treatment is indicatedin patients requiring dialysis. Auro-Nevirapine metabolites may accumulatein patients receiving dialysis; however, the clinical significanceof this accumulation is not known .
3 DOSAGE FORMS ANDSTRENGTHSTablets: 200mg, white, oval, biconvex, tablets embossed with 54 193 on one side
Oral suspension: 50 mg per 5 mL, white to off-white oral suspension
4 CONTRAINDICATIONSAuro-Nevirapine is contraindicated:
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicityand Hepatic ImpairmentSevere, life-threatening, and in some cases fatal hepatotoxicity,including fulminant and cholestatic hepatitis, hepatic necrosis andhepatic failure, have been reported in patients treated with Auro-Nevirapine. In controlled clinical trials, symptomatic hepatic events regardlessof severity occurred in 4% (range 0% to 11%) of subjects who receivedVIRAMUNE and 1% of subjects in control groups.
The risk of symptomatic hepatic events regardless ofseverity was greatest in the first 6 weeks of therapy. The risk continuedto be greater in the Auro-Nevirapine groups compared to controls through18 weeks of treatment. However, hepatic events may occur at any timeduring treatment. In some cases, subjects presented with non-specific,prodromal signs or symptoms of fatigue, malaise, anorexia, nausea,jaundice, liver tenderness or hepatomegaly, with or without initiallyabnormal serum transaminase levels. Rash was observed in approximatelyhalf of the subjects with symptomatic hepatic adverse events. Feverand flu-like symptoms accompanied some of these hepatic events. Someevents, particularly those with rash and other symptoms, have progressedto hepatic failure with transaminase elevation, with or without hyperbilirubinemia,hepatic encephalopathy, prolonged partial thromboplastin time, oreosinophilia. Rhabdomyolysis has been observed in some patients experiencingskin and/or liver reactions associated with Auro-Nevirapine use. Hepatitis/hepaticfailure may be associated with signs of hypersensitivity which caninclude severe rash or rash accompanied by fever, general malaise,fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction. Patients with signs or symptoms of hepatitis mustbe advised to discontinue Auro-Nevirapine and immediately seek medical evaluation,which should include liver enzyme tests.
The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateninghepatic events. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Auro-Nevirapine treatment.
Transaminases should be checked immediately if a patientexperiences signs or symptoms suggestive of hepatitis and/or hypersensitivityreaction. Transaminases should also be checked immediately for allpatients who develop a rash in the first 18 weeks of treatment. Physiciansand patients should be vigilant for the appearance of signs or symptomsof hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice,bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Thediagnosis of hepatotoxicity should be considered in this setting,even if transaminases are initially normal or alternative diagnosesare possible .
If clinical hepatitis or transaminase elevations combinedwith rash or other systemic symptoms occur, permanently discontinueVIRAMUNE. Do not restart Auro-Nevirapine after recovery. In some cases, hepaticinjury progresses despite discontinuation of treatment.
The patients at greatest risk of hepaticevents, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeksof treatment, women have a 3-fold higher risk than men for symptomatic,often rash-associated, hepatic events (6% versus 2%), and patientswith higher CD4+ cell counts at initiationof Auro-Nevirapine therapy are at higher risk for symptomatic hepatic eventswith Auro-Nevirapine. In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepaticadverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11%versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3).However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitoredfor hepatotoxicity since symptomatic hepatic adverse events have beenreported at all CD4+ cell counts. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Auro-Nevirapine are associated with a greater riskof later symptomatic events (6 weeks or more after starting Auro-Nevirapine)and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liverfailure requiring transplantation in one instance) has been reportedin HIV-1 uninfected individuals receiving multiple doses of VIRAMUNEin the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of Auro-Nevirapine for occupational and non-occupational PEP is contraindicated .
Increased Auro-Nevirapine troughconcentrations have been observed in some patients with hepatic fibrosisor cirrhosis. Therefore, carefully monitor patients with either hepaticfibrosis or cirrhosis for evidence of drug-induced toxicity. Do notadminister Auro-Nevirapine to patients with moderate or severe (Child-PughClass B or C, respectively) hepatic impairment .
5.2 Skin ReactionsSevere and life-threatening skin reactions,including fatal cases, have been reported, occurring most frequentlyduring the first 6 weeks of therapy. These have included cases ofStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions characterized by rash, constitutional findings, and organdysfunction including hepatic failure. Rhabdomyolysis has been observedin some patients experiencing skin and/or liver reactions associatedwith Auro-Nevirapine use. In controlled clinical trials, Grade 3 and 4 rasheswere reported during the first 6 weeks in 2% of Auro-Nevirapine recipientscompared to less than 1% of placebo subjects.
Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions must permanently discontinue Auro-Nevirapine and seekmedical evaluation immediately. Do not restart Auro-Nevirapine followingsevere skin rash, skin rash combined with increased transaminasesor other symptoms, or hypersensitivity reaction.
The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateningskin reactions. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Auro-Nevirapine treatment. In addition, the 14-day lead-inperiod with Auro-Nevirapine 200 mg daily dosing has been demonstrated toreduce the frequency of rash .
If patients present with a suspected VIRAMUNE-associatedrash, measure transaminases immediately. Permanently discontinue VIRAMUNEin patients with rash-associated transaminase elevations [seeWarnings and Precautions (5.1)].
Therapy with Auro-Nevirapine mustbe initiated with a 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shownto reduce the frequency of rash. Discontinue Auro-Nevirapine if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Auro-Nevirapine dose to a patient experiencinga mild to moderate rash without constitutional symptoms during the14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The totalduration of the once-daily lead-in dosing period must not exceed 28days at which point an alternative regimen should be sought . Patients must be monitored closely if isolated rash ofany severity occurs. Delay in stopping Auro-Nevirapine treatment after theonset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developingrash with Auro-Nevirapine.
In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Auro-Nevirapine administration) was associated with an increase inincidence and severity of rash during the first 6 weeks of VIRAMUNEtherapy. Therefore, use of prednisone to prevent VIRAMUNE-associatedrash is not recommended.
5.3 ResistanceAuro-Nevirapine must not be used as a single agentto treat HIV-1 or added on as a sole agent to a failing regimen. Resistantvirus emerges rapidly when Auro-Nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combinationwith Auro-Nevirapine should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of Auro-Nevirapine should be taken into account;if antiretrovirals with shorter half-lives than Auro-Nevirapine are stoppedconcurrently, low plasma concentrations of Auro-Nevirapine alone may persistfor a week or longer and virus resistance may subsequently develop .
5.4 Drug InteractionsSee Table 4 for listings of establishedand potential drug interactions .
Concomitant use of St. John's wort (Hypericumperforatum) or St. John's wort-containing products and VIRAMUNEis not recommended. Co-administration of St. John’s wort with non-nucleosidereverse transcriptase inhibitors (NNRTIs), including Auro-Nevirapine, isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Auro-Nevirapine and lead to loss of virologic responseand possible resistance to Auro-Nevirapine or to the class of NNRTIs. Co-administrationof Auro-Nevirapine and efavirenz is not recommended as this combination hasbeen associated with an increase in adverse reactions and no improvementin efficacy.
5.5 Immune ReconstitutionSyndromeImmune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including Auro-Nevirapine. During the initial phase of combinationantiretroviral treatment, patients whose immune system responds maydevelop an inflammatory response to indolent or residual opportunisticinfections (such as Mycobacterium avium infection,cytomegalovirus, Pneumocystis jiroveci pneumonia,or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’disease, polymyositis, and Guillain-Barré syndrome) have also beenreported to occur in the setting of immune reconstitution, however,the time to onset is more variable, and can occur many months afterinitiation of treatment.
5.6 Fat RedistributionRedistribution/accumulation of body fatincluding central obesity, dorsocervical fat enlargement (buffalohump), peripheral wasting, facial wasting, breast enlargement, and“cushingoid appearance” have been observed in patients receiving antiretroviraltherapy. The mechanism and long-term consequences of these eventsare currently unknown. A causal relationship has not been established.
6 ADVERSE REACTIONS
6.1 Clinical Trial ExperienceBecause clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in clinicalpractice.
Clinical Trial Experience in Adult Patients
The most serious adverse reactions associatedwith Auro-Nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome,toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepaticfailure may be isolated or associated with signs of hypersensitivitywhich may include severe rash or rash accompanied by fever, generalmalaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction .
In controlled clinical trials, symptomatichepatic events regardless of severity occurred in 4% (range 0% to11%) of subjects who received Auro-Nevirapine and 1% of subjects in controlgroups. Female gender and higher CD4+ cellcounts (greater than 250 cells/mm3 in womenand greater than 400 cells/mm3 in men)place patients at increased risk of these events .
Asymptomatic transaminase elevations (AST or ALT greaterthan 5X ULN) were observed in 6% (range 0% to 9%) of subjects whoreceived Auro-Nevirapine and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Auro-Nevirapine are associated with a greater riskof later symptomatic events (6 weeks or more after starting Auro-Nevirapine)and asymptomatic increases in AST or ALT.
Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Auro-Nevirapine than in controls.
The most common clinical toxicity of VIRAMUNEis rash, which can be severe or life-threatening . Rash occurs most frequentlywithin the first 6 weeks of therapy. Rashes are usually mild to moderate,maculopapular erythematous cutaneous eruptions, with or without pruritus,located on the trunk, face and extremities. In controlled clinicaltrials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes werereported in 13% of subjects receiving Auro-Nevirapine compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Auro-Nevirapine recipients compared to less than 1%of subjects receiving placebo. Women tend to be at higher risk fordevelopment of VIRAMUNE-associated rash .
Treatment-related, adverse experiences of moderate orsevere intensity observed in greater than 2% of subjects receivingVIRAMUNE in placebo-controlled trials are shown in Table 2.
Liver enzyme test abnormalities(AST, ALT) were observed more frequently in subjects receiving VIRAMUNEthan in controls (Table 3). Asymptomatic elevations in GGT occur frequentlybut are not a contraindication to continue Auro-Nevirapine therapy in theabsence of elevations in other liver enzyme tests. Other laboratoryabnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) wereobserved with similar frequencies in clinical trials comparing VIRAMUNEand control regimens.
Adverse events were assessed in BI Trial 1100.1032 (ACTG245), a double-blind, placebo-controlled trial of Auro-Nevirapine (n=305)in which pediatric subjects received combination treatment with Auro-Nevirapine. In this trial two subjects were reported to experience Stevens-Johnsonsyndrome or Stevens-Johnson/toxic epidermal necrolysis transitionsyndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180),an open-label trial of Auro-Nevirapine (n=37) in which subjects were followedfor a mean duration of 33.9 months (range: 6.8 months to 5.3 years,including long-term follow-up in 29 of these subjects in trial BI1100.892). The most frequently reported adverse events related toVIRAMUNE in pediatric subjects were similar to those observed in adults,with the exception of granulocytopenia, which was more commonly observedin children receiving both zidovudine and Auro-Nevirapine. Cases of allergicreaction, including one case of anaphylaxis, were also reported.
The safety of Auro-Nevirapine was also examinedin BI Trial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naïve subjectsbetween 3 months and 16 years of age received combination treatmentwith Auro-Nevirapine oral suspension, lamivudine and zidovudine for 48 weeks . Rash (all causality) was reported in 21% of the subjects,4 (3%) of whom discontinued drug due to rash. All 4 subjects experiencedthe rash early in the course of therapy (less than 4 weeks) and resolvedupon Auro-Nevirapine discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) .
Safety information on use of Auro-Nevirapine in combinationtherapy in pediatric subjects 2 weeks to less than 3 months of agewas assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopeniawas reported more frequently in this age group compared to the olderpediatric age groups and adults.
6.2 Post-Marketing ExperienceIn addition to the adverse events identified duringclinical trials, the following adverse reactions have been identifiedduring post-approval use of Auro-Nevirapine. Because these reactions arereported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establisha causal relationship to drug exposure.
Body as a Whole: fever,somnolence, drug withdrawal , redistribution/accumulationof body fat
Liver and Biliary: jaundice,fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
Hematology: anemia, eosinophilia, neutropenia
Investigations: decreased serum phosphorus
Musculoskeletal: arthralgia, rhabdomyolysis associatedwith skin and/or liver reactions
Skin and Appendages: allergicreactions including anaphylaxis, angioedema, bullous eruptions, ulcerativestomatitis and urticaria have all been reported. In addition, hypersensitivitysyndrome and hypersensitivity reactions with rash associated withconstitutional findings such as fever, blistering, oral lesions, conjunctivitis,facial edema, muscle or joint aches, general malaise, fatigue, orsignificant hepatic abnormalities, drug reaction with eosinophiliaand systemic symptoms (DRESS) plus one or more of thefollowing: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and/or renal dysfunction have been reported.
In post-marketing surveillance anemia has been morecommonly observed in children although development of anemia due toconcomitant medication use cannot be ruled out.
7 DRUG INTERACTIONSAuro-Nevirapine is principally metabolized bythe liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapineis known to be an inducer of these enzymes. As a result, drugs thatare metabolized by these enzyme systems may have lower than expectedplasma levels when co-administered with Auro-Nevirapine.
The specific pharmacokinetic changes that occur withco-administration of Auro-Nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments aboutpossible dosage modifications based on established drug interactionsare listed in Table 4. The data in Tables 4 and 5 are based on theresults of drug interaction trials conducted in HIV-1 seropositivesubjects unless otherwise indicated. In addition to established druginteractions, there may be potential pharmacokinetic interactionsbetween Auro-Nevirapine and other drug classes that are metabolized bythe cytochrome P450 system. These potential drug interactions arealso listed in Table 4. Although specific drug interaction trialsin HIV-1 seropositive subjects have not been conducted for some classesof drugs listed in Table 4, additional clinical monitoring may bewarranted when co-administering these drugs.
The in vitro interaction between nevirapineand the antithrombotic agent warfarin is complex. As a result, whengiving these drugs concomitantly, plasma warfarin levels may changewith the potential for increases in coagulation time. When warfarinis co-administered with Auro-Nevirapine, anticoagulation levels shouldbe monitored frequently.
8 USE IN SPECIFIC POPULATIONS
8.1 PregnancyPregnancy ExposureRegistry
There is a pregnancy exposure registrythat monitors pregnancy outcomes in women exposed to Auro-Nevirapine duringpregnancy. Healthcare providers are encouraged to register patientsby calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Availabledata from the APR show no difference in the risk of overall majorbirth defects for Auro-Nevirapine compared with the background rate formajor birth defects of 2.7% in the U.S. reference population of theMetropolitan Atlanta Congenital Defects Program (MACDP) . The rate of miscarriageis not reported in the APR. The estimated background rate of miscarriagein clinically recognized pregnancies in the U.S. general populationis 15-20%. The background risk of birth defects and miscarriage forthe indicated population is unknown. Methodological limitations ofthe APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women andinfants from a limited geographic area, and does not include outcomesfor births that occurred at <20 weeks gestation.
In literature reports, immediate-releasenevirapine exposure (Cmin) can be up to 29%lower during pregnancy. However, as this reduction was not found tobe clinically meaningful, dose adjustment is not necessary .
There is a risk for severehepatic events in pregnant women exposed to Auro-Nevirapine . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Auro-Nevirapine during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Auro-Nevirapine approximatelyequal (rats) and 50% higher (rabbits) than the exposure in humansat the recommended 400 mg daily dose.
Maternal adverse reactions
Severe hepatic events, including fatalities,have been reported in pregnant women receiving chronic Auro-Nevirapine therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4+ cellcounts greater than 250 cells/mm3 shouldnot initiate Auro-Nevirapine unless the benefit outweighs the risk. It isunclear if pregnancy augments the risk observed in non-pregnant women .
Based on prospective reportsto the APR of over 2600 exposures to Auro-Nevirapine during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Auro-Nevirapine and overall birth defectscompared with the background birth defect rate of 2.7% in the U.S.reference population of the MACDP. The prevalence of birth defectsin live births was 2.8% (95% CI: 1.9 %, 4.0%) following first trimesterexposure to nevirapine- containing regimens and 3.2% (95% CI: 2.4%,4.3%) for second/third trimester exposure to nevirapine-containingregimens.
Thereare several literature reports of chronic administration of immediate-releasenevirapine during pregnancy, in which Auro-Nevirapine pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Auro-Nevirapine Cmin duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.
Auro-Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25 and 50 mg per kg per day) and rabbits(at 0, 30, 100, and 300 mg per kg per day) through organogenesis (ongestation days 7 through 16, and 6 through 18, respectively). Noadverse developmental effects were observed at doses producing systemicexposures (AUC) approximately equivalent to (rats) or approximately50% higher (rabbits) than human exposure at the recommended dailydose. In rats, decreased fetal body weights were observed at a maternallytoxic dose at an exposure approximately 50% higher than the recommendeddaily dose.
8.2 LactationRisk Summary
The Centers forDisease Control and Prevention recommend that HIV-1 infected mothersin the United States not breastfeed their infants to avoid riskingpostnatal transmission of HIV-1 infection. Published data report thatnevirapine is present in human milk . There are limited dataon the effects of Auro-Nevirapine on the breastfed infant. There is noinformation on the effects of Auro-Nevirapine on milk production. Becauseof the potential for HIV-1 transmission (in HIV-negative infants),(2) developing viral resistance (in HIV-positive infants), and (3)serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving Auro-Nevirapine.
Based on five publications,immediate-release Auro-Nevirapine was excreted in breast-milk at medianconcentrations ranging from 4080 to 6795 ng/mL, and the median maternalbreast-milk to maternal plasma concentration ratio range was 59 to88%. Reported infant Auro-Nevirapine median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Auro-Nevirapine doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Auro-Nevirapine dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Auro-Nevirapine through breastmilk.
8.3 Females and Males of Reproductive PotentialInfertility
Limitedhuman data are insufficient to determine the risk of infertility inhumans. Based on results from animal fertility studies conducted inrats, Auro-Nevirapine may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible .
8.4 Pediatric UseThe safety, pharmacokinetic profile, and virologic and immunologicresponses of Auro-Nevirapine have been evaluated in HIV-1 infected pediatricsubjects age 3 months to 18 years . The safety and pharmacokineticprofile of Auro-Nevirapine has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than 3 months .
The most frequently reported adverse events relatedto Auro-Nevirapine in pediatric subjects were similar to those observed inadults, with the exception of granulocytopenia, which was more commonlyobserved in children receiving both zidovudine and Auro-Nevirapine .
8.5 Geriatric UseClinical trials of Auro-Nevirapine did not include sufficient numbers ofsubjects aged 65 and older to determine whether elderly subjects responddifferently from younger subjects. In general, dose selection foran elderly patient should be cautious, reflecting the greater frequencyof decreased hepatic, renal or cardiac function, and of concomitantdisease or other drug therapy.
8.6 Renal ImpairmentIn subjects with renal impairment, there were no significant changes in the pharmacokineticsof Auro-Nevirapine. Auro-Nevirapine is extensively metabolized by the liverand Auro-Nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis;however, the clinical significance of this accumulation is not known. No adjustment in Auro-Nevirapine dosing is required in patients with CrCLgreater than or equal to 20 mL per min. The pharmacokinetics of nevirapinehave not been evaluated in patients with CrCl less than 20 mL permin. In patients undergoing chronic hemodialysis, an additional 200mg dose following each dialysis treatment is indicated [seeDosage and Administration (2.4) andClinical Pharmacology (12.3)].
8.7 Hepatic ImpairmentBecause increased Auro-Nevirapine levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer Auro-Nevirapine to patients with moderate or severe(Child-Pugh Class B or C, respectively) hepatic impairment .
10 OVERDOSAGEThereis no known antidote for Auro-Nevirapine overdosage. Cases of Auro-Nevirapine overdoseat doses ranging from 800 to 1800 mg per day for up to 15 days havebeen reported. Patients have experienced events including edema, erythemanodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates,rash, vertigo, vomiting, and weight decrease. All events subsidedfollowing discontinuation of Auro-Nevirapine.
11 DESCRIPTIONAuro-Nevirapine is the brand name for Auro-Nevirapine,a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activityagainst Human Immunodeficiency Virus Type 1 (HIV-1). Auro-Nevirapine isstructurally a member of the dipyridodiazepinone chemical class ofcompounds.
The chemical nameof Auro-Nevirapine is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-one. Auro-Nevirapine is a white to off-whitecrystalline powder with the molecular weight of 266.30 and the molecularformula C15H14N4O. Auro-Nevirapine has the following structural formula:
VIRAMUNETablets are for oral administration. Each tablet contains 200 mg ofnevirapine and the inactive ingredients microcrystalline cellulose,lactose monohydrate, povidone, sodium starch glycolate, colloidalsilicon dioxide, and magnesium stearate.
Auro-Nevirapine Oral Suspension is for oral administration. Each 5 mL of Auro-Nevirapine suspension contains 50 mg of Auro-Nevirapine (asnevirapine hemihydrate). The suspension also contains the followingexcipients: carbomer 934P, methylparaben, propylparaben, sorbitol,sucrose, polysorbate 80, sodium hydroxide and purified water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionAuro-Nevirapine is an antiretroviral drug .
Auro-Nevirapine is readily absorbed after oral administrationin healthy volunteers and in adults with HIV-1 infection. Absolutebioavailability in 12 healthy adults following single-dose administrationwas 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oralsolution. Peak plasma Auro-Nevirapine concentrations of 2 ± 0.4 mcg/mL(7.5 micromolar) were attained by 4 hours following a single 200 mgdose. Following multiple doses, Auro-Nevirapine peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough Auro-Nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),(n=242) were attained at 400 mg per day. Auro-Nevirapine tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When Auro-Nevirapine (200 mg) was administered to24 healthy adults (12 female, 12 male), with either a high-fat breakfast(857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of Auro-Nevirapine absorption (AUC)was comparable to that observed under fasting conditions. In a separatetrial in HIV-1 infected subjects (n=6), Auro-Nevirapine steady-state systemicexposure (AUCτ) was not significantly alteredby didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or didanosine.
Auro-Nevirapine is highly lipophilic and is essentiallynonionized at physiologic pH. Following intravenous administrationto healthy adults, the apparent volume of distribution (Vdss) of nevirapinewas 1.21 ± 0.09 L/kg, suggesting that Auro-Nevirapine is widely distributedin humans. Auro-Nevirapine readily crosses the placenta and is also foundin breast milk . Auro-Nevirapine is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Auro-Nevirapine concentrations in human cerebrospinal fluid(n=6) were 45% (±5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.
In vivo trials in humansand in vitro studies with human liver microsomeshave shown that Auro-Nevirapine is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Auro-Nevirapine is mediated primarily by cytochromeP450 (CYP) isozymes from the CYP3A and CYP2B6 families, although otherisozymes may have a secondary role. In a mass balance/excretion trialin eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeleddose was recovered, with urine (81.3 ± 11.1%) representing the primaryroute of excretion compared to feces (10.1 ± 1.5%). Greater than 80%of the radioactivity in urine was made up of glucuronide conjugatesof hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronideconjugation, and urinary excretion of glucuronidated metabolites representthe primary route of Auro-Nevirapine biotransformation and eliminationin humans. Only a small fraction (less than 5%) of the radioactivityin urine (representing less than 3% of the total dose) was made upof parent compound; therefore, renal excretion plays a minor rolein elimination of the parent compound.
Auro-Nevirapine is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Auro-Nevirapine induces CYP3A and CYP2B6by approximately 20-25%, as indicated by erythromycin breath testresults and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediatedmetabolism leads to an approximately 1.5- to 2-fold increase in theapparent oral clearance of Auro-Nevirapine as treatment continues froma single dose to two-to-four weeks of dosing with 200-400 mg per day. Autoinduction also results in a corresponding decrease in the terminalphase half-life of Auro-Nevirapine in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.
HIV-1 seronegative adults with mild (CrCL50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), orsevere (CrCL less than 30 mL per min; n=4) renal impairment receiveda single 200 mg dose of Auro-Nevirapine in a pharmacokinetic trial. Thesesubjects did not require dialysis. The trial included six additionalsubjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate orsevere), there were no significant changes in the pharmacokineticsof Auro-Nevirapine. However, subjects requiring dialysis exhibited a 44%reduction in Auro-Nevirapine AUC over a one-week exposure period. Therewas also evidence of accumulation of Auro-Nevirapine hydroxy-metabolitesin plasma in subjects requiring dialysis. An additional 200 mg dosefollowing each dialysis treatment is indicated .
In a steady-state trial comparing 46 subjectswith mild (n=17; expansion of some portal areas; Ishak Score 1-2),moderate (n=20; expansion of most portal areas with occasional portal-to-portaland portal-to-central bridging; Ishak Score 3-4), or severe (n=9;marked bridging with occasional cirrhosis without decompensation indicatingChild-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment,the multiple dose pharmacokinetic disposition of Auro-Nevirapine and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Auro-Nevirapine troughconcentrations above 9,000 mcg per mL (2-fold the usual mean trough).Therefore, patients with hepatic impairment should be monitored carefullyfor evidence of drug-induced toxicity . The subjects studied werereceiving antiretroviral therapy containing Auro-Nevirapine 200 mg twicedaily for at least 6 weeks prior to pharmacokinetic sampling, witha median duration of therapy of 3.4 years.
In a pharmacokinetic trial where HIV-1 negative cirrhoticsubjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;n=4) hepatic impairment received a single 200 mg dose of Auro-Nevirapine,a significant increase in the AUC of Auro-Nevirapine was observed in onesubject with Child-Pugh B and ascites suggesting that patients withworsening hepatic function and ascites may be at risk of accumulatingnevirapine in the systemic circulation. Because Auro-Nevirapine inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.
Do not administer Auro-Nevirapine to patientswith moderate or severe (Child-Pugh Class B or C, respectively) hepaticimpairment .
In the multinational 2NN trial, a population pharmacokineticsubstudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of Auro-Nevirapine thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Auro-Nevirapine, the effect of gender cannotsolely be explained by body size.
An evaluation of Auro-Nevirapine plasma concentrations (pooleddata from several clinical trials) from HIV-1-infected subjects (27Black, 24 Hispanic, 189 Caucasian) revealed no marked difference innevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mLCaucasian) with long-term Auro-Nevirapine treatment at 400 mg per day. However, the pharmacokinetics of Auro-Nevirapine have not been evaluatedspecifically for the effects of ethnicity.
Black subjects (n=80/group) in Trial 1100.1486 showedapproximately 30% to 35% higher trough concentrations than Caucasiansubjects (250-325 subjects/group) in both immediate-release VIRAMUNEand Auro-Nevirapine XR treatment groups over 96 weeks of treatment at 400mg per day.
Auro-Nevirapine pharmacokinetics in HIV-1-infectedadults do not appear to change with age (range 18–68 years); however,nevirapine has not been extensively evaluated in subjects beyond theage of 55 years .
Pharmacokinetic data for Auro-Nevirapine havebeen derived from two sources: a 48-week pediatric trial in SouthAfrica (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïvesubjects aged 3 months to 16 years; and a consolidated analysis offive Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising495 subjects aged 14 days to 19 years.
BI Trial 1100.1368 studied the safety, efficacy, andpharmacokinetics of a weight-based and a body surface area (BSA)-baseddosing regimen of Auro-Nevirapine. In the weight-based regimen, pediatricsubjects up to 8 years of age received a dose of 4 mg/kg once dailyfor two weeks followed by 7 mg per kg twice daily thereafter. Subjects8 years and older were dosed 4 mg/kg once daily for two weeks followedby 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatricsubjects received 150 mg/m2 once dailyfor two weeks followed by 150 mg/m2 twicedaily thereafter . Dosing of Auro-Nevirapine at150 mg/m2 BID (after a two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough Auro-Nevirapine concentrations between 4-6 mcg per mL (astargeted from adult data). In addition, the observed trough nevirapineconcentrations were comparable between the two dosing regimens studied(BSA- and weight-based methods).
The consolidated analysis of Pediatric AIDS Clinical Trials Group(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluationof pediatric subjects less than 3 months of age (n=17). The plasmanevirapine concentrations observed were within the range observedin adults and the remainder of the pediatric population, but weremore variable between subjects, particularly in the second month ofage. For dose recommendations for pediatric patients [seeDosage and Administration (2.2)].
Auro-Nevirapine induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of Auro-Nevirapine anddrugs primarily metabolized by CYP3A or CYP2B6 may result in decreasedplasma concentrations of these drugs and attenuate their therapeuticeffects.
While primarily an inducerof cytochrome P450 3A and 2B6 enzymes, Auro-Nevirapine may also inhibitthis system. Among human hepatic cytochrome P450s, Auro-Nevirapine wascapable in vitro of inhibiting the 10-hydroxylationof (R)-warfarin (CYP3A). The estimated Ki forthe inhibition of CYP3A was 270 micromolar, a concentration that isunlikely to be achieved in patients as the therapeutic range is lessthan 25 micromolar. Therefore, Auro-Nevirapine may have minimal inhibitoryeffect on other substrates of CYP3A.
Auro-Nevirapine does not appear to affect the plasma concentrationsof drugs that are substrates of other CYP450 enzyme systems, suchas 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.
Table 5 contains the results of drug interactiontrials performed with Auro-Nevirapine and other drugs likely to be co-administered. The effects of Auro-Nevirapine on the AUC, Cmax, andCmin of co-administered drugs are summarized.
Administration of rifampinhad a clinically significant effect on Auro-Nevirapine pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein Auro-Nevirapine exposure, based on a comparison to historic data . The effect of other drugs listed in Table 5 on Auro-Nevirapine pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and Auro-Nevirapine.
Mechanismof ActionAuro-Nevirapine is a non-nucleoside reverse transcriptase inhibitor of HIV-1. Auro-Nevirapine binds directly to reverse transcriptase (RT)and blocks the RNA-dependent and DNA-dependent DNA polymerase activitiesby causing a disruption of the enzyme's catalytic site. The activityof Auro-Nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerasesα, β, γ, or δ) are not inhibited by Auro-Nevirapine.
AntiviralActivityThe antiviral activity of Auro-Nevirapine has been measured in a varietyof cell lines including peripheral blood mononuclear cells, monocyte-derivedmacrophages, and lymphoblastoid cell lines. In an assay using humanembryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of Auro-Nevirapine was 90 nM againsta panel of 2923 wild-type isolates of HIV-1 that were primarily (93%)clade B clinical isolates from the United States. The 99th percentile EC50 value was470 nM in this trial. The median EC50 valuewas 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1clades A, B, C, D, F, G, and H, and circulating recombinant formsCRF01_AE, CRF02_AG and CRF12_BF. Auro-Nevirapine had no antiviral activityin cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates(n=3) replicating in cord blood mononuclear cells. Auro-Nevirapine in combinationwith efavirenz exhibited strong antagonistic anti-HIV-1 activity incell culture and was additive to antagonistic with the protease inhibitorritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activityof Auro-Nevirapine was not antagonistic in combination with the NRTIs abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine,and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity ofnevirapine was antagonized by the anti-HBV drug adefovir and by theanti-HCV drug ribavirin in cell culture.
ResistanceHIV-1 isolateswith reduced susceptibility to Auro-Nevirapine emergein cell culture. Genotypic analysis showed mutations in the HIV-1RT gene encoding Y181C and/or V106A substitutions depending upon thevirus strain and cell line employed. Time to emergence of nevirapineresistance in cell culture was not altered when selection includednevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolatesfrom treatment-naïve subjects receiving either Auro-Nevirapine (n=24) ornevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trialsranging from 1 to 12 weeks or longer. After 1 week of Auro-Nevirapine monotherapy,isolates from 3/3 subjects had decreased susceptibility to nevirapinein cell culture. One or more of the RT mutations resulting in aminoacid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A weredetected in HIV-1 isolates from some subjects as early as 2 weeksafter therapy initiation. By week eight of Auro-Nevirapine monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Auro-Nevirapine in cell culturecompared to baseline, and had one or more of the nevirapine-associatedRT resistance substitutions. Nineteen of these subjects (80%) hadisolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral-naïvesubjects experiencing virologic failure (n=71) receiving nevirapineonce daily (n=25) or twice daily (n=46) in combination with lamivudineand stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25and 23/46 subjects, respectively, contained one or more of the followingNNRTI resistance-associated substitutions: Y181C, K101E, G190A/S,K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.
For trial 1100.1486, genotypic analysiswas performed for baseline and on-therapy isolates from 23 and 34subjects who experienced virologic failure in the Auro-Nevirapine XR andimmediate-release Auro-Nevirapine treatment group, respectively. Nevirapineresistance-associated substitutions developed in the on-therapy isolatesof 78% (18/23) of the subjects who had virologic failures in the VIRAMUNEXR treatment group and 88% (30/34) of the subjects in the immediate-releaseVIRAMUNE treatment group, respectively. The Y181C Auro-Nevirapine resistance-associatedsubstitution was found alone or in combination with other nevirapineresistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I,Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjectsfailing Auro-Nevirapine XR treatment and 25 subjects failing immediate-releaseVIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNEXR treatment group developed a novel amino acid substitution Y181Iand isolates from another subject in the immediate-release VIRAMUNEtreatment group developed a novel amino acid substitution Y188N. Phenotypicanalysis showed that Y188N and Y181I substitutions conferred 103-and 22-fold reductions in susceptibility to Auro-Nevirapine, respectively.
Cross-resistanceRapid emergenceof HIV-1 strains which are cross-resistant to NNRTIs has been observedin cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistantto the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred22- and 7-fold reductions in susceptibility to delavirdine and efavirenz,respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdineand etravirine 3- and 8-fold, respectively, but did not reduce susceptibilityto efavirenz. However, nevirapine-resistant isolates were susceptibleto the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptibleto Auro-Nevirapine in cell culture.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis
Long-term carcinogenicity studiesin mice and rats were carried out with Auro-Nevirapine. Mice were dosedwith 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomasand carcinomas were increased at all doses in males and at the twohigh doses in females. In studies in which rats were administerednevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years,an increase in hepatocellular adenomas was seen in males at all dosesand in females at the high dose. The systemic exposure at all doses in the two animal studies was lower than that measuredin humans at the 200 mg twice daily dose. The mechanism of the carcinogenicpotential is unknown.
However, in genetic toxicology assays, Auro-Nevirapine showed no evidenceof mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assaysfor gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assaysusing a Chinese hamster ovary cell line and a mouse bone marrow micronucleusassay following oral administration. Given the lack of genotoxic activityof Auro-Nevirapine, the relevance to humans of hepatocellular neoplasmsin nevirapine-treated mice and rats is not known.
Impairment of Fertility
In reproductive toxicologystudies, evidence of impaired fertility was seen in female rats atdoses providing systemic exposure, based on AUC, approximately equivalentto that provided with the recommended clinical dose of Auro-Nevirapine.
13.2 Animal Toxicology and/or PharmacologyAnimal studies have shown that nevirapineis widely distributed to nearly all tissues and readily crosses theblood-brain barrier.
14 CLINICAL STUDIES
14.1 Adult PatientsTrial BI 1090 was a placebo-controlled, double-blind, randomizedtrial in 2249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with Auro-Nevirapine + lamivudine+ background therapy versus lamivudine + background therapy in NNRTI-naïvesubjects. Treatment doses were Auro-Nevirapine, 200 mg daily for two weeksfollowed by 200 mg twice daily or placebo, and lamivudine, 150 mgtwice daily. Other antiretroviral agents were given at approved doses. Initial background therapy was one NRTIin 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs andNRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian,79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copiesper mL (38,291 copies per mL). Prior to entering the trial, 45% hadpreviously experienced an AIDS-defining clinical event. Eighty-ninepercent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Priorto unblinding the trial, the primary endpoint was changed to proportionof subjects with HIV-1 RNA less than 50 copies per mL and not previouslyfailed at 48 weeks. Treatment response and outcomes are shown in Table6.
At two years into the trial, 16% of subjects on Auro-Nevirapine had experiencedclass C CDC events as compared to 21% of subjects on the control arm.
Trial BI 1046 (INCAS) was a double-blind,placebo-controlled, randomized, three-arm trial with 151 HIV-1 infectedsubjects with CD4+ cell counts of 200-600cells/mm3 at baseline. BI 1046 comparedtreatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudineand zidovudine+didanosine. Treatment doses were Auro-Nevirapine at 200 mgdaily for two weeks followed by 200 mg twice daily or placebo, zidovudineat 200 mg three times daily, and didanosine at 125 or 200 mg twicedaily (depending on body weight). The subjects had mean baseline HIV-1RNA of 4.41 log10 copies/mL (25,704 copiesper mL) and mean baseline CD4+ cell countof 376 cells/mm3. The primary endpointwas the proportion of subjects with HIV-1 RNA less than 400 copiesper mL and not previously failed at 48 weeks. The virologic responderrates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine,19% for subjects treated with zidovudine+didanosine, and 0% for subjectstreated with VIRAMUNE+zidovudine.
CD4+ cell counts in the VIRAMUNE+ZDV+ddIgroup increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increaseof 87 cells/mm3 in the ZDV+ddI subjects. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm3 below baseline.
14.2 Pediatric PatientsThe pediatric safety and efficacy of Auro-Nevirapine was examined in BITrial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naïve subjectsbetween 3 months and 16 years of age received Auro-Nevirapine oral suspensionfor 48 weeks. Subjects were divided into 4 age groups (3 months toless than 2 years, 2 to less than 7 years, 7 to less than 12 years,and 12 to less than or equal to 16 years) and randomized to receiveone of two Auro-Nevirapine doses, determined by 2 different dosing methods[body surface area (150 mg/m2) and weight-baseddosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine . The total daily dose of Auro-Nevirapine did not exceed 400 mg in eitherregimen. There were 66 subjects in the body surface area (BSA) dosinggroup and 57 subjects in the weight-based (BW) dosing group.
Baseline demographics included: 49% male;81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjectshad a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37-2279).One hundred and five (85%) completed the 48-week period while 18 (15%)discontinued prematurely. Of the subjects who discontinued prematurely,9 (7%) discontinued due to adverse reactions and 3 (2%) discontinueddue to virologic failure. Overall the proportion of subjects who achievedand maintained an HIV-1 RNA less than 400 copies per mL at 48 weekswas 47% (58/123).
16 HOW SUPPLIED/STORAGEAND HANDLINGVIRAMUNEtablets, 200 mg, are white, oval, biconvex tablets, 9.3 mm x 19.1mm. One side is embossed with “54 193”, with a single bisect separatingthe “54” and “193”. The opposite side has a single bisect.
Auro-Nevirapine tablets are supplied in bottlesof 60 (NDC 0597-0046-60).
Dispensein tight container as defined in the USP/NF.
Auro-Nevirapine oral suspension is a white to off-white preservedsuspension containing 50 mg Auro-Nevirapine (as Auro-Nevirapine hemihydrate)in each 5 mL. Auro-Nevirapine suspension is supplied in plastic bottles withchild-resistant closures containing 240 mL of suspension (NDC 0597-0047-24).
Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Store in a safe place outof the reach of children.
17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approvedpatient labeling (Medication Guide).
Hepatotoxicity and Skin Reactions
Inform patientsof the possibility of severe liver disease or skin reactions associatedwith Auro-Nevirapine that may result in death. Instruct patients developingsigns or symptoms of liver disease or severe skin reactions to discontinueVIRAMUNE and seek medical attention immediately, including performanceof laboratory monitoring. Symptoms of liver disease include fatigue,malaise, anorexia, nausea, jaundice, acholic stools, liver tendernessor hepatomegaly. Symptoms of severe skin or hypersensitivity reactionsinclude rash accompanied by fever, general malaise, fatigue, muscleor joint aches, blisters, oral lesions, conjunctivitis, facial edema,and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes,is essential during the first 18 weeks of therapy with Auro-Nevirapine todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Auro-Nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy,which is the period of greatest risk of hepatic events. Advise patientswith signs and symptoms of hepatitis to discontinue Auro-Nevirapine and seekmedical evaluation immediately. If Auro-Nevirapine is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof Auro-Nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatichepatic events, often associated with rash. Advise patients thatco-infection with hepatitis B or C and/or increased transaminasesat the start of therapy with Auro-Nevirapine are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Auro-Nevirapine)and asymptomatic increases in AST or ALT .
The majority of rashes associatedwith Auro-Nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-inperiod, do not escalate the Auro-Nevirapine dose until the rash resolves. The total duration of the once-daily lead-in dosing period shouldnot exceed 28 days, at which point an alternative regimen may needto be started. Any patient experiencing a rash should have their liverenzymes (AST, ALT) evaluated immediately. Patients with severe rashor hypersensitivity reactions should discontinue Auro-Nevirapine immediatelyand consult a physician. Auro-Nevirapine should not be restarted followingsevere skin rash or hypersensitivity reaction. Women tend to be athigher risk for development of VIRAMUNE-associated rash [seeWarnings and Precautions (5.2)].
Administrationand Missed Dosage
Inform patients to take Auro-Nevirapine everyday as prescribed. Advise patients not to alter the dose withoutconsulting their doctor. If a dose is missed, patients should takethe next dose as soon as possible. However, if a dose is skipped,the patient should not double the next dose.
To avoid overdose, inform patients thatthey should never take immediate-release Auro-Nevirapine and extended-releaseVIRAMUNE XR concomitantly.
Auro-Nevirapine may interactwith some drugs; therefore, advise patients to report to their doctorthe use of any other prescription, non-prescription medication orherbal products, particularly St. John's wort .
Immune Reconstitution Syndrome
Advise patientsto inform their healthcare provider immediately of any signs or symptomsof infection, as inflammation from previous infection may occur soonafter combination antiretroviral therapy, including when VIRAMUNEis started .
Inform patientsthat redistribution or accumulation of body fat may occur in patientsreceiving antiretroviral therapy and that the cause and long-termhealth effects of these conditions are not known at this time .
Advise patients that there is a pregnancyregistry that monitors pregnancy outcomes in women exposed to VIRAMUNEduring pregnancy .
Instruct women with HIV-1 infectionnot to breastfeed because HIV-1 can be passed to the baby in the breastmilk .
Advise females of reproductivepotential of the potential for impaired fertility from Auro-Nevirapine
Boehringer IngelheimPharmaceuticals, Inc.
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viramune-tablets-and-oral-suspension-qr-code viramune-xr-qr-code Auro-Nevirapine Oral Suspension 50 mg/5mL
Auro-Nevirapine Oral Suspension 50 mg/5mL Auro-Nevirapine Oral Suspension 50 mg/5mL
Auro-Nevirapine pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Auro-Nevirapine available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Auro-Nevirapine destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Auro-Nevirapine Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Auro-Nevirapine pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Auro-Nevirapine?
Depending on the reaction of the Auro-Nevirapine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Auro-Nevirapine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Auro-Nevirapine addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Auro-Nevirapine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Auro-Nevirapine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology