DRUGS & SUPPLEMENTS

Ritvir

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Ritvir uses


WARNING: LIFE-THREATENING HEPATOTOXICITY and SKINREACTIONS

HEPATOTOXICITY:

Severe, life-threatening,and in some cases fatal hepatotoxicity, particularly in the first18 weeks, has been reported in patients treated with Ritvir. 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 Ritvir in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Ritvir 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 Ritvir 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 Ritvir and seek medical evaluation immediately .

SKINREACTIONS:

Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Ritvir. 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 Ritvir 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 Ritvir 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 Ritvir 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 Ritvir 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.

  • Fatal and non-fatal hepatotoxicity have been reportedin patients taking Ritvir. Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart Ritvir after recovery. (5.1)
  • Fatal and non-fatal skin reactions, including Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionshave been reported. Discontinue immediately if severe skin reactions,hypersensitivity reactions, or any rash with systemic symptoms occur. Check transaminase levels immediately for all patients who developa rash in the first 18 weeks of treatment. Do not restart VIRAMUNEafter recovery. (5.2)
  • Monitoring during the first 18 weeks of therapy isessential. Extra vigilance is warranted during the first 6 weeksof therapy, which is the period of greatest risk of these events. (5.1, 5.2)
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1 INDICATIONS AND USAGE

Ritvir 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, Ritvir is not recommended to be initiated,unless the benefit outweighs the risk, in:

  • adult females with CD4+ cellcounts greater than 250 cells/mm3 or
  • adult males with CD4+ cell countsgreater than 400 cells/mm3 [seeWarnings and Precautions (5.1)].
  • Ritvir is an NNRTI indicated in combination with otherantiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients 15 days andolder. (1)
Limitations of Use:

  • adult females with CD4+ cellcounts greater than 250 cells/mm3
  • adult males with CD4+ cell countsgreater than 400 cells/mm3 (1, 5.1)

2 DOSAGE AND ADMINISTRATION

  • The 14 day lead in period must be strictly followed; ithas been demonstrated to reduce the frequency of rash
  • If any patient experiences rash during the 14-day lead-inperiod, do not increase dose until the rash has resolved. Do not continuethe lead-in dosing regimen beyond 28 days. (2.4)
  • If dosing is interrupted for greater than 7 days, restart14-day lead-in dosing. (2.4)
*Total daily dose should not exceed 400 mg for anypatient.
Adults

(≥16 yrs)

Pediatric Patients*

(≥15 days)

First 14 days 200 mg once daily 150 mg/m2 once daily
After 14 days 200 mg twice daily 150 mg/m2 twice daily

2.1 Adult Patients

The recommended dose for Ritvir 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 Ritvir 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 Patients

The recommended oral dose for pediatricpatients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400mg for any patient.

BSA range Volume (mL)
0.06 – 0.12 1.25
0.12 – 0.25 2.5
0.25 – 0.42 5
0.42 – 0.58 7.5
0.58 – 0.75 10
0.75 – 0.92 12.5
0.92 – 1.08 15
1.08 – 1.25 17.5
1.25+ 20
Ritvir suspension should be shakengently prior to administration. It is important to administer theentire measured dose of suspension by using an oral dosing syringeor dosing cup. An oral dosing syringe is recommended, particularlyfor volumes of 5 mL or less. If a dosing cup is used, it should bethoroughly rinsed with water and the rinse should also be administeredto the patient.

Formula Image

2.3 Monitoring ofPatients

Intensive clinicaland laboratory monitoring, including liver enzyme tests, is essentialat baseline and during the first 18 weeks of treatment with Ritvir. 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 Adjustment

Patients 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 Ritvir. Do not restartVIRAMUNE after recovery .

Patients with Dose Interruption

For patients who interrupt Ritvir 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 Ritvir dosing. The pharmacokinetics of Ritvir have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Ritvir following each dialysis treatment is indicatedin patients requiring dialysis. Ritvir metabolites may accumulatein patients receiving dialysis; however, the clinical significanceof this accumulation is not known .

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3 DOSAGE FORMS ANDSTRENGTHS

Tablets: 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

  • 200 mg tablets (3)
  • 50 mg per 5 mL oral suspension (3)

4 CONTRAINDICATIONS

Ritvir is contraindicated:

  • in patients with moderate or severe (Child-Pugh Class Bor C, respectively) hepatic impairment .
  • for use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens .
  • Patients with moderate or severe (Child-Pugh Class B orC, respectively) hepatic impairment. (4, 5.1, 8.7)
  • Use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens, an unapproved use. (4, 5.1)

5 WARNINGS AND PRECAUTIONS

  • Monitor patients for immune reconstitution syndrome andfat redistribution.

5.1 Hepatotoxicityand Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity,including fulminant and cholestatic hepatitis, hepatic necrosis andhepatic failure, have been reported in patients treated with Ritvir. 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 Ritvir 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 Ritvir 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 Ritvir 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 Ritvir 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 Ritvir 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 Ritvir therapy are at higher risk for symptomatic hepatic eventswith Ritvir. 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 Ritvir are associated with a greater riskof later symptomatic events (6 weeks or more after starting Ritvir)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 Ritvir for occupational and non-occupational PEP is contraindicated .

Increased Ritvir 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 Ritvir to patients with moderate or severe (Child-PughClass B or C, respectively) hepatic impairment .

5.2 Skin Reactions

Severe 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 Ritvir use. In controlled clinical trials, Grade 3 and 4 rasheswere reported during the first 6 weeks in 2% of Ritvir recipientscompared to less than 1% of placebo subjects.

Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions must permanently discontinue Ritvir and seekmedical evaluation immediately. Do not restart Ritvir 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 Ritvir treatment. In addition, the 14-day lead-inperiod with Ritvir 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 Ritvir 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 Ritvir if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Ritvir 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 Ritvir treatment after theonset of rash may result in a more serious reaction.

Women appear to be at higher risk than men of developingrash with Ritvir.

In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Ritvir 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 Resistance

Ritvir 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 Ritvir is administered as monotherapy. The choice of new antiretroviral agents to be used in combinationwith Ritvir should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of Ritvir should be taken into account;if antiretrovirals with shorter half-lives than Ritvir are stoppedconcurrently, low plasma concentrations of Ritvir alone may persistfor a week or longer and virus resistance may subsequently develop .

5.4 Drug Interactions

See 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 Ritvir, isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Ritvir and lead to loss of virologic responseand possible resistance to Ritvir or to the class of NNRTIs. Co-administrationof Ritvir and efavirenz is not recommended as this combination hasbeen associated with an increase in adverse reactions and no improvementin efficacy.

5.5 Immune ReconstitutionSyndrome

Immune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including Ritvir. 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 Redistribution

Redistribution/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.

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6 ADVERSE REACTIONS

  • The most common adverse reaction is rash. In adults theincidence of rash is 15% versus 6% with placebo, with Grade 3/4 rashoccurring in 2% of subjects.
  • In pediatric subjects the incidence of rash (all causality)was 21%. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because 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 Ritvir 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 .

Hepatic Reaction

In controlled clinical trials, symptomatichepatic events regardless of severity occurred in 4% (range 0% to11%) of subjects who received Ritvir 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 Ritvir and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Ritvir are associated with a greater riskof later symptomatic events (6 weeks or more after starting Ritvir)and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Ritvir than in controls.

Skin Reaction

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 Ritvir compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Ritvir 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.

1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3.

2 Backgroundtherapy included ZDV and ZDV+ddI; Ritvir monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.

Trial 10901 Trials 1037, 1038, 10462
Ritvir Placebo Ritvir Placebo
(n=1121) (n=1128) (n=253) (n=203)
Median exposure (weeks) 58 52 28 28
Any adverse event 15% 11% 32% 13%
Rash 5 2 7 2
Nausea 1 1 9 4
Granulocytopenia 2 3 <1 0
Headache 1 <1 4 1
Fatigue <1 <1 5 4
Diarrhea <1 1 2 1
Abdominal pain <1 <1 2 0
Myalgia <1 0 1 2
Laboratory Abnormalities

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 Ritvir 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.

1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3.

2 Backgroundtherapy included ZDV and ZDV+ddI; Ritvir monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.

Trial 10901 Trials 1037, 1038, 10462
Ritvir Placebo Ritvir Placebo
Laboratory Abnormality (n=1121) (n=1128) (n=253) (n=203)
Blood Chemistry
SGPT (ALT) >250 U/L 5 4 14 4
SGOT (AST) >250 U/L 4 3 8 2
Bilirubin >2.5 mg/dL 2 2 2 2
Hematology
Hemoglobin <8.0 g/dL 3 4 0 0
Platelets <50,000/mm3 1 1 <1 2
Neutrophils <750/mm3 13 14 4 1
ClinicalTrial Experience in Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG245), a double-blind, placebo-controlled trial of Ritvir (n=305)in which pediatric subjects received combination treatment with Ritvir. 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 Ritvir (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 Ritvir. Cases of allergicreaction, including one case of anaphylaxis, were also reported.

The safety of Ritvir 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 Ritvir 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 Ritvir discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) .

Safety information on use of Ritvir 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 Experience

In addition to the adverse events identified duringclinical trials, the following adverse reactions have been identifiedduring post-approval use of Ritvir. 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

Gastrointestinal: vomiting

Liver and Biliary: jaundice,fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: anemia, eosinophilia, neutropenia

Investigations: decreased serum phosphorus

Musculoskeletal: arthralgia, rhabdomyolysis associatedwith skin and/or liver reactions

Neurologic: paraesthesia

Skin and Appendages: allergicreactions including anaphylaxis, angioedema, bullous eruptions, ulcerativestomatitis and urticaria have all been reported. In addition, hypersensitivitysyndrome and hypersensitivity reactions with rash associated withconstitutional findings such as fever, blistering, oral lesions, conjunctivitis,facial edema, muscle or joint aches, general malaise, fatigue, orsignificant hepatic abnormalities, drug reaction with eosinophiliaand systemic symptoms (DRESS) 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.

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7 DRUG INTERACTIONS

Ritvir 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 Ritvir.

The specific pharmacokinetic changes that occur withco-administration of Ritvir 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 Ritvir 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 Ritvir, anticoagulation levels shouldbe monitored frequently.

* The interactionbetween Ritvir and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of

Ritvir or Concomitant Drug

Clinical Comment
HIV Antiviral Agents:Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir

↑ Ritvir

Do not co-administer Ritvir withatazanavir because Ritvir substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity dueto increased Ritvir exposures.

Fosamprenavir*

↓ Amprenavir

↑ Ritvir

Co-administration of Ritvir and fosamprenavirwithout ritonavir is not recommended.

Fosamprenavir/Ritonavir*

↓ Amprenavir

↑ Ritvir

No dosing adjustments are required when Ritvir is co-administeredwith 700/100 mg of fosamprenavir/ritonavir twice daily. The combinationof Ritvir administered with fosamprenavir/ritonavir once dailyhas not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavirand Ritvir with respect to efficacy and safety have not been established.

Lopinavir/Ritonavir*

↓Lopinavir

Dosing in adult patients:

A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twicedaily or 533/133 mg (6.5 mL) oral solution twice daily is recommendedwhen used in combination with Ritvir. Neither lopinavir/ritonavirtablets nor oral solution should be administered once daily in combinationwith Ritvir.

Dosing in pediatric patients:

Please refer to the Kaletra® prescribing information for dosing recommendations based on bodysurface area and body weight. Neither lopinavir/ritonavir tabletsnor oral solution should be administered once daily in combinationwith Ritvir.

Nelfinavir*

↓Nelfinavir M8 Metabolite

↓NelfinavirCmin

The appropriate doses of the combination of nevirapineand nelfinavir with respect to safety and efficacy have not been established.

Saquinavir/ritonavir

The interaction between Ritvir andsaquinavir/ritonavir has not been evaluated

The appropriate doses of thecombination of Ritvir and saquinavir/ritonavir with respect tosafety and efficacy have not been established.

HIV Antiviral Agents:Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*

↓ Efavirenz

The appropriate doses of these combinations withrespect to safety and efficacy have not been established.

Delavirdine

Etravirine

Rilpivirine

Plasma concentrations may be altered. Nevirapineshould not be coadministered with another NNRTI as this combinationhas not been shown to be beneficial.

Hepatitis C AntiviralAgents
Boceprevir

Plasma concentrations of boceprevir maybe decreased due to induction of CYP3A4/5 by Ritvir.

Ritvir and boceprevirshould not be coadministered because decreases in boceprevir plasmaconcentrations may result in a reduction in efficacy.

Telaprevir

Plasma concentrations of telaprevir maybe decreased due to induction of CYP3A4 by Ritvir and plasma concentrationsof Ritvir may be increased due to inhibition of CYP3A4 by telaprevir.

Ritvir and telaprevirshould not be coadministered because changes in plasma concentrationsof Ritvir, telaprevir, or both may result in a reduction in telaprevirefficacy or an increase in nevirapine-associated adverse events.

Other Agents
Analgesics:
Methadone*

↓ Methadone

Methadone levels were decreased;increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning Ritvir therapy shouldbe monitored for evidence of withdrawal and methadone dose shouldbe adjusted accordingly.

Antiarrhythmics:
Amiodarone, disopyramide, lidocaine

Plasma concentrations may be decreased.

Appropriate doses for this combination havenot been established.

Antibiotics:
Clarithromycin*

↓ Clarithromycin

↑ 14-OH clarithromycin

Clarithromycin exposure was significantly decreased by Ritvir;however, 14-OH metabolite concentrations were increased. Becauseclarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activityagainst this pathogen may be altered. Alternatives to clarithromycin,such as azithromycin, should be considered.

Rifabutin*

↑ Rifabutin

Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients mayexperience large increases in rifabutin exposure and may be at higherrisk for rifabutin toxicity. Therefore, caution should be used inconcomitant administration.

Rifampin*

↓ Ritvir

Ritvir and rifampin should not be administeredconcomitantly because decreases in Ritvir plasma concentrationsmay reduce the efficacy of the drug. Physicians needing to treatpatients co-infected with tuberculosis and using a nevirapine-containingregimen may use rifabutin instead.

Anticonvulsants:

Carbamazepine, clonazepam, ethosuximide


Plasma concentrations of nevirapineand the anticonvulsant may be decreased.


Use with cautionand monitor virologic response and levels of anticonvulsants.

Antifungals:
Fluconazole*

↑Nevirapine

Because of the risk of increased exposure to Ritvir, cautionshould be used in concomitant administration, and patients shouldbe monitored closely for nevirapine-associated adverse events.

Ketoconazole*

↓ Ketoconazole

Ritvir and ketoconazole should not be administered concomitantlybecause decreases in ketoconazole plasma concentrations may reducethe efficacy of the drug.

Itraconazole

↓ Itraconazole

Ritvir and itraconazole should not be administeredconcomitantly due to potential decreases in itraconazole plasma concentrationsthat may reduce efficacy of the drug.

Antithrombotics:

Warfarin


Plasma concentrations may beincreased.


Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Calcium channel blockers:

Diltiazem, nifedipine, verapamil


Plasma concentrations may bedecreased.


Appropriate doses for thesecombinations have not been established.

Cancer chemotherapy:

Cyclophosphamide


Plasma concentrations may bedecreased.


Appropriate doses for thiscombination have not been established.

Ergot alkaloids:

Ergotamine


Plasma concentrations may bedecreased.


Appropriate doses for thiscombination have not been established.

Immunosuppressants:

Cyclosporine, tacrolimus, sirolimus


Plasma concentrations may bedecreased.


Appropriate doses for thesecombinations have not been established.

Motility agents:

Cisapride


Plasma concentrations may bedecreased.


Appropriate doses for thiscombination have not been established.

Opiate agonists:

Fentanyl


Plasma concentrations may bedecreased.


Appropriate doses for thiscombination have not been established.

Oral contraceptives:
Ethinyl estradiol and Norethindrone*

↓ Ethinyl estradiol

↓ Norethindrone

Despite lower ethinyl estradiol and norethindroneexposures when coadministered with Ritvir, literature reportssuggest that Ritvir has no effect on pregnancy rates among HIV-infectedwomen on combined oral contraceptives. When coadministered with Ritvir,no dose adjustment of ethinyl estradiol or norethindrone is neededwhen used in combination for contraception.

When these oral contraceptives are used for hormonal regulationduring Ritvir therapy, the therapeutic effect of the hormonal therapyshould be monitored.

Co-administration of Ritvir can alterthe concentrations of other drugs and other drugs may alter the concentrationof Ritvir. The potential for drug interactions must be consideredprior to and during therapy. (5.4, 7, 12.3)

8 USE IN SPECIFIC POPULATIONS

  • Lactation: Women infected with HIV-1 should be instructednot to breastfeed due to the potential for HIV-1 transmission.
  • No dose adjustment is required for patients with renal impairmentwith a creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose of 200 mg followingeach dialysis treatment. (2.4, 8.6)
  • Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug induced toxicity. Do not administer VIRAMUNEto patients with Child-Pugh B or C. (5.1, 8.7)

8.1 Pregnancy

Pregnancy ExposureRegistry

There is a pregnancy exposure registrythat monitors pregnancy outcomes in women exposed to Ritvir duringpregnancy. Healthcare providers are encouraged to register patientsby calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Availabledata from the APR show no difference in the risk of overall majorbirth defects for Ritvir 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 Ritvir . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Ritvir during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Ritvir approximatelyequal (rats) and 50% higher (rabbits) than the exposure in humansat the recommended 400 mg daily dose.

Clinical Considerations

Maternal adverse reactions

Severe hepatic events, including fatalities,have been reported in pregnant women receiving chronic Ritvir therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4+ cellcounts greater than 250 cells/mm3 shouldnot initiate Ritvir unless the benefit outweighs the risk. It isunclear if pregnancy augments the risk observed in non-pregnant women .

Data

Human Data

Based on prospective reportsto the APR of over 2600 exposures to Ritvir during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Ritvir 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 Ritvir pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Ritvir Cmin duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.

Animal Data

Ritvir 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 Lactation

Risk 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 Ritvir on the breastfed infant. There is noinformation on the effects of Ritvir 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 Ritvir.

Data

Based on five publications,immediate-release Ritvir 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 Ritvir median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Ritvir doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Ritvir dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Ritvir through breastmilk.

8.3 Females and Males of Reproductive Potential

Infertility

Limitedhuman data are insufficient to determine the risk of infertility inhumans. Based on results from animal fertility studies conducted inrats, Ritvir may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible .

8.4 Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologicresponses of Ritvir have been evaluated in HIV-1 infected pediatricsubjects age 3 months to 18 years . The safety and pharmacokineticprofile of Ritvir has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than 3 months .

The most frequently reported adverse events relatedto Ritvir in pediatric subjects were similar to those observed inadults, with the exception of granulocytopenia, which was more commonlyobserved in children receiving both zidovudine and Ritvir .

8.5 Geriatric Use

Clinical trials of Ritvir 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 Impairment

In subjects with renal impairment, there were no significant changes in the pharmacokineticsof Ritvir. Ritvir is extensively metabolized by the liverand Ritvir 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 Ritvir dosing is required in patients with CrCLgreater than or equal to 20 mL per min. The pharmacokinetics of nevirapinehave not been evaluated in patients with CrCl less than 20 mL permin. In patients undergoing chronic hemodialysis, an additional 200mg dose following each dialysis treatment is indicated [seeDosage and Administration (2.4) andClinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Because increased Ritvir levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer Ritvir to patients with moderate or severe(Child-Pugh Class B or C, respectively) hepatic impairment .

10 OVERDOSAGE

Thereis no known antidote for Ritvir overdosage. Cases of Ritvir 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 Ritvir.

11 DESCRIPTION

Ritvir is the brand name for Ritvir,a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activityagainst Human Immunodeficiency Virus Type 1 (HIV-1). Ritvir isstructurally a member of the dipyridodiazepinone chemical class ofcompounds.

The chemical nameof Ritvir is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-one. Ritvir is a white to off-whitecrystalline powder with the molecular weight of 266.30 and the molecularformula C15H14N4O. Ritvir 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.

Ritvir Oral Suspension is for oral administration. Each 5 mL of Ritvir suspension contains 50 mg of Ritvir (asnevirapine hemihydrate). The suspension also contains the followingexcipients: carbomer 934P, methylparaben, propylparaben, sorbitol,sucrose, polysorbate 80, sodium hydroxide and purified water.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ritvir is an antiretroviral drug .

12.3 Pharmacokinetics

Adults

Absorptionand Bioavailability

Ritvir 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 Ritvir concentrations of 2 ± 0.4 mcg/mL(7.5 micromolar) were attained by 4 hours following a single 200 mgdose. Following multiple doses, Ritvir peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough Ritvir concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),(n=242) were attained at 400 mg per day. Ritvir tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When Ritvir (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 Ritvir absorption (AUC)was comparable to that observed under fasting conditions. In a separatetrial in HIV-1 infected subjects (n=6), Ritvir 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.

Distribution

Ritvir 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 Ritvir is widely distributedin humans. Ritvir readily crosses the placenta and is also foundin breast milk . Ritvir is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Ritvir concentrations in human cerebrospinal fluid(n=6) were 45% (±5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo trials in humansand in vitro studies with human liver microsomeshave shown that Ritvir is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Ritvir 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 Ritvir 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.

Ritvir is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Ritvir 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 Ritvir 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 Ritvir in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.

SpecificPopulations

Renal Impairment

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 Ritvir 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 Ritvir. However, subjects requiring dialysis exhibited a 44%reduction in Ritvir AUC over a one-week exposure period. Therewas also evidence of accumulation of Ritvir hydroxy-metabolitesin plasma in subjects requiring dialysis. An additional 200 mg dosefollowing each dialysis treatment is indicated .

Hepatic Impairment

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 Ritvir and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Ritvir 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 Ritvir 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 Ritvir,a significant increase in the AUC of Ritvir 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 Ritvir inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer Ritvir to patientswith moderate or severe (Child-Pugh Class B or C, respectively) hepaticimpairment .

Gender

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 Ritvir thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Ritvir, the effect of gender cannotsolely be explained by body size.

Race

An evaluation of Ritvir 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 Ritvir treatment at 400 mg per day. However, the pharmacokinetics of Ritvir 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 Ritvir XR treatment groups over 96 weeks of treatment at 400mg per day.

Geriatric Subjects

Ritvir 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 .

Pediatric Subjects

Pharmacokinetic data for Ritvir 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 Ritvir. 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 Ritvir at150 mg/m2 BID (after a two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough Ritvir 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)].

Drug Interactions

Ritvir induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of Ritvir 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, Ritvir may also inhibitthis system. Among human hepatic cytochrome P450s, Ritvir 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, Ritvir may have minimal inhibitoryeffect on other substrates of CYP3A.

Ritvir 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 Ritvir and other drugs likely to be co-administered. The effects of Ritvir on the AUC, Cmax, andCmin of co-administered drugs are summarized.

§ = Cmin below detectable levelof the assay

↑ = Increase, ↓ = Decrease, ⇔ = No Effect

a For information regarding clinicalrecommendations, see Drug Interactions (7) .

b Pediatricsubjects ranging in age from 6 months to 12 years

c Parallel group design; n for VIRAMUNE+lopinavir/ritonavir,n for lopinavir/ritonavir alone.

d Parallel group design; n=23 for atazanavir/ritonavir + Ritvir,n=22 for atazanavir/ritonavir without Ritvir. Changes in atazanavirPK are relative to atazanavir/ritonavir 300/100 mg alone.

e Based on between-trial comparison.

f Based on historical controls.

Co-administeredDrug Dose of Co-administeredDrug Dose Regimen ofVIRAMUNE n % Change of Co-administered Drug Pharmacokinetic Parameters (90%CI)
Antiretrovirals AUC Cmax Cmin
Atazanavir/Ritonavira, d 300/100 mg QD

day4–13, then 400/100 mg QD, day 14–23

200 mg BID day 1-23. Subjectswere treated with Ritvir prior to trial entry. 23 Atazanavir

300/100mg

↓42

(↓52 to ↓29)

Atazanavir

300/100mg

↓28

(↓40 to ↓14)

Atazanavir

300/100mg

↓72

(↓80 to ↓60)

Atazanavir

400/100mg

↓19

(↓35 to ↑2)

Atazanavir

400/100mg

↑2

(↓15 to ↑24)

Atazanavir

400/100mg

↓59

(↓73 to ↓40)

Darunavir/Ritonavir e 400/100 mg BID 200 mg BID 8 ↑24

(↓3 to ↑57)

↑40

(↑14 to ↑73)

↑2

(↓21 to ↑32)

Didanosine 100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 §
Efavirenza 600 mg QD 200 mg QD x 14 days; 400 mg QD x 14 days 17 ↓28

(↓34 to ↓14)

↓12

(↓23 to ↑1)

↓32

(↓35 to ↓19)

Fosamprenavir 1400 mg BID 200 mg BID. Subjects were treated withnevirapine prior to trial entry. 17 ↓33

(↓45 to ↓20)

↓25

(↓37 to ↓10)

↓35

(↓50 to ↓15)

Fosamprenavir/Ritonavir 700/100 mg BID 200 mg BID. Subjects were treated withnevirapine prior to trial entry 17 ↓11

(↓23 to ↑3)


↓19

(↓32 to ↓4)

Indinavira 800 mg q8H 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↓31

(↓39 to ↓22)

↓15

(↓24 to ↓4)

↓44

(↓53 to ↓33)

Lopinavira, b 300/75 mg/m2 (lopinavir/

ritonavir) b

7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1week 12, 15 c ↓22

(↓44 to ↑9)

↓14

(↓36 to ↑16)

↓55

(↓75 to ↓19)

Lopinavira 400/100 mg BID (lopinavir/ritonavir) 200 mg QD x 14 days; 200 mg BID >1 year 22, 19 c ↓27

(↓47 to ↓2)

↓19

(↓38 to ↑5)

↓51

(↓72 to ↓26)

Maraviroc f 300 mg SD 200 mg BID 8 ↑1

(↓35 to ↑55)

↑54

(↓6 to ↑151)

Nelfinavira 750 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 23 ↓32

(↓50 to ↑5)

Nelfinavir-M8 metabolite ↓62

(↓70 to ↓53)

↓59

(↓68 to ↓48)

↓66

(↓74 to ↓55)

Ritonavir 600 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18
Stavudine 30-40 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 22 §
Zalcitabine 0.125-0.25 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 6 §
Zidovudine 100-200 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 11 ↓28

(↓40 to ↓4)

↓30

(↓51 to ↑14)

§
Other Medications AUC Cmax Cmin
Clarithromycina 500 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 15 ↓31

(↓38 to ↓24)

↓23

(↓31 to ↓14)

↓56

(↓70 to ↓36)

Metabolite

14-OH-clarithromycin

↑42

(↑16 to ↑73)

↑47

(↑21 to ↑80)

Ethinyl estradiola

and

Norethindronea

0.035 mg

(as Ortho-Novum® 1/35)

200 mg QD x 14 days; 200 mgBID x 14 days

10

↓20

(↓33 to ↓3)

§
1 mg

(as Ortho-Novum® 1/35)

↓19

(↓30 to ↓7)

↓16

(↓27 to ↓3)

§
Depomedroxy-progesterone acetate 150 mg every 3 months 200 mg QD x 14 days; 200 mg BID x 14 days 32
Fluconazole 200 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19
Ketoconazolea 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓72

(↓80 to ↓60)

↓44

(↓58 to ↓27)

§
Methadonea Individual Subject Dosing 200 mg QD x 14 days; 200 mg BID ≥7 days 9 In a controlled pharmacokinetictrial with 9 subjects receiving chronic methadone to whom steady-statenevirapine therapy was added, the clearance of methadone was increasedby 3-fold, resulting in symptoms of withdrawal, requiring dose adjustmentsin 10 mg segments, in 7 of the 9 subjects. Methadone did not haveany effect on Ritvir clearance.
Rifabutina 150 or 300 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↑17

(↓2 to ↑40)

↑28

(↑9 to ↑51)

Metabolite

25-O-desacetyl-rifabutin

↑24

(↓16 to ↑84)

↑29

(↓2 to ↑68)

↑22

(↓14 to ↑74)

Rifampina 600 mg QD 200 mg QD x 14 days; 200 mg BID x14 days 14 ↑11

(↓4 to ↑28)

§
Because of the design of the druginteraction trials (addition of 28 days of Ritvir therapy to existingHIV-1 therapy), the effect of the concomitant drug on plasma nevirapinesteady-state concentrations was estimated by comparison to historicalcontrols.

Administration of rifampinhad a clinically significant effect on Ritvir pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein Ritvir exposure, based on a comparison to historic data . The effect of other drugs listed in Table 5 on Ritvir pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and Ritvir.

12.4 Microbiology

Mechanismof Action

Ritvir is a non-nucleoside reverse transcriptase inhibitor of HIV-1. Ritvir 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 Ritvir 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 Ritvir.

AntiviralActivity

The antiviral activity of Ritvir 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 Ritvir 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. Ritvir 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. Ritvir 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 Ritvir was not antagonistic in combination with the NRTIs abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine,and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity ofnevirapine was antagonized by the anti-HBV drug adefovir and by theanti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolateswith reduced susceptibility to Ritvir 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 Ritvir (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 Ritvir 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 Ritvir monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Ritvir 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 Ritvir XR andimmediate-release Ritvir 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 Ritvir 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 Ritvir 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 Ritvir, respectively.

Cross-resistance

Rapid emergenceof HIV-1 strains which are cross-resistant to NNRTIs has been observedin cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistantto the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred22- and 7-fold reductions in susceptibility to delavirdine and efavirenz,respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdineand etravirine 3- and 8-fold, respectively, but did not reduce susceptibilityto efavirenz. However, nevirapine-resistant isolates were susceptibleto the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptibleto Ritvir in cell culture.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studiesin mice and rats were carried out with Ritvir. 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.

Mutagenesis

However, in genetic toxicology assays, Ritvir 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 Ritvir, 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 Ritvir.

13.2 Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapineis widely distributed to nearly all tissues and readily crosses theblood-brain barrier.

14 CLINICAL STUDIES

14.1 Adult Patients

Trial 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 Ritvir + lamivudine+ background therapy versus lamivudine + background therapy in NNRTI-naïvesubjects. Treatment doses were Ritvir, 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.

1 including change to open-labelnevirapine

2 includes withdrawalof consent, lost to follow-up, non-compliance with protocol, otheradministrative reasons

Outcome Ritvir (N=1121)

%

Placebo

(N=1128)

%

Responders at 48 weeks: HIV-1 RNA <50 copies/mL 18 2
Treatment Failure 82 98
Never suppressed viral load 45 66
Virologic failure after response 7 4
CDC category C event or death 10 11
Added antiretroviral therapy1 while <50 copies/mL 5 1
Discontinued trial therapy due to AE 7 6
Discontinued trial <48 weeks2 9 10
The change from baseline in CD4+ cell count through one year of therapy was significantlygreater for the Ritvir group compared to the placebo group for theoverall trial population (64 cells/mm3 versus22 cells/mm3, respectively), as well asfor subjects who entered the trial as treatment-naïve or having receivedonly ZDV (85 cells/mm3 versus 25 cells/mm3, respectively).

At two years into the trial, 16% of subjects on Ritvir 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 Ritvir 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 Patients

The pediatric safety and efficacy of Ritvir 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 Ritvir 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 Ritvir 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 Ritvir 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 HANDLING

VIRAMUNEtablets, 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.

Ritvir tablets are supplied in bottlesof 60 (NDC 0597-0046-60).

Dispensein tight container as defined in the USP/NF.

Ritvir oral suspension is a white to off-white preservedsuspension containing 50 mg Ritvir (as Ritvir hemihydrate)in each 5 mL. Ritvir suspension is supplied in plastic bottles withchild-resistant closures containing 240 mL of suspension (NDC 0597-0047-24).

Storage

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 INFORMATION

Advise the patient to read the FDA-approvedpatient labeling (Medication Guide).

Hepatotoxicity and Skin Reactions

Inform patientsof the possibility of severe liver disease or skin reactions associatedwith Ritvir 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 Ritvir todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Ritvir 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 Ritvir and seekmedical evaluation immediately. If Ritvir is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof Ritvir 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 Ritvir are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Ritvir)and asymptomatic increases in AST or ALT .

The majority of rashes associatedwith Ritvir 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 Ritvir 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 Ritvir immediatelyand consult a physician. Ritvir 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 Ritvir 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 Ritvir and extended-releaseVIRAMUNE XR concomitantly.

Drug Interactions

Ritvir 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 .

Fat Redistribution

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 .

Pregnancy Registry

Advise patients that there is a pregnancyregistry that monitors pregnancy outcomes in women exposed to VIRAMUNEduring pregnancy .

Lactation

Instruct women with HIV-1 infectionnot to breastfeed because HIV-1 can be passed to the baby in the breastmilk .

Infertility

Advise females of reproductivepotential of the potential for impaired fertility from Ritvir

Distributed by:

Boehringer IngelheimPharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Copyright © 2017 Boehringer Ingelheim Pharmaceuticals,Inc.

ALL RIGHTS RESERVED

OT1801ZD32017

MEDICATIONGUIDE
Ritvir® (VIH-rah-mune)

(nevirapine)

oral suspension

Ritvir® (VIH-rah-mune)

(nevirapine)

tablets

Ritvir XR® (VIH-rah-mune)

(nevirapine)

extended-release tablets

What is the most importantinformation I should know about Ritvir?

Ritvir can cause severe liver and skin problems that may lead todeath. These problems can happen at any time during treatment, butyour risk is higher during the first 18 weeks of treatment.

Ritvir can cause serious side effects, including:

  • Severe liver problems. Some people taking VIRAMUNEmay develop severe liver problems that can lead to liver failure andthe need for a liver transplant, or death. If you have liver problemsyou may get a rash.
    • Women have a higher risk of developing liver problems duringtreatment with Ritvir than men.
    • People who have abnormal liver test results before startingVIRAMUNE and people with hepatitis B or C also have a greater riskof getting liver problems.

      People who have higherCD4+ cell counts when they begin VIRAMUNEhave a higher risk of liver problems, especially:

    • Women with CD4+ counts higherthan 250 cells/mm3. This group has thehighest risk.
    • Men with CD4+ counts higher than400 cells/mm3.

      Stop takingVIRAMUNE and call your doctor right away if you have any of the followingsymptoms of liver problems with or without a skin rash:

  • dark (tea colored) urine
  • light-colored bowel movements (stools)
  • feeling sick to your stomach (nausea)
  • pain or tenderness on your right side below your ribs
  • loss of appetite
  • yellowing of your skin or whites of your eyes
  • fever
  • feel unwell or like you have the flu
  • tiredness
  • Severe skin reactions and rash. Some skinreactions and rashes may be severe, life-threatening, and in somepeople, may lead to death. Most severe skin reactions and rashes happenin the first 6 weeks of treatment with Ritvir.
    • Women have a higher risk of developing a rash during treatmentwith Ritvir than men.

      Stop taking Ritvir andcall your doctor right away if you get a rash with any of the followingsymptoms:

  • Blisters
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • swelling of your face
  • feel unwell or like you have the flu
  • muscle or joint aches
  • mouth sores
  • fever
  • tiredness
  • Your doctor should do blood tests often to check your liverfunction and check for severe skin reactions during the first 18 weeksof treatment with Ritvir. You should continue to see your doctorand have your liver checked regularly during your treatment with Ritvir. It is important for you to keep all of your doctor appointments.
  • If your doctor tells you to stop treatment with VIRAMUNEbecause you have had any of the severe liver or skin symptoms listedabove, you should never take Ritvir again.
See "What are the possible side effects of Ritvir?"for more information about side effects.
What is Ritvir?

Ritvir tablets and Ritvir oral solution are prescriptionHIV-1 medicines used with other HIV-1 medicines to treat HIV-1 (HumanImmunodeficiency Virus 1) in adults and in children 15 days of ageand older. HIV-1 is the virus that causes AIDS (Acquired Immune DeficiencySyndrome).

Ritvir XR extended-release tablets is a prescriptionmedicine used with other HIV-1 medicines to treat HIV-1 (Human ImmunodeficiencyVirus 1) in adults and in children 6 years of age to less than 18years of age.

  • If you are a woman with CD4+ countshigher than 250 cells/mm3 or a man withCD4+ counts higher than 400 cells/mm3,you and your doctor willdecide if starting Ritvir is right for you.
  • Ritvir XR extended-release tablets are not recommendedfor use in children less than 6 years of age.
Do not takeVIRAMUNE:
  • if you have liver problems.
  • as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens. Ritvir is only for people diagnosedwith HIV-1. If you have not been diagnosed as HIV positive, then donot take Ritvir.
Before takingVIRAMUNE, tell your doctor about all your or your child’s medicalconditions, including if you or your

Child:

  • have or have had hepatitis (inflammation of your liver)or problems with your liver. See “What is the most importantinformation I should know about Ritvir?”
  • receive dialysis
  • have trouble swallowing pills
  • are pregnant or plan to become pregnant. It is not knownif Ritvir will harm your unborn baby.

    PregnancyRegistry: There is a pregnancy registry for women who takeVIRAMUNE during pregnancy. The purpose of the registry is to collectinformation about the health of you and your baby. Talk to your doctorabout how you can take part in this registry.

  • are breastfeeding or plan to breastfeed. Ritvir can passinto your breast milk and may harm your baby. You should not breastfeedif you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed during treatment with Ritvir. Talk to your doctorabout the best way to feed your baby.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins andherbal supplements. Especially tell your doctor if you takeSt. John’s wort.
  • Some medicines interact with Ritvir. Keep a list of yourmedicines to show your doctor or pharmacist.
  • You can ask your doctor or pharmacist for a list of medicinesthat interact with Ritvir.
  • Do not start taking a new medicine without tellingyour doctor. Your doctor can tell you if it is safe to takeVIRAMUNE with other medicines.
How shouldI take Ritvir?
  • Take Ritvir exactly as your doctor tells you totake it. Do not change your dose unless your doctor tells you to.
  • Ritvir is always taken in combination with other antiretroviralmedicines.
  • Ritvir comes in three different forms. Your doctor willprescribe the form of Ritvir that is right for you.
    • Ritvir tablets
    • Ritvir oral suspension
    • Ritvir XR extended-release tablets
  • You should not take more than one form of Ritvir at thesame time. Talk to your doctor if you have any questions.
  • If your child is prescribed Ritvir, your child’s doctorwill tell you exactly how Ritvir should be taken.
  • Ritvir can be taken with or without food.
  • Swallow Ritvir XR extended-release tablets whole. Do notchew, crush, or divide Ritvir XR extended-release tablets.
  • Do not miss a dose of Ritvir. If you miss a dose of Ritvir,take the missed dose as soon as you remember. If it is almost timefor your next dose, do not take the missed dose. You should take thenext dose at your regular time. Do not take 2 doses at the same time.
  • If you stop taking Ritvir for more than 7 days, ask yourdoctor how much to take before you start taking it again. You mayneed to begin taking the Ritvir starting dose again, which is taken1 time each day for 14 days.
Starting VIRAMUNEtablets:
  • Your doctor should start you with 1 dose each day to loweryour chance of getting a serious rash. It is important thatyou only take 1 dose of Ritvir each day for the first 14 days.
    • Call your doctor right away if you get a skin rashduring the first 14 days of Ritvir treatment.
    • Do not increase your dose to 2 times a day if youhave a rash.
    • You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have a rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of Ritvir.
  • Day 15, you will take 1 Ritvir tablet 2 times a day.
Starting VIRAMUNEXR extended-release tablets when this is the first time you are takingany form of Ritvir:

  • Your doctor should start you with 1 dose of Ritvir tabletsor oral suspension each day to lower your risk of getting a seriousrash. It is important that you only take 1 dose of VIRAMUNEeach day for the first 14 days.
    • Call your doctor right away if you get a skin rashduring the first 14 days of Ritvir treatment.
    • You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have a rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of Ritvir.
    • Do not start Ritvir XR extended-release tabletsif you have a rash.
  • Day 15, take Ritvir XR extended-release tablets 1 timea day as prescribed by your doctor.
Switching from Ritvir tablets or oral suspension toVIRAMUNE XR extended-release tablets:
  • Take Ritvir XR extended-release tablets 1 time a day asprescribed by your doctor.
  • You may sometimes pass a soft mass in your stools (bowelmovement) that looks like your Ritvir XR extended-release tablets. This will not affect the way your medicine works.
If you take Ritvir oral suspension:
  • If you or your child takes Ritvir oral suspension (liquid),shake it gently before each use. Use an oral dosing syringe or dosingcup to measure the right dose. The oral dosing syringe and dosingcup are not provided with Ritvir oral suspension. Ask your pharmacistfor a syringe or cup if you do not have one.
  • After drinking the medicine, fill the dosing cup with waterand drink it to make sure you get all the medicine.
  • If the dose is less than 1 teaspoon (5 mL), use the syringeinstead of the dosing cup.
What are thepossible side effects of Ritvir?

VIRAMUNEmay cause serious side effects, including:

See "What is the most important information I should know about Ritvir?"

  • Changes in your immune system (Immune ReconstitutionSyndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infectionsthat have been hidden in your body for a long time. Tell your doctorright away if you start having new symptoms after starting your HIV-1medicine.
  • Changes in body fat can happen in people whotake HIV-1 medicines. These changes may include increased amount offat in the upper back and neck (“buffalo hump”), breast, and aroundthe middle of your body (trunk). Loss of fat from your legs, arms,and face may also happen. The exact cause and long-term health effectsof these conditions are not known.
The most common side effect of Ritvir is rash.

Ritvir may cause decreased fertility in females. Talkto your doctor if you have concerns about fertility.

Theseare not all the possible side effects of Ritvir. For more information,ask your doctor or pharmacist.

Call your doctor for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How shouldI store Ritvir?
  • Store Ritvir at room temperature between 68°F to 77°F(20°C to 25°C).
  • Throw away Ritvir that is no longer needed.
Keep Ritvir and all medicines out of the reach of children.
General informationabout the safe and effective use of Ritvir.

Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use Ritvir for a condition for which itwas not prescribed. Do not give Ritvir to other people, even ifthey have the same condition you have. It may harm them. You can askyour pharmacist or doctor for information about Ritvir that is writtenfor health professionals.

What are the ingredientsin Ritvir?

Active ingredient: Ritvir

Inactive ingredients:

Ritvir tablets: microcrystalline cellulose, lactose monohydrate, povidone, sodiumstarch glycolate, colloidal silicon dioxide, and magnesium stearate

Ritvir oral suspension: carbomer 934P, methylparaben,propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide,and purified water

Ritvir XR tablets: lactosemonohydrate, hypromellose, iron oxide, and magnesium stearate

Distributed by:

Boehringer Ingelheim Pharmaceuticals,Inc. Ridgefield, CT 06877, USA

For current prescribinginformation for Ritvir or Ritvir XR, scan the codes below or foradditional information you may also call Boehringer Ingelheim Pharmaceuticals,Inc., at 1-800-542-6257, (TTY) 1-800-459-9906.

Ritvir tablets and oral suspension Ritvir XR extended-release tablets
Copyright © 2017 BoehringerIngelheim International GmbH.

ALL RIGHTS RESERVED

OT1801ZD32017

This Medication Guidehas been approved by the U.S. Food and Drug Administration                                                                                                                                                                                                                                                                     Revised:March 2017

viramune-tablets-and-oral-suspension-qr-code viramune-xr-qr-code Ritvir Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Ritvir Oral Suspension 50 mg/5mL Ritvir Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Ritvir

200 mg

60 Tablets

NDC 0597-0046-60

Viramune

Ritvir pharmaceutical active ingredients containing related brand and generic drugs:

infoActive 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.


Ritvir available forms, composition, doses:

infoForm 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.


Ritvir destination | category:

infoDestination 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.


Ritvir Anatomical Therapeutic Chemical codes:

infoA 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.


Ritvir pharmaceutical companies:

infoPharmaceutical 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.


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References

  1. Dailymed."VIRAMUNE (NEVIRAPINE) SUSPENSION VIRAMUNE (NEVIRAPINE) TABLET [BOEHRINGER INGELHEIM PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."NEVIRAPINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "nevirapine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Ritvir?

Depending on the reaction of the Ritvir after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ritvir 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 Ritvir 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.

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Review

sDrugs.com conducted a study on Ritvir, 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 Ritvir 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.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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