Triomune

Lamivudine:

• Triomune Mcneil & Argus Pharmaceuticals information
• Triomune Mcneil & Argus Pharmaceuticals warnings
• Triomune Mcneil & Argus Pharmaceuticals side effects
• Triomune Mcneil & Argus Pharmaceuticals overdose
• Triomune Mcneil & Argus Pharmaceuticals usage guidelines
• Triomune (Lamivudine) reviews

Triomune Mcneil & Argus Pharmaceuticals information

Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals is an anti-HIV treatment in the class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). The body breaks down these drugs into chemicals that stop HIV from infecting uninfected cells in the body, but they do not help cells that have already been infected with the virus. This product is an important part of combination anti-HIV treatment. Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.

Triomune Mcneil & Argus Pharmaceuticals warnings

Before taking the medication, tell your doctor if you have:

kidney disease

liver disease

pancreatitis

problems with your muscles

problems with your blood counts.

Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals does not reduce the risk of passing the HIV or hepatitis B virus to others. Avoid alcohol while taking the medicine. Alcohol may increase the risk of damage to the pancreas and / or liver. It is not known whether Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals will be harmful to an unborn baby. It is very important to treat HIV / AIDS during pregnancy to reduce the risk of infecting the baby. It is not known whether Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed. The drug may interact with other medications resulting in reduced effectiveness and / or side effects. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medications, including herbal products.

Triomune Mcneil & Argus Pharmaceuticals side effects

The possible side effects of Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals are lactic acidosis and severe liver problems, including fatal cases, have been reported with the use of reverse transcriptase inhibitors, alone or in combination. Contact your doctor immediately if you experience nausea, vomiting, or unusual or unexpected stomach discomfort; weakness and tiredness; shortness of breath; weakness in the arms and legs; yellowing of the skin or eyes; or pain in the upper stomach area. These may be early symptoms of lactic acidosis or liver problems. Serious cases of pancreatitis (inflammation of the pancreas) have also been reported with the use of Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals. Notify your doctor immediately if you develop symptoms of pancreatitis including nausea, vomiting, diarrhea, abdominal pain. If you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives), stop taking this medication and seek emergency medical attention.

Triomune Mcneil & Argus Pharmaceuticals overdose

Seek emergency medical attention. Symptoms of a Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals overdose are not known. Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication unless your doctor directs otherwise.

Triomune Mcneil & Argus Pharmaceuticals usage guidelines

Take this medicine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you. Take each dose with a full glass of water. Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals can be taken with or without food. For the treatment of HIV or AIDS, this drug is usually taken twice a day and is often used in combination with other HIV medicines. Follow your doctor's instructions. For the treatment of chronic hepatitis B, this product is usually taken once a day. Follow your doctor's instructions. Store Triomune (Lamivudine) Mcneil & Argus Pharmaceuticals at room temperature away from moisture and heat.

Nevirapine:

• Warning: life-threatening (including fatal) hepatotoxicity and skinreactions
• Indications and usage
• Dosage and administration
• Dosage forms andstrengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storageand handling
• Patient counseling information
• Triomune (Nevirapine) reviews

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 Triomune (Nevirapine). Insome cases, patients presented with non-specific prodromal signs orsymptoms of hepatitis and progressed to hepatic failure. These eventsare often associated with rash. Female gender and higher CD4⁺ cell counts at initiation of therapy place patientsat increased risk; women with CD4⁺ cellcounts greater than 250 cells/mm³, includingpregnant women receiving Triomune (Nevirapine) in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Triomune (Nevirapine) use can occur in both genders,all CD4⁺ cell counts and at any time duringtreatment. Hepatic failure has also been reported in patients withoutHIV taking Triomune (Nevirapine) for post-exposure prophylaxis (PEP). Use of VIRAMUNEfor occupational and non-occupational PEP is contraindicated . Patients with signs or symptoms of hepatitis, or with increasedtransaminases combined with rash or other systemic symptoms, mustdiscontinue Triomune (Nevirapine) and seek medical evaluation immediately .

SKINREACTIONS:

Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Triomune (Nevirapine). These have included cases of Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionscharacterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions orhypersensitivity reactions must discontinue Triomune (Nevirapine) and seek medicalevaluation immediately. Transaminase levels should be checked immediatelyfor all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with Triomune (Nevirapine) 200 mg daily dosing has beenobserved to decrease the incidence of rash and must be followed .

MONITORINGFOR HEPATOTOXICITY AND SKIN REACTIONS:

Patients must be monitored intensively during thefirst 18 weeks of therapy with Triomune (Nevirapine) to detect potentially life-threateninghepatotoxicity or skin reactions. Extra vigilance is warranted duringthe first 6 weeks of therapy, which is the period of greatest riskof these events. Do not restart Triomune (Nevirapine) following clinical hepatitis,or transaminase elevations combined with rash or other systemic symptoms,or following severe skin rash or hypersensitivity reactions. In somecases, hepatic injury has progressed despite discontinuation of treatment.

WARNING: LIFE-THREATENING (INCLUDING FATAL)HEPATOTOXICITY and SKIN REACTIONS

See full prescribing informationfor complete boxed warning.

• Fatal and non-fatal hepatotoxicity have been reportedin patients taking Triomune (Nevirapine). Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart Triomune (Nevirapine) 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)

1 INDICATIONS AND USAGE

Triomune (Nevirapine) is indicated in combination withother antiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients 15 days andolder .

Limitations of Use:

Based onserious and life-threatening hepatotoxicity observed in controlledand uncontrolled trials, Triomune (Nevirapine) 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)].

• Triomune (Nevirapine) 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 Triomune (Nevirapine) is one200 mg tablet daily for the first 14 days, followed by one 200 mgtablet twice daily, in combination with other antiretroviral agents. The 14-day lead-in period with Triomune (Nevirapine) 200 mg daily dosing must bestrictly followed as the lead-in period has been observed to decreasethe incidence of rash . If rash persists beyondthe 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond28 days, at which point, an alternative regimen should be sought. For concomitantly administered antiretroviral therapy, the manufacturer’srecommended dosage and monitoring should be followed.

2.2 Pediatric 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

Triomune (Nevirapine) 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 Triomune (Nevirapine).The optimal frequency of monitoring during this period has not beenestablished. Some experts recommend clinical and laboratory monitoringmore often than once per month, and in particular, would include monitoringof liver enzyme tests at baseline, prior to dose escalation, and attwo weeks post-dose escalation. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE treatment . In some cases, hepatic injuryhas progressed despite discontinuation of treatment.

2.4 Dosage 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 Triomune (Nevirapine). Do not restartVIRAMUNE after recovery .

Patients with Dose Interruption

For patients who interrupt Triomune (Nevirapine) dosing for morethan 7 days, restart the recommended dosing, using one 200 mg tabletdaily (150 mg/m²/day in pediatric patients)for the first 14 days (lead-in) followed by one 200 mg tablet twicedaily (150 mg/m² twice daily for pediatricpatients).

Patients with RenalImpairment

Patients with CrCLgreater than or equal to 20 mL per min do not require an adjustmentin Triomune (Nevirapine) dosing. The pharmacokinetics of Triomune (Nevirapine) have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Triomune (Nevirapine) following each dialysis treatment is indicatedin patients requiring dialysis. Triomune (Nevirapine) metabolites may accumulatein patients receiving dialysis; however, the clinical significanceof this accumulation is not known .

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

Triomune (Nevirapine) 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 Triomune (Nevirapine).In controlled clinical trials, symptomatic hepatic events regardlessof severity occurred in 4% (range 0% to 11%) of subjects who receivedVIRAMUNE and 1% of subjects in control groups.

The risk of symptomatic hepatic events regardless ofseverity was greatest in the first 6 weeks of therapy. The risk continuedto be greater in the Triomune (Nevirapine) groups compared to controls through18 weeks of treatment. However, hepatic events may occur at any timeduring treatment. In some cases, subjects presented with non-specific,prodromal signs or symptoms of fatigue, malaise, anorexia, nausea,jaundice, liver tenderness or hepatomegaly, with or without initiallyabnormal serum transaminase levels. Rash was observed in approximatelyhalf of the subjects with symptomatic hepatic adverse events. Feverand flu-like symptoms accompanied some of these hepatic events. Someevents, particularly those with rash and other symptoms, have progressedto hepatic failure with transaminase elevation, with or without hyperbilirubinemia,hepatic encephalopathy, prolonged partial thromboplastin time, oreosinophilia. Rhabdomyolysis has been observed in some patients experiencingskin and/or liver reactions associated with Triomune (Nevirapine) use. Hepatitis/hepaticfailure may be associated with signs of hypersensitivity which caninclude severe rash or rash accompanied by fever, general malaise,fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction. Patients with signs or symptoms of hepatitis mustbe advised to discontinue Triomune (Nevirapine) and immediately seek medical evaluation,which should include liver enzyme tests.

The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateninghepatic events. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Triomune (Nevirapine) treatment.

Transaminases should be checked immediately if a patientexperiences signs or symptoms suggestive of hepatitis and/or hypersensitivityreaction. Transaminases should also be checked immediately for allpatients who develop a rash in the first 18 weeks of treatment. Physiciansand patients should be vigilant for the appearance of signs or symptomsof hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice,bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Thediagnosis of hepatotoxicity should be considered in this setting,even if transaminases are initially normal or alternative diagnosesare possible .

If clinical hepatitis or transaminase elevations combinedwith rash or other systemic symptoms occur, permanently discontinueVIRAMUNE. Do not restart Triomune (Nevirapine) after recovery. In some cases, hepaticinjury progresses despite discontinuation of treatment.

The patients at greatest risk of hepaticevents, including potentially fatal events, are women with high CD4⁺ cell counts. In general, during the first 6 weeksof treatment, women have a 3-fold higher risk than men for symptomatic,often rash-associated, hepatic events (6% versus 2%), and patientswith higher CD4⁺ cell counts at initiationof Triomune (Nevirapine) therapy are at higher risk for symptomatic hepatic eventswith Triomune (Nevirapine). In a retrospective review, women with CD4⁺ cell counts greater than 250 cells/mm³ had a 12-fold higher risk of symptomatic hepaticadverse events compared to women with CD4⁺ cell counts less than 250 cells/mm³ (11%versus 1%). An increased risk was observed in men with CD4⁺ cell counts greater than 400 cells/mm³ (6% versus 1% for men with CD4⁺ cell counts less than 400 cells/mm³).However, all patients, regardless of gender, CD4⁺ cell count, or antiretroviral treatment history, should be monitoredfor hepatotoxicity since symptomatic hepatic adverse events have beenreported at all CD4⁺ cell counts. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Triomune (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Triomune (Nevirapine))and asymptomatic increases in AST or ALT.

In addition, serious hepatotoxicity (including liverfailure requiring transplantation in one instance) has been reportedin HIV-1 uninfected individuals receiving multiple doses of VIRAMUNEin the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of Triomune (Nevirapine) for occupational and non-occupational PEP is contraindicated .

Increased Triomune (Nevirapine) troughconcentrations have been observed in some patients with hepatic fibrosisor cirrhosis. Therefore, carefully monitor patients with either hepaticfibrosis or cirrhosis for evidence of drug-induced toxicity. Do notadminister Triomune (Nevirapine) 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 Triomune use. In controlled clinical trials, Grade 3 and 4 rasheswere reported during the first 6 weeks in 2% of Triomune (Nevirapine) recipientscompared to less than 1% of placebo subjects.

Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions (including, but not limitedto, severe rash or rash accompanied by fever, general malaise, fatigue,muscle or joint aches, blisters, oral lesions, conjunctivitis, facialedema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and renal dysfunction) must permanently discontinue Triomune (Nevirapine) and seekmedical evaluation immediately. Do not restart Triomune (Nevirapine) followingsevere skin rash, skin rash combined with increased transaminasesor other symptoms, or hypersensitivity reaction.

The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateningskin reactions. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Triomune (Nevirapine) treatment. In addition, the 14-day lead-inperiod with Triomune (Nevirapine) 200 mg daily dosing has been demonstrated toreduce the frequency of rash .

If patients present with a suspected VIRAMUNE-associatedrash, measure transaminases immediately. Permanently discontinue VIRAMUNEin patients with rash-associated transaminase elevations [seeWarnings and Precautions (5.1)].

Therapy with Triomune (Nevirapine) mustbe initiated with a 14-day lead-in period of 200 mg per day (150 mg/m² per day in pediatric patients), which has been shownto reduce the frequency of rash. Discontinue Triomune (Nevirapine) if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Triomune (Nevirapine) dose to a patient experiencinga mild to moderate rash without constitutional symptoms during the14-day lead-in period of 200 mg per day (150 mg/m²/day in pediatric patients) until the rash has resolved. The totalduration of the once-daily lead-in dosing period must not exceed 28days at which point an alternative regimen should be sought . Patients must be monitored closely if isolated rash ofany severity occurs. Delay in stopping Triomune (Nevirapine) treatment after theonset of rash may result in a more serious reaction.

Women appear to be at higher risk than men of developingrash with Triomune (Nevirapine).

In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Triomune (Nevirapine) administration) was associated with an increase inincidence and severity of rash during the first 6 weeks of VIRAMUNEtherapy. Therefore, use of prednisone to prevent VIRAMUNE-associatedrash is not recommended.

5.3 Resistance

Triomune (Nevirapine) must not be used as a single agentto treat HIV-1 or added on as a sole agent to a failing regimen. Resistantvirus emerges rapidly when Triomune (Nevirapine) is administered as monotherapy. The choice of new antiretroviral agents to be used in combinationwith Triomune (Nevirapine) should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of Triomune (Nevirapine) should be taken into account;if antiretrovirals with shorter half-lives than Triomune (Nevirapine) are stoppedconcurrently, low plasma concentrations of Triomune (Nevirapine) 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 Triomune (Nevirapine), isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Triomune (Nevirapine) and lead to loss of virologic responseand possible resistance to Triomune (Nevirapine) or to the class of NNRTIs. Co-administrationof Triomune (Nevirapine) 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 Triomune (Nevirapine). During the initial phase of combinationantiretroviral treatment, patients whose immune system responds maydevelop an inflammatory response to indolent or residual opportunisticinfections (such as Mycobacterium avium infection,cytomegalovirus, Pneumocystis jiroveci pneumonia,or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’disease, polymyositis, and Guillain-Barré syndrome) have also beenreported to occur in the setting of immune reconstitution, however,the time to onset is more variable, and can occur many months afterinitiation of treatment.

5.6 Fat 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.

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 Triomune (Nevirapine) are hepatitis, hepatic failure, Stevens-Johnson syndrome,toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepaticfailure may be isolated or associated with signs of hypersensitivitywhich may include severe rash or rash accompanied by fever, generalmalaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction .

Hepatic Reaction

In controlled clinical trials, symptomatichepatic events regardless of severity occurred in 4% (range 0% to11%) of subjects who received Triomune (Nevirapine) and 1% of subjects in controlgroups. Female gender and higher CD4⁺ cellcounts (greater than 250 cells/mm³ in womenand greater than 400 cells/mm³ in men)place patients at increased risk of these events .

Asymptomatic transaminase elevations (AST or ALT greaterthan 5X ULN) were observed in 6% (range 0% to 9%) of subjects whoreceived Triomune (Nevirapine) and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Triomune (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Triomune (Nevirapine))and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Triomune (Nevirapine) 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 Triomune (Nevirapine) compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Triomune (Nevirapine) recipients compared to less than 1%of subjects receiving placebo. Women tend to be at higher risk fordevelopment of VIRAMUNE-associated rash .

Treatment-related, adverse experiences of moderate orsevere intensity observed in greater than 2% of subjects receivingVIRAMUNE in placebo-controlled trials are shown in Table 2.

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; Triomune (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.
	Trial 10901		Trials 1037, 1038, 10462
	Triomune (Nevirapine)	Placebo	Triomune (Nevirapine)	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 Triomune (Nevirapine) therapy in theabsence of elevations in other liver enzyme tests. Other laboratoryabnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) wereobserved with similar frequencies in clinical trials comparing VIRAMUNEand control regimens.

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; Triomune (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.
	Trial 10901		Trials 1037, 1038, 10462
	Triomune (Nevirapine)	Placebo	Triomune (Nevirapine)	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 Triomune (Nevirapine) (n=305)in which pediatric subjects received combination treatment with Triomune (Nevirapine).In this trial two subjects were reported to experience Stevens-Johnsonsyndrome or Stevens-Johnson/toxic epidermal necrolysis transitionsyndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180),an open-label trial of Triomune (Nevirapine) (n=37) in which subjects were followedfor a mean duration of 33.9 months (range: 6.8 months to 5.3 years,including long-term follow-up in 29 of these subjects in trial BI1100.892). The most frequently reported adverse events related toVIRAMUNE in pediatric subjects were similar to those observed in adults,with the exception of granulocytopenia, which was more commonly observedin children receiving both zidovudine and Triomune (Nevirapine). Cases of allergicreaction, including one case of anaphylaxis, were also reported.

The safety of Triomune (Nevirapine) was also examinedin BI Trial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naïve subjectsbetween 3 months and 16 years of age received combination treatmentwith Triomune (Nevirapine) oral suspension, lamivudine and zidovudine for 48 weeks . Rash (all causality) was reported in 21% of the subjects,4 (3%) of whom discontinued drug due to rash. All 4 subjects experiencedthe rash early in the course of therapy (less than 4 weeks) and resolvedupon Triomune (Nevirapine) discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) .

Safety information on use of Triomune (Nevirapine) in combinationtherapy in pediatric subjects 2 weeks to less than 3 months of agewas assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopeniawas reported more frequently in this age group compared to the olderpediatric age groups and adults.

6.2 Post-Marketing Experience

In addition to the adverse events identified duringclinical trials, the following adverse reactions have been identifiedduring post-approval use of Triomune (Nevirapine). Because these reactions arereported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establisha causal relationship to drug exposure.

Body as a Whole: fever,somnolence, drug withdrawal , redistribution/accumulationof body fat

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.

7 DRUG INTERACTIONS

Triomune (Nevirapine) is principally metabolized bythe liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapineis known to be an inducer of these enzymes. As a result, drugs thatare metabolized by these enzyme systems may have lower than expectedplasma levels when co-administered with Triomune (Nevirapine).

The specific pharmacokinetic changes that occur withco-administration of Triomune (Nevirapine) and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments aboutpossible dosage modifications based on established drug interactionsare listed in Table 4. The data in Tables 4 and 5 are based on theresults of drug interaction trials conducted in HIV-1 seropositivesubjects unless otherwise indicated. In addition to established druginteractions, there may be potential pharmacokinetic interactionsbetween Triomune (Nevirapine) and other drug classes that are metabolized bythe cytochrome P450 system. These potential drug interactions arealso listed in Table 4. Although specific drug interaction trialsin HIV-1 seropositive subjects have not been conducted for some classesof drugs listed in Table 4, additional clinical monitoring may bewarranted when co-administering these drugs.

The in vitro interaction between nevirapineand the antithrombotic agent warfarin is complex. As a result, whengiving these drugs concomitantly, plasma warfarin levels may changewith the potential for increases in coagulation time. When warfarinis co-administered with Triomune (Nevirapine), anticoagulation levels shouldbe monitored frequently.

* The interactionbetween Triomune (Nevirapine) and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Triomune (Nevirapine) or Concomitant Drug	Clinical Comment
HIV Antiviral Agents:Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Triomune (Nevirapine)	Do not co-administer Triomune (Nevirapine) withatazanavir because Triomune (Nevirapine) substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity dueto increased Triomune (Nevirapine) exposures.
Fosamprenavir*	↓ Amprenavir ↑ Triomune (Nevirapine)	Co-administration of Triomune (Nevirapine) and fosamprenavirwithout ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Triomune (Nevirapine)	No dosing adjustments are required when Triomune (Nevirapine) is co-administeredwith 700/100 mg of fosamprenavir/ritonavir twice daily. The combinationof Triomune (Nevirapine) administered with fosamprenavir/ritonavir once dailyhas not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavirand Triomune (Nevirapine) 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 Triomune (Nevirapine). Neither lopinavir/ritonavirtablets nor oral solution should be administered once daily in combinationwith Triomune (Nevirapine). 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 Triomune (Nevirapine).
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 Triomune (Nevirapine) andsaquinavir/ritonavir has not been evaluated	The appropriate doses of thecombination of Triomune (Nevirapine) 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 Triomune (Nevirapine).	Triomune (Nevirapine) 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 Triomune (Nevirapine) and plasma concentrationsof Triomune (Nevirapine) may be increased due to inhibition of CYP3A4 by telaprevir.	Triomune (Nevirapine) and telaprevirshould not be coadministered because changes in plasma concentrationsof Triomune (Nevirapine), 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 Triomune (Nevirapine) 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 Triomune (Nevirapine);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*	↓ Triomune (Nevirapine)	Triomune (Nevirapine) and rifampin should not be administeredconcomitantly because decreases in Triomune (Nevirapine) 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 Triomune (Nevirapine), cautionshould be used in concomitant administration, and patients shouldbe monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Triomune (Nevirapine) and ketoconazole should not be administered concomitantlybecause decreases in ketoconazole plasma concentrations may reducethe efficacy of the drug.
Itraconazole	↓ Itraconazole	Triomune (Nevirapine) 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 Triomune (Nevirapine), literature reportssuggest that Triomune (Nevirapine) has no effect on pregnancy rates among HIV-infectedwomen on combined oral contraceptives. When coadministered with Triomune (Nevirapine),no dose adjustment of ethinyl estradiol or norethindrone is neededwhen used in combination for contraception. When these oral contraceptives are used for hormonal regulationduring Triomune (Nevirapine) therapy, the therapeutic effect of the hormonal therapyshould be monitored.

Co-administration of Triomune (Nevirapine) can alterthe concentrations of other drugs and other drugs may alter the concentrationof Triomune (Nevirapine). 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 Triomune (Nevirapine) 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 Triomune (Nevirapine) compared with the background rate formajor birth defects of 2.7% in the U.S. reference population of theMetropolitan Atlanta Congenital Defects Program (MACDP) . The rate of miscarriageis not reported in the APR. The estimated background rate of miscarriagein clinically recognized pregnancies in the U.S. general populationis 15-20%. The background risk of birth defects and miscarriage forthe indicated population is unknown. Methodological limitations ofthe APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women andinfants from a limited geographic area, and does not include outcomesfor births that occurred at <20 weeks gestation.

In literature reports, immediate-releasenevirapine exposure (C_min) 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 Triomune (Nevirapine) . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Triomune (Nevirapine) during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Triomune (Nevirapine) 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 Triomune (Nevirapine) therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4⁺ cellcounts greater than 250 cells/mm³ shouldnot initiate Triomune (Nevirapine) 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 Triomune (Nevirapine) during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Triomune (Nevirapine) and overall birth defectscompared with the background birth defect rate of 2.7% in the U.S.reference population of the MACDP. The prevalence of birth defectsin live births was 2.8% (95% CI: 1.9 %, 4.0%) following first trimesterexposure to nevirapine- containing regimens and 3.2% (95% CI: 2.4%,4.3%) for second/third trimester exposure to nevirapine-containingregimens.

Thereare several literature reports of chronic administration of immediate-releasenevirapine during pregnancy, in which Triomune (Nevirapine) pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Triomune (Nevirapine) C_min duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.

Animal Data

Triomune (Nevirapine) was administered orally to pregnant rats (at 0, 12.5, 25 and 50 mg per kg per day) and rabbits(at 0, 30, 100, and 300 mg per kg per day) through organogenesis (ongestation days 7 through 16, and 6 through 18, respectively). Noadverse developmental effects were observed at doses producing systemicexposures (AUC) approximately equivalent to (rats) or approximately50% higher (rabbits) than human exposure at the recommended dailydose. In rats, decreased fetal body weights were observed at a maternallytoxic dose at an exposure approximately 50% higher than the recommendeddaily dose.

8.2 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 Triomune on the breastfed infant. There is noinformation on the effects of Triomune (Nevirapine) on milk production. Becauseof the potential for (1) HIV-1 transmission (in HIV-negative infants),(2) developing viral resistance (in HIV-positive infants), and (3)serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving Triomune (Nevirapine).

Data

Based on five publications,immediate-release Triomune (Nevirapine) was excreted in breast-milk at medianconcentrations ranging from 4080 to 6795 ng/mL, and the median maternalbreast-milk to maternal plasma concentration ratio range was 59 to88%. Reported infant Triomune (Nevirapine) median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Triomune (Nevirapine) doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Triomune (Nevirapine) dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Triomune (Nevirapine) 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, Triomune (Nevirapine) 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 Triomune have been evaluated in HIV-1 infected pediatricsubjects age 3 months to 18 years . The safety and pharmacokineticprofile of Triomune (Nevirapine) has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than 3 months .

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

8.5 Geriatric Use

Clinical trials of Triomune (Nevirapine) did not include sufficient numbers ofsubjects aged 65 and older to determine whether elderly subjects responddifferently from younger subjects. In general, dose selection foran elderly patient should be cautious, reflecting the greater frequencyof decreased hepatic, renal or cardiac function, and of concomitantdisease or other drug therapy.

8.6 Renal Impairment

In subjects with renal impairment, there were no significant changes in the pharmacokineticsof Triomune (Nevirapine). Triomune (Nevirapine) is extensively metabolized by the liverand Triomune (Nevirapine) metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis;however, the clinical significance of this accumulation is not known. No adjustment in Triomune (Nevirapine) dosing is required in patients with CrCLgreater than or equal to 20 mL per min. The pharmacokinetics of nevirapinehave not been evaluated in patients with CrCl less than 20 mL permin. In patients undergoing chronic hemodialysis, an additional 200mg dose following each dialysis treatment is indicated [seeDosage and Administration (2.4) andClinical Pharmacology (12.3)].

8.7 Hepatic Impairment

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

10 OVERDOSAGE

Thereis no known antidote for Triomune (Nevirapine) overdosage. Cases of Triomune (Nevirapine) overdoseat doses ranging from 800 to 1800 mg per day for up to 15 days havebeen reported. Patients have experienced events including edema, erythemanodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates,rash, vertigo, vomiting, and weight decrease. All events subsidedfollowing discontinuation of Triomune (Nevirapine).

11 DESCRIPTION

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

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

VIRAMUNETablets are for oral administration. Each tablet contains 200 mg ofnevirapine and the inactive ingredients microcrystalline cellulose,lactose monohydrate, povidone, sodium starch glycolate, colloidalsilicon dioxide, and magnesium stearate.

Triomune (Nevirapine) Oral Suspension is for oral administration. Each 5 mL of Triomune (Nevirapine) suspension contains 50 mg of Triomune (Nevirapine) (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

Triomune is an antiretroviral drug .

12.3 Pharmacokinetics

Adults

Absorptionand Bioavailability

Triomune is readily absorbed (greater than 90%) after oral administrationin healthy volunteers and in adults with HIV-1 infection. Absolutebioavailability in 12 healthy adults following single-dose administrationwas 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oralsolution. Peak plasma Triomune (Nevirapine) concentrations of 2 ± 0.4 mcg/mL(7.5 micromolar) were attained by 4 hours following a single 200 mgdose. Following multiple doses, Triomune (Nevirapine) peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough Triomune (Nevirapine) concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),(n=242) were attained at 400 mg per day. Triomune (Nevirapine) tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When Triomune (Nevirapine) (200 mg) was administered to24 healthy adults (12 female, 12 male), with either a high-fat breakfast(857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox^® 30 mL), the extent of Triomune (Nevirapine) absorption (AUC)was comparable to that observed under fasting conditions. In a separatetrial in HIV-1 infected subjects (n=6), Triomune (Nevirapine) steady-state systemicexposure (AUC_τ) 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

Triomune (Nevirapine) is highly lipophilic and is essentiallynonionized at physiologic pH. Following intravenous administrationto healthy adults, the apparent volume of distribution (Vdss) of nevirapinewas 1.21 ± 0.09 L/kg, suggesting that Triomune (Nevirapine) is widely distributedin humans. Triomune (Nevirapine) readily crosses the placenta and is also foundin breast milk . Triomune (Nevirapine) is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Triomune (Nevirapine) concentrations in human cerebrospinal fluid(n=6) were 45% (±5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo trials in humansand in vitro studies with human liver microsomeshave shown that Triomune (Nevirapine) is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Triomune (Nevirapine) is mediated primarily by cytochromeP450 (CYP) isozymes from the CYP3A and CYP2B6 families, although otherisozymes may have a secondary role. In a mass balance/excretion trialin eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by a single 50 mg dose of ¹⁴C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeleddose was recovered, with urine (81.3 ± 11.1%) representing the primaryroute of excretion compared to feces (10.1 ± 1.5%). Greater than 80%of the radioactivity in urine was made up of glucuronide conjugatesof hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronideconjugation, and urinary excretion of glucuronidated metabolites representthe primary route of Triomune (Nevirapine) biotransformation and eliminationin humans. Only a small fraction (less than 5%) of the radioactivityin urine (representing less than 3% of the total dose) was made upof parent compound; therefore, renal excretion plays a minor rolein elimination of the parent compound.

Triomune (Nevirapine) is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Triomune (Nevirapine) induces CYP3A and CYP2B6by approximately 20-25%, as indicated by erythromycin breath testresults and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediatedmetabolism leads to an approximately 1.5- to 2-fold increase in theapparent oral clearance of Triomune (Nevirapine) as treatment continues froma single dose to two-to-four weeks of dosing with 200-400 mg per day. Autoinduction also results in a corresponding decrease in the terminalphase half-life of Triomune (Nevirapine) 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 Triomune (Nevirapine) in a pharmacokinetic trial. Thesesubjects did not require dialysis. The trial included six additionalsubjects with renal failure requiring dialysis.

In subjects with renal impairment (mild, moderate orsevere), there were no significant changes in the pharmacokineticsof Triomune (Nevirapine). However, subjects requiring dialysis exhibited a 44%reduction in Triomune (Nevirapine) AUC over a one-week exposure period. Therewas also evidence of accumulation of Triomune (Nevirapine) 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 Triomune (Nevirapine) and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Triomune (Nevirapine) troughconcentrations above 9,000 mcg per mL (2-fold the usual mean trough).Therefore, patients with hepatic impairment should be monitored carefullyfor evidence of drug-induced toxicity . The subjects studied werereceiving antiretroviral therapy containing Triomune (Nevirapine) 200 mg twicedaily for at least 6 weeks prior to pharmacokinetic sampling, witha median duration of therapy of 3.4 years.

In a pharmacokinetic trial where HIV-1 negative cirrhoticsubjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;n=4) hepatic impairment received a single 200 mg dose of Triomune (Nevirapine),a significant increase in the AUC of Triomune (Nevirapine) was observed in onesubject with Child-Pugh B and ascites suggesting that patients withworsening hepatic function and ascites may be at risk of accumulatingnevirapine in the systemic circulation. Because Triomune (Nevirapine) inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer Triomune (Nevirapine) 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 Triomune (Nevirapine) thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Triomune (Nevirapine), the effect of gender cannotsolely be explained by body size.

Race

An evaluation of Triomune (Nevirapine) plasma concentrations (pooleddata from several clinical trials) from HIV-1-infected subjects (27Black, 24 Hispanic, 189 Caucasian) revealed no marked difference innevirapine steady-state trough concentrations (median C_minss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mLCaucasian) with long-term Triomune (Nevirapine) treatment at 400 mg per day. However, the pharmacokinetics of Triomune (Nevirapine) have not been evaluatedspecifically for the effects of ethnicity.

Black subjects (n=80/group) in Trial 1100.1486 showedapproximately 30% to 35% higher trough concentrations than Caucasiansubjects (250-325 subjects/group) in both immediate-release VIRAMUNEand Triomune (Nevirapine) XR treatment groups over 96 weeks of treatment at 400mg per day.

Geriatric Subjects

Triomune (Nevirapine) pharmacokinetics in HIV-1-infectedadults do not appear to change with age (range 18–68 years); however,nevirapine has not been extensively evaluated in subjects beyond theage of 55 years .

Pediatric Subjects

Pharmacokinetic data for Triomune (Nevirapine) havebeen derived from two sources: a 48-week pediatric trial in SouthAfrica (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïvesubjects aged 3 months to 16 years; and a consolidated analysis offive Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising495 subjects aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, andpharmacokinetics of a weight-based and a body surface area (BSA)-baseddosing regimen of Triomune (Nevirapine). In the weight-based regimen, pediatricsubjects up to 8 years of age received a dose of 4 mg/kg once dailyfor two weeks followed by 7 mg per kg twice daily thereafter. Subjects8 years and older were dosed 4 mg/kg once daily for two weeks followedby 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatricsubjects received 150 mg/m² once dailyfor two weeks followed by 150 mg/m² twicedaily thereafter . Dosing of Triomune (Nevirapine) at150 mg/m² BID (after a two-week lead-inof 150 mg/m² QD) produced geometric meanor mean trough Triomune (Nevirapine) concentrations between 4-6 mcg per mL (astargeted from adult data). In addition, the observed trough nevirapineconcentrations were comparable between the two dosing regimens studied(BSA- and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluationof pediatric subjects less than 3 months of age (n=17). The plasmanevirapine concentrations observed were within the range observedin adults and the remainder of the pediatric population, but weremore variable between subjects, particularly in the second month ofage. For dose recommendations for pediatric patients [seeDosage and Administration (2.2)].

Drug Interactions

Triomune (Nevirapine) induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of Triomune (Nevirapine) anddrugs primarily metabolized by CYP3A or CYP2B6 may result in decreasedplasma concentrations of these drugs and attenuate their therapeuticeffects.

While primarily an inducerof cytochrome P450 3A and 2B6 enzymes, Triomune (Nevirapine) may also inhibitthis system. Among human hepatic cytochrome P450s, Triomune (Nevirapine) wascapable in vitro of inhibiting the 10-hydroxylationof (R)-warfarin (CYP3A). The estimated K_i 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, Triomune (Nevirapine) may have minimal inhibitoryeffect on other substrates of CYP3A.

Triomune (Nevirapine) does not appear to affect the plasma concentrationsof drugs that are substrates of other CYP450 enzyme systems, suchas 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Table 5 contains the results of drug interactiontrials performed with Triomune (Nevirapine) and other drugs likely to be co-administered. The effects of Triomune (Nevirapine) on the AUC, C_max, andC_min 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 + Triomune (Nevirapine),n=22 for atazanavir/ritonavir without Triomune (Nevirapine). 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 Triomune (Nevirapine) 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 Triomune (Nevirapine) 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 Triomune (Nevirapine) 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 Triomune (Nevirapine) pharmacokinetics,decreasing AUC and C_max by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein Triomune (Nevirapine) exposure, based on a comparison to historic data . The effect of other drugs listed in Table 5 on Triomune (Nevirapine) pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and Triomune (Nevirapine).

12.4 Microbiology

Mechanismof Action

Triomune is a non-nucleoside reverse transcriptase inhibitor (NNRTI)of HIV-1. Triomune (Nevirapine) binds directly to reverse transcriptase (RT)and blocks the RNA-dependent and DNA-dependent DNA polymerase activitiesby causing a disruption of the enzyme's catalytic site. The activityof Triomune (Nevirapine) does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerasesα, β, γ, or δ) are not inhibited by Triomune (Nevirapine).

AntiviralActivity

The antiviral activity of Triomune (Nevirapine) has been measured in a varietyof cell lines including peripheral blood mononuclear cells, monocyte-derivedmacrophages, and lymphoblastoid cell lines. In an assay using humanembryonic kidney 293 cells, the median EC₅₀ value (50% inhibitory concentration) of Triomune (Nevirapine) was 90 nM againsta panel of 2923 wild-type isolates of HIV-1 that were primarily (93%)clade B clinical isolates from the United States. The 99^th 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. Triomune (Nevirapine) had no antiviral activityin cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates(n=3) replicating in cord blood mononuclear cells. Triomune (Nevirapine) in combinationwith efavirenz exhibited strong antagonistic anti-HIV-1 activity incell culture and was additive to antagonistic with the protease inhibitorritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activityof Triomune (Nevirapine) was not antagonistic in combination with the NRTIs abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine,and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity ofnevirapine was antagonized by the anti-HBV drug adefovir and by theanti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolateswith reduced susceptibility to Triomune (Nevirapine) emergein cell culture. Genotypic analysis showed mutations in the HIV-1RT gene encoding Y181C and/or V106A substitutions depending upon thevirus strain and cell line employed. Time to emergence of nevirapineresistance in cell culture was not altered when selection includednevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolatesfrom treatment-naïve subjects receiving either Triomune (Nevirapine) (n=24) ornevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trialsranging from 1 to 12 weeks or longer. After 1 week of Triomune (Nevirapine) monotherapy,isolates from 3/3 subjects had decreased susceptibility to nevirapinein cell culture. One or more of the RT mutations resulting in aminoacid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A weredetected in HIV-1 isolates from some subjects as early as 2 weeksafter therapy initiation. By week eight of Triomune (Nevirapine) monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Triomune (Nevirapine) in cell culturecompared to baseline, and had one or more of the nevirapine-associatedRT resistance substitutions. Nineteen of these subjects (80%) hadisolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïvesubjects experiencing virologic failure (n=71) receiving nevirapineonce daily (n=25) or twice daily (n=46) in combination with lamivudineand stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25and 23/46 subjects, respectively, contained one or more of the followingNNRTI resistance-associated substitutions: Y181C, K101E, G190A/S,K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.

For trial 1100.1486, genotypic analysiswas performed for baseline and on-therapy isolates from 23 and 34subjects who experienced virologic failure in the Triomune (Nevirapine) XR andimmediate-release Triomune (Nevirapine) treatment group, respectively. Nevirapineresistance-associated substitutions developed in the on-therapy isolatesof 78% (18/23) of the subjects who had virologic failures in the VIRAMUNEXR treatment group and 88% (30/34) of the subjects in the immediate-releaseVIRAMUNE treatment group, respectively. The Y181C Triomune (Nevirapine) resistance-associatedsubstitution was found alone or in combination with other nevirapineresistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I,Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjectsfailing Triomune (Nevirapine) XR treatment and 25 subjects failing immediate-releaseVIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNEXR treatment group developed a novel amino acid substitution Y181Iand isolates from another subject in the immediate-release VIRAMUNEtreatment group developed a novel amino acid substitution Y188N. Phenotypicanalysis showed that Y188N and Y181I substitutions conferred 103-and 22-fold reductions in susceptibility to Triomune (Nevirapine), respectively.

Cross-resistance

Rapid emergenceof HIV-1 strains which are cross-resistant to NNRTIs has been observedin cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistantto the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred22- and 7-fold reductions in susceptibility to delavirdine and efavirenz,respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdineand etravirine 3- and 8-fold, respectively, but did not reduce susceptibilityto efavirenz. However, nevirapine-resistant isolates were susceptibleto the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptibleto Triomune (Nevirapine) 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 Triomune. 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 (based on AUCs)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, Triomune (Nevirapine) showed no evidenceof mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assaysfor gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assaysusing a Chinese hamster ovary cell line and a mouse bone marrow micronucleusassay following oral administration. Given the lack of genotoxic activityof Triomune (Nevirapine), the relevance to humans of hepatocellular neoplasmsin nevirapine-treated mice and rats is not known.

Impairment of Fertility

In reproductive toxicologystudies, evidence of impaired fertility was seen in female rats atdoses providing systemic exposure, based on AUC, approximately equivalentto that provided with the recommended clinical dose of Triomune (Nevirapine).

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 Triomune + lamivudine+ background therapy versus lamivudine + background therapy in NNRTI-naïvesubjects. Treatment doses were Triomune (Nevirapine), 200 mg daily for two weeksfollowed by 200 mg twice daily or placebo, and lamivudine, 150 mgtwice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) 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	Triomune (Nevirapine) (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 Triomune (Nevirapine) 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 Triomune (Nevirapine) had experiencedclass C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind,placebo-controlled, randomized, three-arm trial with 151 HIV-1 infectedsubjects with CD4⁺ cell counts of 200-600cells/mm³ at baseline. BI 1046 comparedtreatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudineand zidovudine+didanosine. Treatment doses were Triomune (Nevirapine) at 200 mgdaily for two weeks followed by 200 mg twice daily or placebo, zidovudineat 200 mg three times daily, and didanosine at 125 or 200 mg twicedaily (depending on body weight). The subjects had mean baseline HIV-1RNA of 4.41 log₁₀ copies/mL (25,704 copiesper mL) and mean baseline CD4⁺ cell countof 376 cells/mm³. The primary endpointwas the proportion of subjects with HIV-1 RNA less than 400 copiesper mL and not previously failed at 48 weeks. The virologic responderrates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine,19% for subjects treated with zidovudine+didanosine, and 0% for subjectstreated with VIRAMUNE+zidovudine.

CD4⁺ cell counts in the VIRAMUNE+ZDV+ddIgroup increased above baseline by a mean of 139 cells/mm³ at one year, significantly greater than the increaseof 87 cells/mm³ in the ZDV+ddI subjects. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm³ below baseline.

14.2 Pediatric Patients

The pediatric safety and efficacy of Triomune (Nevirapine) was examined in BITrial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naïve subjectsbetween 3 months and 16 years of age received Triomune (Nevirapine) oral suspensionfor 48 weeks. Subjects were divided into 4 age groups (3 months toless than 2 years, 2 to less than 7 years, 7 to less than 12 years,and 12 to less than or equal to 16 years) and randomized to receiveone of two Triomune (Nevirapine) doses, determined by 2 different dosing methods[body surface area (150 mg/m²) and weight-baseddosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine . The total daily dose of Triomune (Nevirapine) did not exceed 400 mg in eitherregimen. There were 66 subjects in the body surface area (BSA) dosinggroup and 57 subjects in the weight-based (BW) dosing group.

Baseline demographics included: 49% male;81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjectshad a median baseline HIV-1 RNA of 5.45 log₁₀ copies per mL and a median baseline CD4⁺ cell count of 527 cells/mm³ (range 37-2279).One hundred and five (85%) completed the 48-week period while 18 (15%)discontinued prematurely. Of the subjects who discontinued prematurely,9 (7%) discontinued due to adverse reactions and 3 (2%) discontinueddue to virologic failure. Overall the proportion of subjects who achievedand maintained an HIV-1 RNA less than 400 copies per mL at 48 weekswas 47% (58/123).

16 HOW SUPPLIED/STORAGEAND 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.

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

Dispensein tight container as defined in the USP/NF.

Triomune (Nevirapine) oral suspension is a white to off-white preservedsuspension containing 50 mg Triomune (Nevirapine) (as Triomune (Nevirapine) hemihydrate)in each 5 mL. Triomune (Nevirapine) 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 Triomune (Nevirapine) that may result in death. Instruct patients developingsigns or symptoms of liver disease or severe skin reactions to discontinueVIRAMUNE and seek medical attention immediately, including performanceof laboratory monitoring. Symptoms of liver disease include fatigue,malaise, anorexia, nausea, jaundice, acholic stools, liver tendernessor hepatomegaly. Symptoms of severe skin or hypersensitivity reactionsinclude rash accompanied by fever, general malaise, fatigue, muscleor joint aches, blisters, oral lesions, conjunctivitis, facial edema,and/or hepatitis.

Intensive clinical and laboratory monitoring, including liver enzymes,is essential during the first 18 weeks of therapy with Triomune (Nevirapine) todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Triomune (Nevirapine) treatment. Extra vigilance is warranted during the first 6 weeks of therapy,which is the period of greatest risk of hepatic events. Advise patientswith signs and symptoms of hepatitis to discontinue Triomune (Nevirapine) and seekmedical evaluation immediately. If Triomune (Nevirapine) is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4⁺ cell count at initiationof Triomune (Nevirapine) therapy (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in men) are at substantially higher risk for development of symptomatichepatic events, often associated with rash. Advise patients thatco-infection with hepatitis B or C and/or increased transaminasesat the start of therapy with Triomune (Nevirapine) are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Triomune (Nevirapine))and asymptomatic increases in AST or ALT .

The majority of rashes associatedwith Triomune (Nevirapine) occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-inperiod, do not escalate the Triomune (Nevirapine) dose until the rash resolves. The total duration of the once-daily lead-in dosing period shouldnot exceed 28 days, at which point an alternative regimen may needto be started. Any patient experiencing a rash should have their liverenzymes (AST, ALT) evaluated immediately. Patients with severe rashor hypersensitivity reactions should discontinue Triomune (Nevirapine) immediatelyand consult a physician. Triomune (Nevirapine) should not be restarted followingsevere skin rash or hypersensitivity reaction. Women tend to be athigher risk for development of VIRAMUNE-associated rash [seeWarnings and Precautions (5.2)].

Administrationand Missed Dosage

Inform patients to take Triomune (Nevirapine) everyday as prescribed. Advise patients not to alter the dose withoutconsulting their doctor. If a dose is missed, patients should takethe next dose as soon as possible. However, if a dose is skipped,the patient should not double the next dose.

To avoid overdose, inform patients thatthey should never take immediate-release Triomune (Nevirapine) and extended-releaseVIRAMUNE XR concomitantly.

Drug Interactions

Triomune (Nevirapine) may interactwith some drugs; therefore, advise patients to report to their doctorthe use of any other prescription, non-prescription medication orherbal products, particularly St. John's wort .

Immune Reconstitution Syndrome

Advise patientsto inform their healthcare provider immediately of any signs or symptomsof infection, as inflammation from previous infection may occur soonafter combination antiretroviral therapy, including when VIRAMUNEis started .

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 Triomune (Nevirapine)

Distributed by:

Boehringer IngelheimPharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Copyright © 2017 Boehringer Ingelheim Pharmaceuticals,Inc.

ALL RIGHTS RESERVED

OT1801ZD32017

MEDICATIONGUIDE
Triomune (Nevirapine)® (VIH-rah-mune) (nevirapine) oral suspension	Triomune (Nevirapine)® (VIH-rah-mune) (nevirapine) tablets	Triomune (Nevirapine) XR® (VIH-rah-mune) (nevirapine) extended-release tablets
What is the most importantinformation I should know about Triomune (Nevirapine)? Triomune (Nevirapine) 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. Triomune (Nevirapine) 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 Triomune (Nevirapine) 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 Triomune (Nevirapine). Women have a higher risk of developing a rash during treatmentwith Triomune (Nevirapine) than men. Stop taking Triomune (Nevirapine) 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 Triomune (Nevirapine). You should continue to see your doctorand have your liver checked regularly during your treatment with Triomune (Nevirapine).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 Triomune (Nevirapine) again. See "What are the possible side effects of Triomune (Nevirapine)?"for more information about side effects.
What is Triomune (Nevirapine)? Triomune (Nevirapine) tablets and Triomune (Nevirapine) 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). Triomune (Nevirapine) 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 Triomune (Nevirapine) is right for you. Triomune (Nevirapine) 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. Triomune (Nevirapine) is only for people diagnosedwith HIV-1. If you have not been diagnosed as HIV positive, then donot take Triomune (Nevirapine).
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 Triomune (Nevirapine)?” receive dialysis have trouble swallowing pills are pregnant or plan to become pregnant. It is not knownif Triomune (Nevirapine) 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. Triomune (Nevirapine) 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 Triomune (Nevirapine). 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 Triomune (Nevirapine). 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 Triomune (Nevirapine). 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 Triomune (Nevirapine)? Take Triomune (Nevirapine) exactly as your doctor tells you totake it. Do not change your dose unless your doctor tells you to. Triomune (Nevirapine) is always taken in combination with other antiretroviralmedicines. Triomune (Nevirapine) comes in three different forms. Your doctor willprescribe the form of Triomune (Nevirapine) that is right for you. Triomune (Nevirapine) tablets Triomune (Nevirapine) oral suspension Triomune (Nevirapine) XR extended-release tablets You should not take more than one form of Triomune (Nevirapine) at thesame time. Talk to your doctor if you have any questions. If your child is prescribed Triomune (Nevirapine), your child’s doctorwill tell you exactly how Triomune (Nevirapine) should be taken. Triomune (Nevirapine) can be taken with or without food. Swallow Triomune (Nevirapine) XR extended-release tablets whole. Do notchew, crush, or divide Triomune (Nevirapine) XR extended-release tablets. Do not miss a dose of Triomune (Nevirapine). If you miss a dose of Triomune (Nevirapine),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 Triomune (Nevirapine) for more than 7 days, ask yourdoctor how much to take before you start taking it again. You mayneed to begin taking the Triomune (Nevirapine) 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 Triomune (Nevirapine) each day for the first 14 days. Call your doctor right away if you get a skin rashduring the first 14 days of Triomune (Nevirapine) 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 Triomune (Nevirapine). Day 15, you will take 1 Triomune (Nevirapine) tablet 2 times a day. Starting VIRAMUNEXR extended-release tablets when this is the first time you are takingany form of Triomune (Nevirapine): Your doctor should start you with 1 dose of Triomune (Nevirapine) 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 Triomune (Nevirapine) 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 Triomune (Nevirapine). Do not start Triomune (Nevirapine) XR extended-release tabletsif you have a rash. Day 15, take Triomune (Nevirapine) XR extended-release tablets 1 timea day as prescribed by your doctor. Switching from Triomune (Nevirapine) tablets or oral suspension toVIRAMUNE XR extended-release tablets: Take Triomune (Nevirapine) 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 Triomune (Nevirapine) XR extended-release tablets. This will not affect the way your medicine works. If you take Triomune (Nevirapine) oral suspension: If you or your child takes Triomune (Nevirapine) 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 Triomune (Nevirapine) 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 Triomune (Nevirapine)? VIRAMUNEmay cause serious side effects, including: See "What is the most important information I should know about Triomune (Nevirapine)?" 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 Triomune (Nevirapine) is rash. Triomune (Nevirapine) may cause decreased fertility in females. Talkto your doctor if you have concerns about fertility. Theseare not all the possible side effects of Triomune (Nevirapine). 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 Triomune (Nevirapine)? Store Triomune (Nevirapine) at room temperature between 68°F to 77°F(20°C to 25°C). Throw away Triomune (Nevirapine) that is no longer needed. Keep Triomune (Nevirapine) and all medicines out of the reach of children.
General informationabout the safe and effective use of Triomune (Nevirapine). Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use Triomune (Nevirapine) for a condition for which itwas not prescribed. Do not give Triomune (Nevirapine) to other people, even ifthey have the same condition you have. It may harm them. You can askyour pharmacist or doctor for information about Triomune (Nevirapine) that is writtenfor health professionals.
What are the ingredientsin Triomune (Nevirapine)? Active ingredient: Triomune (Nevirapine) Inactive ingredients: Triomune (Nevirapine) tablets: microcrystalline cellulose, lactose monohydrate, povidone, sodiumstarch glycolate, colloidal silicon dioxide, and magnesium stearate Triomune (Nevirapine) oral suspension: carbomer 934P, methylparaben,propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide,and purified water Triomune (Nevirapine) XR tablets: lactosemonohydrate, hypromellose, iron oxide, and magnesium stearate Distributed by: Boehringer Ingelheim Pharmaceuticals,Inc. Ridgefield, CT 06877, USA For current prescribinginformation for Triomune (Nevirapine) or Triomune (Nevirapine) 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.
Triomune (Nevirapine) tablets and oral suspension	Triomune (Nevirapine) 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 Triomune (Nevirapine) Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Triomune (Nevirapine) Oral Suspension 50 mg/5mL Triomune (Nevirapine) Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Triomune (Nevirapine)

200 mg

60 Tablets

NDC 0597-0046-60

Viramune

Stavudine:

• Warning: lactic acidosis and hepatomegaly with steatosis; pancreatitis
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Zerit 15 mg capsules representative packaging
• Zerit 20 mg capsules representative packaging
• Zerit 30 mg capsules representative packaging
• Zerit 40 mg capsules representative packaging
• Zerit for oral solution representative packaging
• Triomune (Stavudine) reviews

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Triomune (Stavudine) and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of Triomune (Stavudine) and didanosine with other antiretroviral agents. The combination of Triomune (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.1) ].

Fatal and nonfatal pancreatitis have occurred during therapy when Triomune (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression [see Warnings and Precautions (5.4) ].

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with

STEATOSIS; PANCREATITIS

See full prescribing information for complete boxed warning.

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of Triomune (Stavudine) and didanosine. (5.1)
• Fatal and nonfatal pancreatitis have occurred when Triomune (Stavudine) was part of a combination regimen that included didanosine. (5.4)

1 INDICATIONS AND USAGE

Triomune (Stavudine)^® (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14) ].

Triomune (Stavudine) (stavudine) is a nucleoside reverse transcriptase inhibitor for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1 infection. (1)

2 DOSAGE AND ADMINISTRATION

The interval between doses of Triomune (stavudine) should be 12 hours. Triomune (Stavudine) may be taken with or without food.

• Recommended dosage for adults:
  • less than 60 kg: 30 mg every 12 hours (2.1)
  • at least 60 kg: 40 mg every 12 hours (2.1)
• Recommended dosage for pediatric patients:
  • newborns from birth to 13 days old: 0.5 mg/kg every 12 hours (2.2)
  • at least 14 days old and weighing less than 30 kg: 1 mg/kg every 12 hours (2.2)
  • weighing at least 30 kg: adult dose (2.2)
• Renal impairment: Dose adjustment is recommended for CrCl ≤50 mL/min. (2.3)
• Oral solution: Requires preparation by a pharmacist. (2.4)

2.1 Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:

• For patients weighing less than 60 kg: 30 mg every 12 hours.
• For patients weighing at least 60 kg: 40 mg every 12 hours.

2.2 Recommended Pediatric Dosage

• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
• For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
• For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

2.3 Dosage Adjustment

Renal Impairment

Adult Patients: Triomune may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Creatinine Clearance (mL/min)	Recommended Triomune (Stavudine) Dose by Patient Weight
	at least 60 kg	less than 60 kg
* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
greater than 50	40 mg every 12 hours	30 mg every 12 hours
26–50	20 mg every 12 hours	15 mg every 12 hours
10–25	20 mg every 24 hours	15 mg every 24 hours
Hemodialysis	20 mg every 24 hours*	15 mg every 24 hours*

Pediatric Patients: Since urinary excretion is also a major route of elimination of Triomune (Stavudine) in pediatric patients, the clearance of Triomune (Stavudine) may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of Triomune (Stavudine) in this patient population.

2.4 Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg Triomune (Stavudine) per mL of solution, as follows:

• Add 202 mL of purified water to the container.
• Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL Triomune (Stavudine) solution. The solution may appear slightly hazy.
• Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

3 DOSAGE FORMS AND STRENGTHS

• Triomune (Stavudine) 15 mg capsules with dark red cap and light yellow body, printed with black ink “BMS 1964” on the cap and with black ink “15” on the body.
• Triomune (Stavudine) 20 mg capsules with light brown cap and light brown body, printed with black ink “BMS 1965” on the cap and with black ink “20” on the body.
• Triomune (Stavudine) 30 mg capsules with dark orange cap and light orange body, printed with black ink “BMS 1966” on the cap and with black ink “30” on the body.
• Triomune (Stavudine) 40 mg capsules with dark orange cap and dark orange body, printed with black ink “BMS 1967” on the cap and with black ink “40” on the body.
• Triomune (Stavudine) for oral solution is a dye-free, fruit-flavored powder that provides 1 mg of Triomune (Stavudine) per milliliter solution after constitution.

• Capsules: 15 mg, 20 mg, 30 mg, 40 mg (3, 16.1)
• Oral solution: 1 mg/mL following constitution (3, 16.2)

4 CONTRAINDICATIONS

Triomune (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Triomune (Stavudine) or to any of the components contained in the formulation.

Triomune (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Triomune (Stavudine) or to any of the components of this product. (4)

5 WARNINGS AND PRECAUTIONS

• Lactic acidosis/severe hepatomegaly with steatosis: Suspend treatment with Triomune in patients who develop clinical symptoms or signs with or without laboratory findings. (5.1)
• Hepatic toxicity: May be severe, fatal. Consider interruption or discontinuation. Avoid use in combination with didanosine and hydroxyurea. Risk of hepatic decompensation exists when used in combination with interferon and ribavirin; closely monitor and consider discontinuation of Triomune (Stavudine). (5.2)
• Neurologic symptoms: Motor weakness, most often seen in the setting of lactic acidosis, may mimic Guillain-Barré syndrome; discontinue treatment. Monitor for peripheral neuropathy, which can be severe; treatment discontinuation should be considered. (5.3)
• Pancreatitis: Suspend treatment, resume with particular caution and close monitoring and avoid use in combination with didanosine. (5.4)
• Patients may develop redistribution/accumulation of body fat, monitor for signs and symptoms of lipoatrophy/lipodystrophy. Alternative antiretrovirals should be considered. (5.5)
• Patients may develop immune reconstitution syndrome. (5.6)

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Triomune (Stavudine) and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing Triomune (Stavudine). Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of Triomune (Stavudine) and didanosine with other antiretroviral agents. The combination of Triomune (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Use in Specific Populations (8.1) ].

Particular caution should be exercised when administering Triomune (Stavudine) to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness [see Warnings and Precautions (5.3) ] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

Treatment with Triomune (Stavudine) (stavudine) should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of Triomune (Stavudine) should be considered for patients with confirmed lactic acidosis.

5.2 Hepatic Toxicity

The safety and efficacy of Triomune have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and Triomune (Stavudine). This combination should be avoided. [See Adverse Reactions (6) .]

Use with Interferon and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as Triomune (Stavudine). Although no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with Triomune (Stavudine) in HIV-1/HCV co-infected patients [see Drug Interactions (7) ], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and Triomune (Stavudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of Triomune (Stavudine) should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (eg, Child-Pugh >6) (see the full prescribing information for interferon and ribavirin).

5.3 Neurologic Symptoms

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including Triomune. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, Triomune (Stavudine) should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving Triomune (Stavudine) therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine [see Adverse Reactions (6) ].

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of Triomune (Stavudine) should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

5.4 Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy when Triomune (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of Triomune (Stavudine) and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of Triomune (Stavudine) after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.

5.5 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with Triomune (Stavudine) compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from Triomune (Stavudine) to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving Triomune (Stavudine) should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using Triomune (Stavudine) including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Triomune (Stavudine). During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions ]
• hepatic toxicity [see Warnings and Precautions (5.2) ]
• neurologic symptoms and motor weakness [see Warnings and Precautions (5.3) ]
• pancreatitis [see Boxed Warning and Warnings and Precautions (5.4) ]
• lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5) ]

When Triomune (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Triomune (Stavudine) is used alone.

• In adults, the most common adverse reactions are headache, diarrhea, neuropathy, rash, nausea, and vomiting. (6.1)
• Adverse reactions in pediatric patients were consistent with those seen in adults. (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Selected adverse reactions that occurred in adult patients receiving Triomune (Stavudine) in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

	Percent (%)
Adverse Reaction	Triomune (Stavudine)b (40 mg twice daily) (n=412)	zidovudine (200 mg 3 times daily) (n=402)
a The incidences reported included all severity grades and all reactions regardless of causality. b Median duration of Triomune (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
Headache	54	49
Diarrhea	50	44
Peripheral Neurologic Symptoms/Neuropathy	52	39
Rash	40	35
Nausea and Vomiting	39	44

Pancreatitis was observed in 3 of the 412 adult patients who received Triomune (Stavudine) in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving Triomune (Stavudine) from two controlled combination studies are provided in Table 3.

	Percent (%)
	START 1		START 2b
Adverse Reaction	Triomune (Stavudine) + lamivudine + indinavir (n=100c)	zidovudine + lamivudine + indinavir (n=102)	Triomune (Stavudine) + didanosine + indinavir (n=102c)	zidovudine + lamivudine + indinavir (n=103)
a The incidences reported included all severity grades and all reactions regardless of causality. b START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either Triomune (Stavudine) (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir. c Duration of Triomune (Stavudine) therapy = 48 weeks.
Nausea	43	63	53	67
Diarrhea	34	16	45	39
Headache	25	26	46	37
Rash	18	13	30	18
Vomiting	18	33	30	35
Peripheral Neurologic Symptoms/Neuropathy	8	7	21	10

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

	Percent (%)
Parameter	Triomune (Stavudine) (40 mg twice daily) (n=412)	zidovudine (200 mg 3 times daily) (n=402)
a Data presented for patients for whom laboratory evaluations were performed. b Median duration of Triomune (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks. ULN = upper limit of normal.
AST (SGOT) (>5.0 × ULN)	11	10
ALT (SGPT) (>5.0 × ULN)	13	11
Amylase (≥1.4 × ULN)	14	13

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

	Percent (%)
	START 1		START 2
Parameter	Triomune (Stavudine) + lamivudine + indinavir (n=100)	zidovudine + lamivudine + indinavir (n=102)	Triomune (Stavudine) + didanosine + indinavir (n=102)	zidovudine + lamivudine + indinavir (n=103)
ULN = upper limit of normal.
Bilirubin (>2.6 × ULN)	7	6	16	8
AST (SGOT) (>5 × ULN)	5	2	7	7
ALT (SGPT) (>5 × ULN)	6	2	8	5
GGT (>5 × ULN)	2	2	5	2
Lipase (>2 × ULN)	6	3	5	5
Amylase (>2 × ULN)	4	<1	8	2

	Percent (%)
	START 1		START 2
Parameter	Triomune (Stavudine) + lamivudine + indinavir (n=100)	zidovudine + lamivudine + indinavir (n=102)	Triomune (Stavudine) + didanosine + indinavir (n=102)	zidovudine + lamivudine + indinavir (n=103)
Total Bilirubin	65	60	68	55
AST (SGOT)	42	20	53	20
ALT (SGPT)	40	20	50	18
GGT	15	8	28	12
Lipase	27	12	26	19
Amylase	21	19	31	17

6.2 Clinical Trial Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. [See Use in Specific Populations .]

6.3 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Triomune (Stavudine). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to Triomune (Stavudine), or a combination of these factors.

• Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat [see Warnings and Precautions (5.5) ].
• Digestive Disorders: anorexia.
• Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4) ].
• Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.
• Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1) ], hepatitis and liver failure.
• Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5) ], diabetes mellitus and hyperglycemia.
• Musculoskeletal: myalgia.
• Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1 , 5.3) ].

Use with Didanosine- and Hydroxyurea-Based Regimens

When Triomune (Stavudine) is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Triomune (Stavudine) is used alone. Thus, patients treated with Triomune (Stavudine) in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5) ]. The combination of Triomune (Stavudine) and hydroxyurea, with or without didanosine, should be avoided.

7 DRUG INTERACTIONS

Triomune (Stavudine) is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of Triomune (Stavudine). Therefore, use of zidovudine in combination with Triomune (Stavudine) (stavudine) should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of Triomune (Stavudine) is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of Triomune (Stavudine) with doxorubicin should be undertaken with caution.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, Triomune (Stavudine), and zidovudine. The clinical significance of the interaction with Triomune (Stavudine) is unknown; therefore, concomitant use of Triomune (Stavudine) with ribavirin should be undertaken with caution. No pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), Triomune (Stavudine) (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.2) ].

• Coadministration of Triomune (Stavudine) with zidovudine should be avoided. (7)
• Coadministration of Triomune (Stavudine) and doxorubicin or ribavirin should be undertaken with caution. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both didanosine and Triomune with other agents. This combination should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk to the fetus. Pregnancy registry available. (8.1)
• Nursing mothers should be instructed not to breastfeed due to the potential for postnatal HIV transmission. (8.3)

8.1 Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits with exposures (based on C_max) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that Triomune (Stavudine) is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well-controlled studies of Triomune (Stavudine) in pregnant women. Triomune (Stavudine) should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of Triomune (Stavudine) and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Boxed Warning and Warnings and Precautions (5.1) ]. The combination of Triomune (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving Triomune (Stavudine) should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Triomune (Stavudine) and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that Triomune is excreted in milk. Although it is not known whether Triomune (Stavudine) is excreted in human milk, there exists the potential for adverse effects from Triomune (Stavudine) in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Triomune (Stavudine).

8.4 Pediatric Use

Use of Triomune (Stavudine) in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of Triomune (Stavudine) in adults with additional pharmacokinetic and safety data in pediatric patients [see Dosage and Administration (2.2) and Adverse Reactions (6.2) ].

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of Triomune (Stavudine) in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received Triomune (Stavudine) 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received Triomune (Stavudine) 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received Triomune (Stavudine) 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Triomune (Stavudine) pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9) ].

8.5 Geriatric Use

Clinical studies of Triomune (stavudine) did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of Triomune (Stavudine) cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Triomune (Stavudine) is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3) ].

8.6 Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Triomune (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the Triomune (Stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Triomune (Stavudine) can be removed by hemodialysis; the mean ± SD hemodialysis clearance of Triomune (Stavudine) is 120 ± 18 mL/min. Whether Triomune (Stavudine) is eliminated by peritoneal dialysis has not been studied.

11 DESCRIPTION

Triomune (Stavudine)^® is the brand name for Triomune (Stavudine) (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for Triomune (Stavudine) is 2′,3′-didehydro-3′-deoxythymidine. Triomune (Stavudine) has the following structural formula:

Triomune (Stavudine) is a white to off-white crystalline solid with the molecular formula C₁₀H₁₂N₂O₄ and a molecular weight of 224.2. The solubility of Triomune (Stavudine) at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of Triomune (Stavudine) at 23°C is 0.144.

Capsules: Triomune (Stavudine) is available as capsules for oral administration containing either 15, 20, 30, or 40 mg of Triomune (Stavudine). Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide, and iron oxides. The capsules are printed with edible inks.

Powder for Oral Solution: Triomune (Stavudine) is available as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL Triomune (Stavudine) oral solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Triomune (Stavudine) chemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Triomune is an antiviral drug [see Clinical Pharmacology (12.4) ].

12.3 Pharmacokinetics

The pharmacokinetics of Triomune (Stavudine) have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of Triomune (Stavudine) with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, Triomune is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to Triomune (Stavudine) is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of Triomune (Stavudine) (stavudine) in HIV-1-infected adults are shown in Table 7.

Parameter	Triomune (Stavudine) 40 mg BID Mean ± SD (n=8)
AUC0–24 = Area under the curve over 24 hours. Cmax = Maximum plasma concentration. Cmin = Trough or minimum plasma concentration.
AUC0–24 (ng-h/mL)	2568 ± 454
Cmax (ng/mL)	536 ± 146
Cmin (ng/mL)	8 ± 9

Distribution

Binding of Triomune (Stavudine) to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Triomune (Stavudine) distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of Triomune. Unchanged Triomune (Stavudine) was the major drug-related component circulating in plasma after an 80-mg dose of ¹⁴C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized Triomune (Stavudine), glucuronide conjugates of Triomune (Stavudine) and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of Triomune (Stavudine).

Elimination

Following an 80-mg dose of ¹⁴C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Parameter	Mean ± SD	n
a Following 1-hour IV infusion. b Following single oral dose. c Assuming a body weight of 70 kg. d Over 12–24 hours.
Oral bioavailability (%)	86.4 ± 18.2	25
Volume of distribution (L)a	46 ± 21	44
Total body clearance (mL/min)a	594 ± 164	44
Apparent oral clearance (mL/min)b	560 ± 182c	113
Renal clearance (mL/min)a	237 ± 98	39
Elimination half-life, IV dose (h)a	1.15 ± 0.35	44
Elimination half-life, oral dose (h)b	1.6 ± 0.23	8
Urinary recovery of Triomune (Stavudine) (% of dose)a,d	42 ± 14	39

Special Populations

Pediatric

Pharmacokinetic parameters of Triomune in pediatric patients are presented in Table 9.

Parameter	Ages 5 weeks to 15 years	n	Ages 14 to 28 days	n	Day of Birth	n
a Following 1-hour IV infusion. b At median time of 2.5 hours (range 2–3 hours) following multiple oral doses. c Following single oral dose. d Over 8 hours. ND = Not determined.
Oral bioavailability (%)	76.9 ± 31.7	20	ND		ND
Volume of distribution (L/kg)a	0.73 ± 0.32	21	ND		ND
Ratio of CSF: plasma concentrations (as %)b	59 ± 35	8	ND		ND
Total body clearance (mL/min/kg)a	9.75 ± 3.76	21	ND		ND
Apparent oral clearance (mL/min/kg)c	13.75 ± 4.29	20	11.52 ± 5.93	30	5.08 ± 2.80	17
Elimination half-life, IV dose (h)a	1.11 ± 0.28	21	ND		ND
Elimination half-life, oral dose (h)c	0.96 ± 0.26	20	1.59 ± 0.29	30	5.27 ± 2.01	17
Urinary recovery of stavudine (% of dose)c,d	34 ± 16	19	ND		ND

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Triomune (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. C_max and T_max were not significantly altered by renal impairment. The mean ± SD hemodialysis clearance value of Triomune (Stavudine) was 120 ± 18 mL/min (n=12); the mean ± SD percentage of the Triomune (Stavudine) dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that Triomune (Stavudine) (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) ].

	Creatinine Clearance			Hemodialysis Patientsb (n=11)
	>50 mL/min (n=10)	26–50 mL/min (n=5)	9–25 mL/min (n=5)
a Single 40-mg oral dose. b Determined while patients were off dialysis. T½ = Terminal elimination half-life. NA = Not applicable.
Creatinine clearance (mL/min)	104 ± 28	41 ± 5	17 ± 3	NA
Apparent oral clearance (mL/min)	335 ± 57	191 ± 39	116 ± 25	105 ± 17
Renal clearance (mL/min)	167 ± 65	73 ± 18	17 ± 3	NA
T½ (h)	1.7 ± 0.4	3.5 ± 2.5	4.6 ± 0.9	5.4 ± 1.4

Hepatic Impairment

Triomune pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40-mg dose.

Geriatric

Triomune (Stavudine) pharmacokinetics have not been studied in patients >65 years of age. [See Use in Specific Populations (8.5) .]

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males and females (n=27).

Race

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other).

Drug Interaction Studies

Triomune does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Because Triomune (Stavudine) is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs.

Tables 11 and 12 summarize the effects on AUC and C_max, with a 95% confidence interval (CI) when available, following coadministration of Triomune (Stavudine) with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Drug	Triomune (Stavudine) Dosage	na	AUC of Triomune (Stavudine) (95% CI)	Cmax of Triomune (Stavudine) (95% CI)
↑ Indicates increase. ↔ Indicates no change, or mean increase or decrease of <10%. a HIV-1-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↑ 17%
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (92.7–100.6%)	↑ 12% (100.3–126.1%)
Nelfinavir, 750 mg q8h for 56 days	30–40 mg q12h for 56 days	8	↔	↔

Drug	Triomune (Stavudine) Dosage	na	AUC of Coadministered Drug (95% CI)	Cmax of Coadministered Drug (95% CI)
↔ Indicates no change, or mean increase or decrease of <10%. a HIV-1-infected patients.
Didanosine, 100 mg q12h for 4 days	40 mg q12h for 4 days	10	↔	↔
Lamivudine, 150 mg single dose	40 mg single dose	18	↔ (90.5–107.6%)	↔ (87.1–110.6%)
Nelfinavir, 750 mg q8h for 56 days	30–40 mg q12h for 56 days	8	↔	↔

12.4 Microbiology

Mechanism of Action

Triomune, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite Triomune (Stavudine) triphosphate. Triomune (Stavudine) triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (K_i=0.0083 to 0.032 µM) and by causing DNA chain termination following its incorporation into viral DNA. Triomune (Stavudine) triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity in Cell Culture

The cell culture antiviral activity of Triomune (Stavudine) was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC₅₀) ranged from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. In cell culture, Triomune (Stavudine) exhibited additive to antagonistic activity in combination with zidovudine. Triomune (Stavudine) in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9–45 µM concentrations tested, reduced the anti-HIV-1 activity of Triomune (Stavudine) by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to Triomune (Stavudine) and the inhibition of HIV-1 replication in humans has not been established.

Resistance

HIV-1 isolates with reduced susceptibility to Triomune have been selected in cell culture (strain-specific) and were also obtained from patients treated with Triomune (Stavudine). Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6–29 months) Triomune (Stavudine) monotherapy showed that post-therapy isolates from four patients exhibited EC₅₀ values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for Triomune (Stavudine) susceptibility changes has not been identified.

Cross-resistance

Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged Triomune (Stavudine) treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to Triomune (Stavudine) in cell culture. These TAMs are seen at a similar frequency with Triomune (Stavudine) and zidovudine in virological treatment. The clinical relevance of these findings suggests that Triomune (Stavudine) should be avoided in the presence of thymidine analogue mutations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in mice and rats, Triomune (Stavudine) was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose.

Triomune (Stavudine) was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Triomune (Stavudine) produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, Triomune (Stavudine) elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 µg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 µg/mL, with and without metabolic activation). In the in vivo micronucleus assay, Triomune (Stavudine) was clastogenic in bone marrow cells following oral Triomune (Stavudine) administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days.

No evidence of impaired fertility was seen in rats with exposures (based on C_max) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

14 CLINICAL STUDIES

Combination Therapy

The combination use of Triomune is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing Triomune (Stavudine) (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4⁺ cell counts through 48 weeks.

Monotherapy

The efficacy of Triomune (Stavudine) was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992–1994) comparing Triomune (Stavudine) with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 Capsules

Triomune ^® (stavudine) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures:

Product Strength	Capsule Shell Color	Markings on Capsule (in Black Ink)		Capsules per Bottle	NDC No.
15 mg	Light yellow & dark red	BMS 1964	15	60	0003-1964-01
20 mg	Light brown	BMS 1965	20	60	0003-1965-01
30 mg	Light orange & dark orange	BMS 1966	30	60	0003-1966-01
40 mg	Dark orange	BMS 1967	40	60	0003-1967-01

16.2 Oral Solution

Triomune (Stavudine)^® (stavudine) for Oral Solution is a dye-free, fruit-flavored powder that provides 1 mg of Triomune (Stavudine) per mL of solution upon constitution with water. Directions for solution preparation are included on the product label and in the Dosage and Administration (2) section of this insert. Triomune (Stavudine) for Oral Solution (NDC No. 0003-1968-01) is available in child-resistant containers that provide 200 mL of solution after constitution with water.

16.3 Storage

Triomune (Stavudine) Capsules should be stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted.

Triomune (Stavudine) for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted. After constitution, store tightly closed containers of Triomune (Stavudine) for Oral Solution in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

17 PATIENT COUNSELING INFORMATION

17.1 General

Patients should be advised that Triomune is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using Triomune (Stavudine) and the importance of adherence to any antiretroviral regimen including those that contain Triomune (Stavudine).

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. It is not known if Triomune (Stavudine) can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

Patients should be informed that when Triomune (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Triomune (Stavudine) is used alone.

Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.

Patients should be instructed if they take too much Triomune (Stavudine), they should contact a poison control center or emergency room right away.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

Patients with diabetes should be aware that Triomune (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

17.2 Lactic Acidosis

Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of Triomune (Stavudine) therapy may be required.

17.3 Hepatic Toxicity

Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with Triomune in combination with didanosine and hydroxyurea. This combination should be avoided.

17.4 Peripheral Neuropathy

Patients should be informed that an important toxicity of Triomune (Stavudine) (stavudine) is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of Triomune (Stavudine) may be required if toxicity develops.

Caregivers of young children receiving Triomune (Stavudine) therapy should be instructed regarding detection and reporting of peripheral neuropathy.

17.5 Pancreatitis

Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of Triomune and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.

The patient should be instructed to avoid alcohol while taking Triomune (Stavudine). Alcohol may increase the patient’s risk of pancreatitis or liver damage.

17.6 Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including Triomune (Stavudine). Patients receiving Triomune (Stavudine) should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.

Medication Guide

Triomune (Stavudine) ^® (Zair-it)

(stavudine)

Triomune (Stavudine)^® Capsules and

Triomune (Stavudine)^® for Oral Solution

Read this Medication Guide before you start taking Triomune (Stavudine) and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. You and your healthcare provider should talk about your treatment with Triomune (Stavudine) before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Triomune (Stavudine).

What is the most important information I should know about Triomune (Stavudine)?

Triomune (Stavudine) can cause serious side effects, including:

1. Build up of acid in your blood (lactic acidosis). Lactic acidosis can cause death and must be treated in the hospital. The risk of lactic acidosis may be higher if you:

• have liver problems
• are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking Triomune (Stavudine) and VIDEX, or Triomune (Stavudine) and VIDEX EC (didanosine).
• are female
• are overweight
• have been treated for a long time with other medicines used to treat HIV

It is important to call your healthcare provider right away if you:

• feel weak or tired
• have unusual (not normal) muscle pain
• have trouble breathing
• have stomach pain with nausea and vomiting
• feel cold, especially in your arms and legs
• feel dizzy or light-headed
• have a fast or irregular heartbeat

2. Liver problems. Some people (including pregnant women) who have taken Triomune (Stavudine) have had serious liver problems. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and death due to liver problems. Your healthcare provider should check your liver function while you are taking Triomune (Stavudine). You should be especially careful if you have a history of heavy alcohol use or liver problems. Use of Triomune (Stavudine) with VIDEX EC or VIDEX (didanosine) may increase your risk for liver damage.

It is important to call your healthcare provider right away if you have:

• yellowing of your skin or the white of your eyes (jaundice)
• dark urine
• pain on the right side of your stomach
• swelling of your stomach
• easy bruising or bleeding
• loss of appetite
• nausea or vomiting

3. Swelling of the pancreas (pancreatitis) that may cause death has occurred when Triomune (Stavudine) was used with VIDEX EC or VIDEX (didanosine). Pancreatitis can happen at any time during your treatment with Triomune (Stavudine).

It is important to call your healthcare provider right away if you have:

• stomach pain
• swelling of your stomach
• nausea and vomiting
• fever

What is Triomune (Stavudine)?

Triomune (Stavudine) is a prescription medicine used with other HIV medicines to treat human immunodeficiency virus (HIV) infection in children and adults. Triomune (Stavudine) belongs to a class of drugs called nucleoside analogues.

Triomune (Stavudine) will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Triomune (Stavudine), you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your healthcare provider regularly and report any medical problems that occur.

Who should not take Triomune (Stavudine)?

Do not take Triomune (Stavudine) if you:

• are allergic to Triomune (Stavudine) or any of the ingredients in Triomune (Stavudine). See the end of this Medication Guide for a complete list of the ingredients in Triomune (Stavudine).

What should I tell my healthcare provider before taking Triomune (Stavudine)?

Before you take Triomune (Stavudine), tell your healthcare provider if you:

• have or had liver problems (such as hepatitis)
• have or had problems with your pancreas (pancreatitis)
• have or had kidney problems
• have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy)
• have gallstones
• drink alcoholic beverages
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if Triomune (Stavudine) will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Triomune (Stavudine). You and your healthcare provider will decide if you should take Triomune (Stavudine) while you are pregnant.
  

  Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

• are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Triomune (Stavudine) can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, or herbal supplements. Triomune (Stavudine) may affect the way other medicines work, and other medicines may affect how Triomune (Stavudine) works.

Especially tell your healthcare provider if you take:

• COMBIVIR^®, RETROVIR^®, TRIZIVIR^® (zidovudine or AZT)
• VIDEX^® or VIDEX EC^® (didanosine)
• ADRIAMYCIN^®, RUBEX^® (doxorubicin)
• COPEGUS^®, REBETOL^®, RIBASPHERE^®, RIBAVIRIN^®, VIRAZOLE^® (ribavirin)
• ROFERON-A^®, INTRON-A^®, and others (interferon)
• HYDREA^®, DROXIA^® (hydroxyurea)

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

How should I take Triomune (Stavudine)?

• Take Triomune (Stavudine) exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much Triomune (Stavudine) to take and when to take it.
• If your child will be taking Triomune (Stavudine), your child’s healthcare provider should give you instructions on how to give this medicine. If your child is taking Triomune (Stavudine) oral solution, shake the bottle well before measuring each dose.
• Your healthcare provider may change your dose. Do not change your dose of Triomune (Stavudine) without talking to your healthcare provider.
• Triomune (Stavudine) may be taken with or without food.
• Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.
• Some medicines may require your healthcare provider to monitor your therapy or change your therapy. Check with your healthcare provider.
• If your kidneys are not working well, your healthcare provider will need to do regular blood and urine tests to check how they are working while you take Triomune (Stavudine). Your healthcare provider may also lower your dosage of Triomune (Stavudine) if your kidneys are not working well.
• If you take too much Triomune (Stavudine), contact a poison control center or emergency room right away.

What should I avoid while taking Triomune (Stavudine)?

• Alcohol. You should avoid drinking alcohol while taking Triomune (Stavudine). Alcohol may increase your risk of getting pain and swelling of your pancreas (pancreatitis) or may damage your liver.

What are the possible side effects of Triomune (Stavudine)?

Triomune (Stavudine) can cause serious side effects including:

• Triomune (Stavudine) can cause lactic acidosis, liver problems, and pancreatitis. See “What is the most important information I should know about Triomune (Stavudine)?”
• Neurologic symptoms. Symptoms include: weakness of your legs, feet, arms, or hands (motor weakness) and numbness or tingling in your hands or feet (neuropathy). These problems can happen more often in people who have advanced HIV disease, have a history of peripheral neuropathy, or in people who take other medicines that also are associated with neuropathy including didanosine. In some cases, neuropathy may temporarily worsen after you stop taking Triomune (Stavudine). Neuropathy can be difficult to notice in children who take Triomune (Stavudine). Ask your child’s healthcare provider for the signs and symptoms of peripheral neuropathy in children.

It is important to call your healthcare provider right away if you have:

• numbness in your hands or feet
• tingling in your hands or feet
• weakness in your legs, feet, arms, or hands
• Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) have been seen in some people taking HIV medicines including Triomune (Stavudine). Loss of body fat (lipoatrophy) happens more often in people who take Triomune (Stavudine) than in people who take other similar HIV medicines.

• These changes may include:
  • more fat in or around your
    • trunk
    • upper back and neck (buffalo hump)
    • breast or chest
  • loss of fat in your
    • legs
    • arms
    • face

Your healthcare provider will monitor you for changes in your body fat. It is important to tell your healthcare provider if you notice any of these changes.

• Changes in your immune system (immune reconstitution syndrome). Your immune system may begin to fight infections that have been in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine.

The most common side effects of Triomune (Stavudine) include:

• headache
• diarrhea
• rash
• nausea
• vomiting

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Triomune (Stavudine). For more information, ask your healthcare provider or pharmacist.

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

How should I store Triomune (Stavudine)?

• Capsules:
  • Store Triomune (Stavudine) capsules in a tightly closed container at room temperature at 59°F to 86°F (15°C to 30°C).
• Oral solution:
  • Store Triomune (Stavudine) oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C).
  • Store Triomune (Stavudine) oral solution in a tightly closed container.
  • Throw away any unused medicine after 30 days.

Keep Triomune (Stavudine) and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Triomune (Stavudine)

If you have diabetes mellitus: Triomune (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

Avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Triomune (Stavudine) for a condition for which it was not prescribed. Do not give Triomune (Stavudine) to other people, even if they have the same symptoms as you have. It may harm them. Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place Triomune (Stavudine) in an unrecognizable closed container in the household trash.

This Medication Guide summarizes the most important information about Triomune (Stavudine). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Triomune (Stavudine) that is written for health professionals. For more information, go to http://www.bms.com/products/Pages/prescribing.aspx or call 1-800-321-1335.

What are the ingredients in Triomune (Stavudine)?

Active Ingredient: Triomune (Stavudine)

Inactive Ingredients:

Triomune (Stavudine) Capsules: microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate.

The gelatin shell contains: gelatin, titanium oxide, and iron oxide.

Triomune (Stavudine) for Oral Solution: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Triomune (Stavudine)^®, VIDEX^®, VIDEX EC^®, HYDREA^®, and DROXIA^® are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

1000007856 / 1349254

Rev December 2012

Triomune 15 mg Capsules Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Triomune (Stavudine).

60 Capsules NDC 0003-1964-01

Triomune (Stavudine) ^®

(stavudine)

Capsules

Rx only

15 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Triomune 20 mg Capsules Representative Packaging

60 Capsules NDC 0003-1965-01

Triomune (Stavudine) ^®

(stavudine)

Capsules

Rx only

20 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Triomune 30 mg Capsules Representative Packaging

60 Capsules NDC 0003-1966-01

Triomune (Stavudine) ^®

(stavudine)

Capsules

Rx only

30 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Triomune 40 mg Capsules Representative Packaging

60 Capsules NDC 0003-1967-01

Triomune (Stavudine) ^®

(stavudine)

Capsules

Rx only

40 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Triomune for Oral Solution Representative Packaging

200 mL NDC 0003-1968-01

Triomune (Stavudine) ^®

(stavudine)

for Oral Solution

Rx only

1 mg Triomune (Stavudine) per mL

when constituted per

label instructions

Detach and dispense the

enclosed Medication Guide

to each patient.