Lamivudine; Nevirapine; Zidovudine

Lamivudine:

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

Lamivudine; Nevirapine; Zidovudine Mcneil & Argus Pharmaceuticals information

Lamivudine; Nevirapine; Zidovudine (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. Lamivudine; Nevirapine; Zidovudine (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.

Lamivudine; Nevirapine; Zidovudine 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.

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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.

Lamivudine; Nevirapine; Zidovudine Mcneil & Argus Pharmaceuticals side effects

The possible side effects of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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.

Lamivudine; Nevirapine; Zidovudine Mcneil & Argus Pharmaceuticals overdose

Seek emergency medical attention. Symptoms of a Lamivudine; Nevirapine; Zidovudine (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.

Lamivudine; Nevirapine; Zidovudine 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. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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
• Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and seek medical evaluation immediately .

SKINREACTIONS:

Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine). Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart Lamivudine; Nevirapine; Zidovudine (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

Lamivudine; Nevirapine; Zidovudine (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, Lamivudine; Nevirapine; Zidovudine (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)].

• Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine). Do not restartVIRAMUNE after recovery .

Patients with Dose Interruption

For patients who interrupt Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) dosing. The pharmacokinetics of Lamivudine; Nevirapine; Zidovudine (Nevirapine) have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Lamivudine; Nevirapine; Zidovudine (Nevirapine) following each dialysis treatment is indicatedin patients requiring dialysis. Lamivudine; Nevirapine; Zidovudine (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

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) therapy are at higher risk for symptomatic hepatic eventswith Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) for occupational and non-occupational PEP is contraindicated .

Increased Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine use. In controlled clinical trials, Grade 3 and 4 rasheswere reported during the first 6 weeks in 2% of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and seekmedical evaluation immediately. Do not restart Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) treatment. In addition, the 14-day lead-inperiod with Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine).

In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Lamivudine; Nevirapine; Zidovudine (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

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) is administered as monotherapy. The choice of new antiretroviral agents to be used in combinationwith Lamivudine; Nevirapine; Zidovudine (Nevirapine) should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of Lamivudine; Nevirapine; Zidovudine (Nevirapine) should be taken into account;if antiretrovirals with shorter half-lives than Lamivudine; Nevirapine; Zidovudine (Nevirapine) are stoppedconcurrently, low plasma concentrations of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine), isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Lamivudine; Nevirapine; Zidovudine (Nevirapine) and lead to loss of virologic responseand possible resistance to Lamivudine; Nevirapine; Zidovudine (Nevirapine) or to the class of NNRTIs. Co-administrationof Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Lamivudine; Nevirapine; Zidovudine (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Lamivudine; Nevirapine; Zidovudine (Nevirapine))and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Lamivudine; Nevirapine; Zidovudine (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; Lamivudine; Nevirapine; Zidovudine (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.
	Trial 10901		Trials 1037, 1038, 10462
	Lamivudine; Nevirapine; Zidovudine (Nevirapine)	Placebo	Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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; Lamivudine; Nevirapine; Zidovudine (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.
	Trial 10901		Trials 1037, 1038, 10462
	Lamivudine; Nevirapine; Zidovudine (Nevirapine)	Placebo	Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) (n=305)in which pediatric subjects received combination treatment with Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine). Cases of allergicreaction, including one case of anaphylaxis, were also reported.

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

Safety information on use of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine).

The specific pharmacokinetic changes that occur withco-administration of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine), anticoagulation levels shouldbe monitored frequently.

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

Co-administration of Lamivudine; Nevirapine; Zidovudine (Nevirapine) can alterthe concentrations of other drugs and other drugs may alter the concentrationof Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Lamivudine; Nevirapine; Zidovudine (Nevirapine) during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4⁺ cellcounts greater than 250 cells/mm³ shouldnot initiate Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Lamivudine; Nevirapine; Zidovudine (Nevirapine) C_min duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.

Animal Data

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine on the breastfed infant. There is noinformation on the effects of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine).

Data

Based on five publications,immediate-release Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Lamivudine; Nevirapine; Zidovudine (Nevirapine) doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Lamivudine; Nevirapine; Zidovudine (Nevirapine) dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Lamivudine; Nevirapine; Zidovudine (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, Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine have been evaluated in HIV-1 infected pediatricsubjects age 3 months to 18 years . The safety and pharmacokineticprofile of Lamivudine; Nevirapine; Zidovudine (Nevirapine) has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than 3 months .

The most frequently reported adverse events relatedto Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) .

8.5 Geriatric Use

Clinical trials of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine). Lamivudine; Nevirapine; Zidovudine (Nevirapine) is extensively metabolized by the liverand Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer Lamivudine; Nevirapine; Zidovudine (Nevirapine) to patients with moderate or severe(Child-Pugh Class B or C, respectively) hepatic impairment .

10 OVERDOSAGE

Thereis no known antidote for Lamivudine; Nevirapine; Zidovudine (Nevirapine) overdosage. Cases of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine).

11 DESCRIPTION

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

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

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

Lamivudine; Nevirapine; Zidovudine is an antiretroviral drug .

12.3 Pharmacokinetics

Adults

Absorptionand Bioavailability

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

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) is widely distributedin humans. Lamivudine; Nevirapine; Zidovudine (Nevirapine) readily crosses the placenta and is also foundin breast milk . Lamivudine; Nevirapine; Zidovudine (Nevirapine) is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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.

Lamivudine; Nevirapine; Zidovudine (Nevirapine) is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine). However, subjects requiring dialysis exhibited a 44%reduction in Lamivudine; Nevirapine; Zidovudine (Nevirapine) AUC over a one-week exposure period. Therewas also evidence of accumulation of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine),a significant increase in the AUC of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Lamivudine; Nevirapine; Zidovudine (Nevirapine), the effect of gender cannotsolely be explained by body size.

Race

An evaluation of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) treatment at 400 mg per day. However, the pharmacokinetics of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) XR treatment groups over 96 weeks of treatment at 400mg per day.

Geriatric Subjects

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) at150 mg/m² BID (after a two-week lead-inof 150 mg/m² QD) produced geometric meanor mean trough Lamivudine; Nevirapine; Zidovudine (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

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

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

12.4 Microbiology

Mechanismof Action

Lamivudine; Nevirapine; Zidovudine is a non-nucleoside reverse transcriptase inhibitor (NNRTI)of HIV-1. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine).

AntiviralActivity

The antiviral activity of Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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. Lamivudine; Nevirapine; Zidovudine (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. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) XR andimmediate-release Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine. 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, Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine + lamivudine+ background therapy versus lamivudine + background therapy in NNRTI-naïvesubjects. Treatment doses were Lamivudine; Nevirapine; Zidovudine (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	Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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.

Lamivudine; Nevirapine; Zidovudine (Nevirapine) tablets are supplied in bottlesof 60 (NDC 0597-0046-60).

Dispensein tight container as defined in the USP/NF.

Lamivudine; Nevirapine; Zidovudine (Nevirapine) oral suspension is a white to off-white preservedsuspension containing 50 mg Lamivudine; Nevirapine; Zidovudine (Nevirapine) (as Lamivudine; Nevirapine; Zidovudine (Nevirapine) hemihydrate)in each 5 mL. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and seekmedical evaluation immediately. If Lamivudine; Nevirapine; Zidovudine (Nevirapine) is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4⁺ cell count at initiationof Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Lamivudine; Nevirapine; Zidovudine (Nevirapine))and asymptomatic increases in AST or ALT .

The majority of rashes associatedwith Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) immediatelyand consult a physician. Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine) and extended-releaseVIRAMUNE XR concomitantly.

Drug Interactions

Lamivudine; Nevirapine; Zidovudine (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 Lamivudine; Nevirapine; Zidovudine (Nevirapine)

Distributed by:

Boehringer IngelheimPharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Copyright © 2017 Boehringer Ingelheim Pharmaceuticals,Inc.

ALL RIGHTS RESERVED

OT1801ZD32017

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

240 mL

NDC 0597-0047-24

Lamivudine; Nevirapine; Zidovudine (Nevirapine) Oral Suspension 50 mg/5mL Lamivudine; Nevirapine; Zidovudine (Nevirapine) Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Lamivudine; Nevirapine; Zidovudine (Nevirapine)

200 mg

60 Tablets

NDC 0597-0046-60

Viramune

Zidovudine:

• Warning: risk of hematological toxicity, myopathy, lactic acidosis
• 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
• Lamivudine; Nevirapine; Zidovudine (Zidovudine) reviews

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS

Hematologic Toxicity: Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets have been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease .

Myopathy: Prolonged use of Lamivudine; Nevirapine; Zidovudine (Zidovudine) has been associated with symptomatic myopathy .

Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Lamivudine; Nevirapine; Zidovudine (Zidovudine) and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur .

WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS

See full prescribing information for complete boxed warning.

• Hematologic toxicity including neutropenia and severe anemia have been associated with the use of Lamivudine; Nevirapine; Zidovudine (Zidovudine). ( 5.1)
• Symptomatic myopathy associated with prolonged use of Lamivudine; Nevirapine; Zidovudine (Zidovudine). ( 5.3)
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including Lamivudine; Nevirapine; Zidovudine (Zidovudine). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. ( 5.4)

1 INDICATIONS AND USAGE

Lamivudine; Nevirapine; Zidovudine is a nucleoside analogue reverse transcriptase inhibitor indicated for:

• Treatment of Human Immunodeficiency Virus (HIV-1) infection in combination with other antiretroviral agents. ( 1.1)
• Prevention of maternal-fetal HIV-1 transmission. ( 1.2)

1.1 Treatment of HIV-1

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

1.2 Prevention of Maternal-Fetal HIV-1 Transmission

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP are indicated for the prevention of maternal-fetal HIV-1 transmission . The indication is based on a dosing regimen that included three components:

• antepartum therapy of HIV-1 infected mothers
• intrapartum therapy of HIV-1 infected mothers
• post-partum therapy of HIV-1 exposed neonate

Points to consider prior to initiating Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:

• In most cases, Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
• Prevention of HIV-1 transmission in women who have received Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP for a prolonged period before pregnancy has not been evaluated.
• Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.

2 DOSAGE AND ADMINISTRATION

• Treatment of HIV-1 infection:
• Adults: Recommended oral dosage is 300 mg twice a day with other antiretroviral agents.
• Pediatric patients (aged 4 weeks to less than 18 years): Dosage should be calculated based on body weight not to exceed adult dose. ( 2.2)
• Prevention of maternal-fetal HIV-1 transmission:
• Specific dosage instructions for mother and infant. ( 2.3)
• Patients with severe anemia and/or neutropenia:
• Dosage interruption may be necessary. ( 2.4)
• Renal impairment: Recommended oral dosage in hemodialysis or peritoneal dialysis or in patients with creatinine clearance (CrCl) less than 15 mL per minute is 100 mg every 6 to 8 hours. ( 2.5)

2.1 Adults – Treatment of HIV-1 Infection

Oral Dosing

The recommended oral dose of Lamivudine; Nevirapine; Zidovudine tablets is 300 mg twice daily in combination with other antiretroviral agents.

2.2 Pediatric Patients (Aged 4 Weeks to Less Than 18 Years)

Healthcare professionals should pay special attention to accurate calculation of the dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.

Prescribers should calculate the appropriate dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.

Before prescribing Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablet, the Lamivudine; Nevirapine; Zidovudine (Zidovudine) syrup formulation should be prescribed.

The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and weighing greater than or equal to 4 kg is provided in Table 1. Lamivudine; Nevirapine; Zidovudine (Zidovudine) syrup should be used to provide accurate dosage when whole tablets are not appropriate.

Body Weight (kg)	Total Daily Dose	Dosage Regimen and Dose
		Twice Daily	Three Times Daily
4 to < 9	24 mg/kg/day	12 mg/kg	8 mg/kg
≥ 9 to < 30	18 mg/kg/day	9 mg/kg	6 mg/kg
≥ 30	600 mg/day	300 mg	200 mg

Alternatively, dosing for Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets can be based on body surface area (BSA) for each child. The recommended oral dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets is 480 mg per m ² per day in divided doses (240 mg per m ² twice daily or 160 mg per m ² three times daily). In some cases the dose calculated by mg per kg will not be the same as that calculated by BSA.

2.3 Prevention of Maternal-Fetal HIV-1 Transmission

The recommended dosage regimen for administration to pregnant women and their neonates is:

Maternal Dosing

100 mg orally 5 times per day until the start of labor . During labor and delivery, intravenous Lamivudine; Nevirapine; Zidovudine (Zidovudine) should be administered at 2 mg per kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until clamping of the umbilical cord.

Neonatal Dosing

Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered Lamivudine; Nevirapine; Zidovudine intravenously. See Table 2.

Route	Total Daily Dose	Dose and Dosage Regimen
Oral	8 mg/kg/day	2 mg/kg every 6 hours
Intravenous	6 mg/kg/day	1.5 mg/kg infused over 30 minutes, every 6 hours

2.4 Patients with Severe Anemia and/or Neutropenia

Significant anemia (hemoglobin less than 7.5 g per dL or reduction greater than 25% of baseline) and/or significant neutropenia (granulocyte count less than 750 cells per mm ³ or reduction greater than 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed . In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoietin level and patient tolerance.

2.5 Patients with Renal Impairment

In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to 8 hours .

2.6 Patients with Hepatic Impairment

There are insufficient data to recommend dose adjustment of Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised .

3 DOSAGE FORMS AND STRENGTHS

Lamivudine; Nevirapine; Zidovudine (Zidovudine) Tablets USP, 300 mg are white, biconvex, round, film-coated tablets debossed with "S2" on one side and blank on the other side.

Tablets: 300 mg ( 3)

4 CONTRAINDICATIONS

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets are contraindicated in patients who have had a potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.

Hypersensitivity to Lamivudine; Nevirapine; Zidovudine (Zidovudine) or any of the components (e.g., anaphylaxis, Stevens-Johnson syndrome). ( 4)

5 WARNINGS AND PRECAUTIONS

• See boxed warning for information about the following: hematologic toxicity, myopathy, and lactic acidosis and severe hepatomegaly.
• Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and Lamivudine; Nevirapine; Zidovudine (Zidovudine). Coadministration of ribavirin and Lamivudine; Nevirapine; Zidovudine (Zidovudine) is not advised. ( 5.5)
• Hepatic decompensation, (some fatal), has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with/without ribavirin. Discontinue Lamivudine; Nevirapine; Zidovudine (Zidovudine) as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.5)
• Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets should not be administered with other zidovudine-containing combination products. ( 5.6)
• Immune reconstitution syndrome ( 5.7) and redistribution/accumulation of body fat ( 5.8) have been reported in patients treated with combination antiretroviral therapy.

5.1 Hematologic Toxicity/Bone Marrow Suppression

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm ³ or hemoglobin less than 9.5 g per dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of Lamivudine; Nevirapine; Zidovudine (Zidovudine), which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of Lamivudine; Nevirapine; Zidovudine (Zidovudine), and/or blood transfusions, has occurred during treatment with Lamivudine; Nevirapine; Zidovudine (Zidovudine) alone or in combination with other antiretrovirals.

Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with Lamivudine; Nevirapine; Zidovudine (Zidovudine). For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed .

5.3 Myopathy

Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of Lamivudine; Nevirapine; Zidovudine.

5.4 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 Lamivudine; Nevirapine; Zidovudine (Zidovudine) and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering Lamivudine; Nevirapine; Zidovudine (Zidovudine) to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Lamivudine; Nevirapine; Zidovudine (Zidovudine) should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

5.5 Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV Co-infected Patients

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as Lamivudine; Nevirapine; Zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with Lamivudine; Nevirapine; Zidovudine (Zidovudine) in HIV-1/HCV co-infected subjects , exacerbation of anemia due to ribavirin has been reported when Lamivudine; Nevirapine; Zidovudine (Zidovudine) is part of the HIV regimen. Coadministration of ribavirin and Lamivudine; Nevirapine; Zidovudine (Zidovudine) is not advised. Consideration should be given to replacing Lamivudine; Nevirapine; Zidovudine (Zidovudine) in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.

Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Lamivudine; Nevirapine; Zidovudine (Zidovudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia.

Discontinuation of Lamivudine; Nevirapine; Zidovudine (Zidovudine) should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).

5.6 Use with Other Zidovudine-containing Products

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets should not be administered with combination products that contain Lamivudine; Nevirapine; Zidovudine (Zidovudine) as one of their components (e.g., COMBIVIR ^® [lamivudine and zidovudine] tablets or TRIZIVIR ^® [abacavir sulfate, lamivudine, and zidovudine] tablets).

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Lamivudine; Nevirapine; Zidovudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii 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.

5.8 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

6 ADVERSE REACTIONS

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

• Hematologic toxicity, including neutropenia and anemia .
• Symptomatic myopathy .
• Lactic acidosis and severe hepatomegaly with steatosis .
• Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C .

• Most commonly reported adverse reactions (incidence greater than or equal to 15%) in adult HIV-1 clinical trials were headache, malaise, nausea, anorexia, and vomiting. ( 6.1)
• Most commonly reported adverse reactions (incidence greater than or equal to 15%) in pediatric HIV-1 clinical trials were fever and cough. ( 6.1)
• Most commonly reported adverse reactions in neonates (incidence greater than or equal to 15%) in the prevention of maternal-fetal transmission of HIV-1 clinical trial were anemia and neutropenia. ( 6.1)
  

To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-800-325-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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

Adults

The frequency and severity of adverse reactions associated with the use of Lamivudine; Nevirapine; Zidovudine are greater in patients with more advanced infection at the time of initiation of therapy.

Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral Lamivudine; Nevirapine; Zidovudine (Zidovudine) in a monotherapy trial.

Adverse Reaction	Lamivudine; Nevirapine; Zidovudine (Zidovudine) 500 mg/day (n = 453)	Placebo (n = 428)
Body as a whole
Asthenia	9% Not statistically significant versus placebo.	6%
Headache	63%	53%
Malaise	53%	45%
Gastrointestinal
Anorexia	20%	11%
Constipation	6%	4%
Nausea	51%	30%
Vomiting	17%	10%

In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.

Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral Lamivudine; Nevirapine; Zidovudine (Zidovudine) are shown in Table 4.

ULN = Upper limit of normal.
Test (Abnormal Level)	Lamivudine; Nevirapine; Zidovudine (Zidovudine) 500 mg/day (n = 453)	Placebo (n = 428)
Anemia (Hgb < 8 g/dL)	1%	< 1%
Granulocytopenia (< 750 cells/mm 3)	2%	2%
Thrombocytopenia (platelets < 50,000/mm 3)	0%	< 1%
ALT (> 5 x ULN)	3%	3%
AST (> 5 x ULN)	1%	2%

Pediatrics

The clinical adverse reactions reported among adult recipients of Lamivudine; Nevirapine; Zidovudine (Zidovudine) may also occur in pediatric patients.

Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR ^® (lamivudine) oral suspension 4 mg per kg twice daily plus Lamivudine; Nevirapine; Zidovudine (Zidovudine) 160 mg per m ² 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.

Adverse Reaction	EPIVIR plus Lamivudine; Nevirapine; Zidovudine (Zidovudine) (n = 236)	Didanosine (n = 235)
Body as a whole
Fever	25%	32%
Digestive
Hepatomegaly	11%	11%
Nausea & vomiting	8%	7%
Diarrhea	8%	6%
Stomatitis	6%	12%
Splenomegaly	5%	8%
Respiratory
Cough	15%	18%
Abnormal breath sounds/wheezing	7%	9%
Ear, Nose, and Throat
Signs or symptoms of ears Includes pain, discharge, erythema, or swelling of an ear.	7%	6%
Nasal discharge or congestion	8%	11%
Other
Skin rashes	12%	14%
Lymphadenopathy	9%	11%

Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.

ULN = Upper limit of normal.
ANC = Absolute neutrophil count.
Test (Abnormal Level)	EPIVIR plus Lamivudine; Nevirapine; Zidovudine (Zidovudine)	Didanosine
Neutropenia (ANC < 400 cells/mm 3)	8%	3%
Anemia (Hgb < 7 g/dL)	4%	2%
Thrombocytopenia (platelets < 50,000/mm 3)	1%	3%
ALT (> 10 x ULN)	1%	3%
AST (> 10 x ULN)	2%	4%
Lipase (> 2.5 x ULN)	3%	3%
Total amylase (> 2.5 x ULN)	3%	3%

Macrocytosis was reported in the majority of pediatric subjects receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine) 180 mg per m ² every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.

Use for the Prevention of Maternal-Fetal Transmission of HIV-1

In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of Lamivudine; Nevirapine; Zidovudine for the prevention of maternal-fetal HIV-1 transmission, Lamivudine; Nevirapine; Zidovudine (Zidovudine) syrup at 2 mg per kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin less than 9.0 g per dL) and neutropenia (less than 1,000 cells per mm ³). Anemia occurred in 22% of the neonates who received Lamivudine; Nevirapine; Zidovudine (Zidovudine) and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g per dL for neonates receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine) compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine). Neutropenia in neonates was reported with similar frequency in the group that received Lamivudine; Nevirapine; Zidovudine (Zidovudine) (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to Lamivudine; Nevirapine; Zidovudine (Zidovudine) are unknown.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Lamivudine; Nevirapine; Zidovudine (Zidovudine). 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.

Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/

accumulation of body fat .

Cardiovascular: Cardiomyopathy, syncope.

Eye: Macular edema.

Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.

General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.

Hematologic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.

Hepatobiliary: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.

Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.

Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.

Reproductive System and Breast: Gynecomastia.

Respiratory: Dyspnea, rhinitis, sinusitis.

Skin and Subcutaneous Tissue: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria.

Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.

Renal and Urinary: Urinary frequency, urinary hesitancy.

7 DRUG INTERACTIONS

• Stavudine: Concomitant use with Lamivudine; Nevirapine; Zidovudine should be avoided. ( 7.1)
• Doxorubicin: Use with Lamivudine; Nevirapine; Zidovudine (Zidovudine) should be avoided. ( 7.2)
• Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of Lamivudine; Nevirapine; Zidovudine (Zidovudine). ( 7.3)

7.1 Antiretroviral Agents

Stavudine

Concomitant use of Lamivudine; Nevirapine; Zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.

Nucleoside Analogues Affecting DNA Replication

Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of Lamivudine; Nevirapine; Zidovudine (Zidovudine) against HIV-1; concomitant use of such drugs should be avoided.

7.2 Doxorubicin

Concomitant use of Lamivudine; Nevirapine; Zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.

7.3 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of Lamivudine; Nevirapine; Zidovudine (Zidovudine).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

In humans, treatment with Lamivudine; Nevirapine; Zidovudine during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with Lamivudine; Nevirapine; Zidovudine (Zidovudine) . There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of Lamivudine; Nevirapine; Zidovudine (Zidovudine) for the prevention of maternal-fetal HIV-1-transmission . Congenital abnormalities occurred with similar frequency between neonates born to mothers who received Lamivudine; Nevirapine; Zidovudine (Zidovudine) and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of Lamivudine; Nevirapine; Zidovudine (Zidovudine) that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine). There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received Lamivudine; Nevirapine; Zidovudine (Zidovudine) up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day Lamivudine; Nevirapine; Zidovudine (Zidovudine)). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose .

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to Lamivudine; Nevirapine; Zidovudine (Zidovudine), an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

Lamivudine; Nevirapine; Zidovudine is excreted in human milk. After administration of a single dose of 200 mg Lamivudine; Nevirapine; Zidovudine (Zidovudine) to 13 HIV-1-infected women, the mean concentration of Lamivudine; Nevirapine; Zidovudine (Zidovudine) was similar in human milk and serum.

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine).

8.4 Pediatric Use

Lamivudine; Nevirapine; Zidovudine (Zidovudine) has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Lamivudine; Nevirapine; Zidovudine (Zidovudine) has also been studied in neonates perinatally exposed to HIV-1 .

8.5 Geriatric Use

Clinical studies of Lamivudine; Nevirapine; Zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Unchanged Lamivudine; Nevirapine; Zidovudine (Zidovudine) and its glucuronide metabolite (formed in the liver) are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended .

8.7 Hepatic Impairment

Lamivudine; Nevirapine; Zidovudine (Zidovudine) is primarily eliminated by hepatic metabolism and Lamivudine; Nevirapine; Zidovudine (Zidovudine) concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of Lamivudine; Nevirapine; Zidovudine (Zidovudine) in patients with impaired hepatic function or liver cirrhosis .

10 OVERDOSAGE

Acute overdoses of Lamivudine; Nevirapine; Zidovudine (Zidovudine) have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with Lamivudine; Nevirapine; Zidovudine (Zidovudine) apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of Lamivudine; Nevirapine; Zidovudine (Zidovudine) while elimination of its primary metabolite, 3ʹ‑azido-3ʹ-deoxy-5ʹ- O-β- D-glucopyranuronosylthymidine (GZDV), is enhanced. If overdose occurs, the patient should be monitored for evidence of toxicity and given standard supportive treatment as required.

11 DESCRIPTION

Lamivudine; Nevirapine; Zidovudine (Zidovudine) (formerly called azidothymidine [AZT]), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of Lamivudine; Nevirapine; Zidovudine (Zidovudine) is 3ʹ-Azido-3ʹ-deoxythymidine; it has the following structural formula:

Lamivudine; Nevirapine; Zidovudine (Zidovudine) is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C ₁₀H ₁₃N ₅O ₄.

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets USP are for oral administration. Each film-coated tablet contains 300 mg of Lamivudine; Nevirapine; Zidovudine (Zidovudine) and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, polyethylene glycol, titanium dioxide, polyvinyl alcohol-part hydrolyzed, talc and lecithin soya.

Lamivudine; Nevirapine; Zidovudine (Zidovudine) Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lamivudine; Nevirapine; Zidovudine is an antiviral agent .

12.3 Pharmacokinetics

Absorption and Bioavailability

In adults, following oral administration, Lamivudine; Nevirapine; Zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when Lamivudine; Nevirapine; Zidovudine (Zidovudine) was administered as Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets or syrup compared with Lamivudine; Nevirapine; Zidovudine (Zidovudine) capsules. The pharmacokinetic properties of Lamivudine; Nevirapine; Zidovudine (Zidovudine) in fasting adult subjects are summarized in Table 7.

Parameter	Mean ± SD (except where noted)
Oral bioavailability (%)	64 ± 10 (n = 5)
Apparent volume of distribution (L/kg)	1.6 ± 0.6 (n = 8)
Cerebrospinal fluid (CSF):plasma ratio Median [range] for 50 paired samples drawn 1 to 8 hours after the last dose in subjects on chronic therapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine).	0.6 [0.04 to 2.62] (n = 39)
Systemic clearance (L/h/kg)	1.6 ± 0.6 (n = 6)
Renal clearance (L/h/kg)	0.34 ± 0.05 (n = 9)
Elimination half-life (h) Approximate range.	0.5 to 3 (n = 19)

Distribution

The apparent volume of distribution of Lamivudine; Nevirapine; Zidovudine (Zidovudine) is 1.6 ± 0.6 L per kg (Table 7); and binding to plasma protein is low (less than 38%).

Metabolism and Elimination

Lamivudine; Nevirapine; Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of Lamivudine; Nevirapine; Zidovudine (Zidovudine) is GZDV. GZDV AUC is about 3-fold greater than the Lamivudine; Nevirapine; Zidovudine (Zidovudine) AUC. Urinary recovery of Lamivudine; Nevirapine; Zidovudine (Zidovudine) and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3ʹ-amino-3ʹ‑deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of Lamivudine; Nevirapine; Zidovudine (Zidovudine). The AMT AUC was one-fifth of the Lamivudine; Nevirapine; Zidovudine (Zidovudine) AUC. Pharmacokinetics of Lamivudine; Nevirapine; Zidovudine (Zidovudine) were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours.

Effect of Food on Absorption

Lamivudine; Nevirapine; Zidovudine (Zidovudine) may be administered with or without food. The Lamivudine; Nevirapine; Zidovudine (Zidovudine) AUC was similar when a single dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine) was administered with food.

Special Populations

Renal Impairment: Lamivudine; Nevirapine; Zidovudine clearance was decreased resulting in increased Lamivudine; Nevirapine; Zidovudine (Zidovudine) and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.

Parameter	Control Subjects (Normal Renal Function) (n = 6)	Subjects With Renal Impairment (n = 14)
CrCl (mL/min)	120 ± 8	18 ± 2
Lamivudine; Nevirapine; Zidovudine (Zidovudine) AUC (ng-h/mL)	1,400 ± 200	3,100 ± 300
Lamivudine; Nevirapine; Zidovudine (Zidovudine) half-life (h)	1 ± 2	1.4 ± 0.1

Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of Lamivudine; Nevirapine; Zidovudine (Zidovudine) were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent Lamivudine; Nevirapine; Zidovudine (Zidovudine) oral clearance was approximately 50% of that reported in subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of Lamivudine; Nevirapine; Zidovudine (Zidovudine), whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis .

Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of Lamivudine; Nevirapine; Zidovudine (Zidovudine) are limited. However, Lamivudine; Nevirapine; Zidovudine (Zidovudine) is eliminated primarily by hepatic metabolism and it appears that Lamivudine; Nevirapine; Zidovudine (Zidovudine) clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of Lamivudine; Nevirapine; Zidovudine (Zidovudine) in patients with impaired hepatic function or liver cirrhosis .

Pediatric Patients: Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9).

Patients Aged 3 Months to 12 Years: Overall, Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics in pediatric patients older than 3 months are similar to those in adult patients. Proportional increases in plasma Lamivudine; Nevirapine; Zidovudine (Zidovudine) concentrations were observed following administration of oral solution from 90 to 240 mg per m ² every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV .

Patients Aged Less Than 3 Months Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics have been evaluated in pediatric subjects from birth to 3 months of life. Lamivudine; Nevirapine; Zidovudine (Zidovudine) elimination was determined immediately following birth in eight neonates who were exposed to Lamivudine; Nevirapine; Zidovudine (Zidovudine) in utero. The half-life was 13 ± 5.8 hours. In neonates less than or equal to 14 days, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates .

Parameter	Birth to 14 Days	Aged 14 Days to 3 Months	Aged 3 Months to 12 Years
Oral bioavailability (%)	89 ± 19 (n = 15)	61 ± 19 (n = 17)	65 ± 24 (n = 18)
CSF:plasma ratio	no data	no data	0.68 [0.03 to 3.25] Median [range]. (n = 38)
CL (L/h/kg)	0.65 ± 0.29 (n = 18)	1.14 ± 0.24 (n = 16)	1.85 ± 0.47 (n = 20)
Elimination half-life (h)	3.1 ± 1.2 (n = 21)	1.9 ± 0.7 (n = 18)	1.5 ± 0.7 (n = 21)

Pregnancy: Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics have been studied in a Phase I trial of eight women during the last trimester of pregnancy. Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, Lamivudine; Nevirapine; Zidovudine (Zidovudine) concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .

Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics.

Geriatric Patients: Lamivudine; Nevirapine; Zidovudine (Zidovudine) pharmacokinetics have not been studied in subjects over 65 years of age.

Gender: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no differences in Lamivudine; Nevirapine; Zidovudine (Zidovudine) AUC when a single dose of Lamivudine; Nevirapine; Zidovudine (Zidovudine) was administered as the

300 mg Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablet.

Drug Interactions

.

↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.
Note: ROUTINE DOSE MODIFICATION OF Lamivudine; Nevirapine; Zidovudine (Zidovudine) IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.
Coadministered Drug and Dose	Lamivudine; Nevirapine; Zidovudine (Zidovudine) Oral Dose	n	Lamivudine; Nevirapine; Zidovudine (Zidovudine) Concentrations		Concentration of Coadministered Drug
			AUC	Variability
Atovaquone 750 mg every 12 h with food	200 mg every 8 h	14	↑AUC 31%	Range: 23% to 78% Estimated range of percent difference.	↔
Clarithromycin 500 mg twice daily	100 mg every 4 h x 7 days	4	↓AUC 12%	Range: ↓34% to ↑14%	Not Reported
Fluconazole 400 mg daily	200 mg every 8 h	12	↑AUC 74%	95% CI: 54% to 98%	Not Reported
Lamivudine 300 mg every 12 h	single 200 mg	12	↑AUC 13%	90% CI: 2% to 27%	↔
Methadone 30 mg to 90 mg daily	200 mg every 4 h	9	↑AUC 43%	Range: 16% to 64%	↔
Nelfinavir 750 mg every 8 h x 7 to 10 days	single 200 mg	11	↓AUC 35%	Range: 28% to 41%	↔
Probenecid 500 mg every 6 h x 2 days	2 mg/kg every 8 h x 3 days	3	↑AUC 106%	Range: 100% to 170%	Not Assessed
Rifampin 600 mg daily x 14 days	200 mg q 8 h x 14 days	8	↓AUC 47%	90% CI: 41% to 53%	Not Assessed
Ritonavir 300 mg every 6 h x 4 days	200 mg every 8 h x 4 days	9	↓AUC 25%	95% CI: 15% to 34%	↔
Valproic acid 250 mg or 500 mg every 8 h x 4 days	100 mg every 8 h x 4 days	6	↑AUC 80%	Range: 64% to 130%	Not Assessed

Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine), while in one case a high level was documented. However, in a pharmacokinetic interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state Lamivudine; Nevirapine; Zidovudine (Zidovudine) conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on Lamivudine; Nevirapine; Zidovudine (Zidovudine) kinetics, a 30% decrease in oral Lamivudine; Nevirapine; Zidovudine (Zidovudine) clearance was observed with phenytoin.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and Lamivudine; Nevirapine; Zidovudine (Zidovudine). However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or Lamivudine; Nevirapine; Zidovudine (Zidovudine) (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects .

12.4 Microbiology

Mechanism of Action

Lamivudine; Nevirapine; Zidovudine is a synthetic nucleoside analogue. Intracellularly, Lamivudine; Nevirapine; Zidovudine (Zidovudine) is phosphorylated to its active 5ʹ-triphosphate metabolite, Lamivudine; Nevirapine; Zidovudine (Zidovudine) triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity

The antiviral activity of Lamivudine; Nevirapine; Zidovudine (Zidovudine) against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC ₅₀ and EC ₉₀ values for Lamivudine; Nevirapine; Zidovudine (Zidovudine) were 0.01 to 0.49 µM (1 µM = 0.27 mcg per mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC ₅₀ values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC ₅₀ values of Lamivudine; Nevirapine; Zidovudine (Zidovudine) against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, Lamivudine; Nevirapine; Zidovudine (Zidovudine) demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of Lamivudine; Nevirapine; Zidovudine (Zidovudine) in cell culture.

Resistance

Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions that confer Lamivudine; Nevirapine; Zidovudine (Zidovudine) resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to Lamivudine; Nevirapine; Zidovudine (Zidovudine) was restored by 12 weeks of treatment with lamivudine and Lamivudine; Nevirapine; Zidovudine (Zidovudine). Combination therapy with lamivudine plus Lamivudine; Nevirapine; Zidovudine (Zidovudine) delayed the emergence of substitutions conferring resistance to Lamivudine; Nevirapine; Zidovudine (Zidovudine).

Cross-Resistance

In a trial of 167 HIV-1-infected subjects, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and Lamivudine; Nevirapine; Zidovudine (Zidovudine) were recovered from subjects treated for at least 1 year with Lamivudine; Nevirapine; Zidovudine (Zidovudine) plus didanosine or Lamivudine; Nevirapine; Zidovudine (Zidovudine) plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with Lamivudine; Nevirapine; Zidovudine (Zidovudine) monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and Lamivudine; Nevirapine; Zidovudine (Zidovudine). Thymidine analogue mutations (TAMs) are selected by Lamivudine; Nevirapine; Zidovudine (Zidovudine) and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lamivudine; Nevirapine; Zidovudine was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.

In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.

In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.

At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Two transplacental carcinogenicity studies were conducted in mice. One study administered Lamivudine; Nevirapine; Zidovudine (Zidovudine) at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of Lamivudine; Nevirapine; Zidovudine (Zidovudine) administered in this study produced Lamivudine; Nevirapine; Zidovudine (Zidovudine) exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered Lamivudine; Nevirapine; Zidovudine (Zidovudine) at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of Lamivudine; Nevirapine; Zidovudine (Zidovudine).

Mutagenesis

Lamivudine; Nevirapine; Zidovudine (Zidovudine) was mutagenic in a 5178Y/TK ^+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.

Impairment of Fertility

Lamivudine; Nevirapine; Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, had no effect on fertility judged by conception rates.

13.2 Animal Toxicology and/or Pharmacology

Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with Lamivudine; Nevirapine; Zidovudine (Zidovudine). Lamivudine; Nevirapine; Zidovudine (Zidovudine) treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak Lamivudine; Nevirapine; Zidovudine (Zidovudine) plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, Lamivudine; Nevirapine; Zidovudine (Zidovudine) exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg per kg per day (very near the oral median lethal dose in rats of 3683 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak Lamivudine; Nevirapine; Zidovudine (Zidovudine) plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.

14 CLINICAL STUDIES

Therapy with Lamivudine; Nevirapine; Zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.

14.1 Adults

Combination Therapy

Lamivudine; Nevirapine; Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.

The clinical efficacy of a combination regimen that includes Lamivudine; Nevirapine; Zidovudine (Zidovudine) was demonstrated in trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial that compared Lamivudine; Nevirapine; Zidovudine (Zidovudine) 600 mg per day plus EPIVIR 300 mg per day to Lamivudine; Nevirapine; Zidovudine (Zidovudine) plus EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1% versus 10.9%, respectively).

Monotherapy

In controlled trials of treatment-naive subjects conducted between 1986 and 1989, monotherapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine), as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These trials enrolled subjects with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and 500 cells per mm ³ (ACTG 016 and ACTG 019). A survival benefit for monotherapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine) was not demonstrated in the latter two trials. Subsequent trials showed that the clinical benefit of monotherapy with Lamivudine; Nevirapine; Zidovudine (Zidovudine) was time limited.

14.2 Pediatric Patients

ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of EPIVIR plus Lamivudine; Nevirapine; Zidovudine to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric subjects were enrolled in these two treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells per mm ³, and the mean baseline plasma HIV-1 RNA was 5.0 log ₁₀ copies per mL. The median duration that subjects remained on trial was approximately 10 months. Results are summarized in Table 11.

Endpoint	EPIVIR plus Lamivudine; Nevirapine; Zidovudine (Zidovudine) (n = 236)	Didanosine (n = 235)
HIV disease progression or death (total)	15 (6.4%)	37 (15.7%)
Physical growth failure	7 (3%)	6 (2.6%)
Central nervous system deterioration	4 (1.7%)	12 (5.1%)
CDC Clinical Category C	2 (0.8%)	8 (3.4%)
Death	2 (0.8%)	11 (4.7%)

14.3 Prevention of Maternal-Fetal HIV-1 Transmission

The utility of Lamivudine; Nevirapine; Zidovudine (Zidovudine) for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm ³ (median in the treated group: 560 cells per mm ³) who had little or no previous exposure to Lamivudine; Nevirapine; Zidovudine (Zidovudine). Oral Lamivudine; Nevirapine; Zidovudine (Zidovudine) was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of Lamivudine; Nevirapine; Zidovudine (Zidovudine) during labor and delivery. Following birth, neonates received oral Lamivudine; Nevirapine; Zidovudine (Zidovudine) syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine) and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine) and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Lamivudine; Nevirapine; Zidovudine (Zidovudine) was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lamivudine; Nevirapine; Zidovudine (Zidovudine) Tablets USP, 300 mg are supplied as white, biconvex, round, film-coated tablets containing 300 mg of Lamivudine; Nevirapine; Zidovudine (Zidovudine) per tablet. Each tablet has one side debossed with “S2” and blank on the other side.

Bottles of 60 (NDC 0527-1905-06).

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions

Inform patients that potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) can occur while receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine). Instruct patients to immediately contact their healthcare provider if they develop rash, as it may be a sign of a more serious reaction. Advise patients that it is very important that they remain under a healthcare provider’s care during treatment with Lamivudine; Nevirapine; Zidovudine (Zidovudine).

Neutropenia and Anemia

Inform patients that the major toxicities of Lamivudine; Nevirapine; Zidovudine (Zidovudine) are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Advise patients that if toxicity develops, they may require transfusions or drug discontinuation. Advise patients of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease .

Myopathy

Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of Lamivudine; Nevirapine; Zidovudine (Zidovudine) .

Lactic Acidosis/Hepatomegaly

Inform patients that some HIV medicines, including Lamivudine; Nevirapine; Zidovudine (Zidovudine), can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) .

HIV-1/HCV Co-infection

Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin .

Use with Other Zidovudine-containing Products

Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets should not be administered with combination products that contain Lamivudine; Nevirapine; Zidovudine (Zidovudine) as one of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR [abacavir sulfate, lamivudine, and zidovudine] tablets) .

Immune Reconstitution Syndrome

In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection .

Redistribution/Accumulation of Body Fat:

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time .

Common Adverse Reactions:

Inform patients that the most commonly reported adverse reactions in adult patients being treated with Lamivudine; Nevirapine; Zidovudine (Zidovudine) were headache, malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in pediatric patients receiving Lamivudine; Nevirapine; Zidovudine (Zidovudine) were fever, cough, and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with Lamivudine; Nevirapine; Zidovudine (Zidovudine) .

Drug Interactions

Caution patients about the use of other medications, including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of Lamivudine; Nevirapine; Zidovudine (Zidovudine) .

Pregnancy

Inform pregnant women considering the use of Lamivudine; Nevirapine; Zidovudine (Zidovudine) during pregnancy for prevention of HIV-1 transmission to their infants that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to Lamivudine; Nevirapine; Zidovudine (Zidovudine) are unknown, including the possible risk of cancer .

Advise HIV-1-infected pregnant women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected .

Information About HIV-1 Infection

Lamivudine; Nevirapine; Zidovudine (Zidovudine) is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-1-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician when using Lamivudine; Nevirapine; Zidovudine (Zidovudine) tablets.

Patients should be informed to take all HIV medications exactly as prescribed.

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.
• Continue to practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Female patients should be advised not to breastfeed. Lamivudine; Nevirapine; Zidovudine (Zidovudine) is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Instruct patients that if they miss a dose, they should just take their next dose at the usual time. Patients should not double their next dose.

COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of the ViiV Healthcare group of companies.

Manufactured by:

Sunshine Lake Pharma Co., Ltd.

Guangdong Province 523808

P.R. China

Manufactured for:

Lannett Company, Inc.

Philadelphia, PA 19136

Revised: 12/2015, Revision 1

10-003

1425

Logo

PRINCIPAL DISPLAY PANEL – 300 mg

NDC 0527-1905-06

Lamivudine; Nevirapine; Zidovudine (Zidovudine)

TABLETS, USP

300 mg

Rx only

60 Tablets

Each tablet contains 300 mg of Lamivudine; Nevirapine; Zidovudine (Zidovudine).

Usual

Dosage: See package insert for Dosage and Administration.

Store at 20° to 25°C (68° to 77°F). Preserve in tight, light-resistant containers.

Manufactured for:

Lannett Company, Inc.

Philadelphia, PA19136

by:

Sunshine Lake Pharma Co., Ltd.

Guangdong Province, China

Rev. 12/13 10-002

1412