Lamivudine, Nevirapine, and Zidovudine

LAMIVUDINE, NEVIRAPINE, AND ZIDOVUDINE — lamivudine, nevirapine and zidovudine tablet, film coated
Micro Labs Limited

WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXOCITY, SKIN REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, EXACERBATIONS OF HEPATITIS B

HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine, a component of lamivudine, nevirapine, and zidovudine tablets. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4 + cell counts at initiation of therapy place patients at increased risk; women with CD4 + cell counts greater than 250 cells per mm 3 , including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4 + cell counts and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is contraindicated [ see Contraindications (4) ]. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately [ see Warnings and Precautions (5.1) ].

SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue lamivudine, nevirapine, and zidovudine tablets and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with nevirapine daily dosing has been observed to decrease the incidence of rash and must be followed [ see Warnings and Precautions (5.2) ].

MONITORING FOR HEPATOTOXICITY AND SKIN REACTIONS: Patients must be monitored intensively during the first 18 weeks of therapy with lamivudine, nevirapine, and zidovudine tablets to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of these events. Do not restart lamivudine, nevirapine, and zidovudine tablets following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.

HEMATOLOGIC TOXICITY: Zidovudine, a component of lamivudine, nevirapine, and zidovudine tablets, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see Warnings and Precautions (5.3)].

MYOPATHY: Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.4)] .

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine and zidovudine, two components of lamivudine, nevirapine, and zidovudine tablets. Discontinue lamivudine, nevirapine, and zidovudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.5)] .

EXACERBATIONS OF HEPATIS B: Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, which is one component of lamivudine, nevirapine, and zidovudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue lamivudine, nevirapine, and zidovudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.6)] .

1 INDICATIONS AND USAGE

Lamivudine, nevirapine, and zidovudine tablets is indicated alone as a complete regimen or in combination with other antiretrovirals for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 35 kg.

Additional important use regarding the use of nevirapine, a component of lamivudine, nevirapine, and zidovudine tablets, for the treatment of HIV-1 infection:

  • Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, lamivudine, nevirapine, and zidovudine tablets is not recommended to be initiated, unless the benefit outweighs the risk in:
    • adult females with CD4 + cell counts greater than 250 cells per mm 3 or
    • adult males with CD4 + cell counts greater than 400 cells per mm 3 [ see Warnings and Precautions (5.1) ].

2 DOSAGE AND ADMINISTRATION

2.1 Adults and Pediatric Patients Weighing at Least 35 kg

Lead-in Period (First 14 days of dosing)

One lamivudine, nevirapine, and zidovudine fixed-dose tablet (containing 150 mg of lamivudine, 200 mg of nevirapine, and 300 mg of zidovudine) taken orally once daily followed by a daily oral dose of lamivudine 150 mg and zidovudine 300 mg 12 hours later.

Maintenance (After 14 days of dosing)

If the initial 14 days of dosing is tolerated without any incidence of rash, the recommended maintenance dose is one lamivudine, nevirapine, and zidovudine fixed-dose tablet (containing 150 mg of lamivudine, 200 mg of nevirapine, and 300 mg of zidovudine) taken orally twice daily.

Lamivudine, nevirapine, and zidovudine tablets can be taken with or without food.

2.2 Monitoring of Patients

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with lamivudine, nevirapine, and zidovudine tablets. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at two weeks post-dose escalation. After the initial 18week period, frequent clinical and laboratory monitoring should continue throughout lamivudine, zidovudine, and nevirapine tablets treatment [ see Warnings and Precautions (5) ]. In some cases, hepatic injury has progressed despite discontinuation of treatment.

2.3 Dosage Adjustment

Because lamivudine, nevirapine, and zidovudine tablets is a fixed-dose combination and cannot be adjusted, it is not recommended for:

Liquid and solid oral formulations of the individual components of lamivudine, nevirapine, and zidovudine tablets are available for these populations.

Patients with Rash

Discontinue lamivudine, nevirapine, and zidovudine tablets if a patient experiences severe rash or any rash accompanied by constitutional findings [ see Warnings and Precautions (5.2)] . Do not increase nevirapine dose if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day until the rash has resolved [ see Warnings and Precautions (5.2)] . The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.

Patients with Hepatic Events

If a clinical (symptomatic) hepatic event occurs, permanently discontinue lamivudine, nevirapine, and zidovudine tablets. Do not restart lamivudine, nevirapine, and zidovudine tablets after recovery [ see Warnings and Precautions (5.1)]

Patients with Dose Interruption

For patients who interrupt lamivudine, nevirapine, and zidovudine tablets dosing for more than 7 days, restart the recommended dosing of lamivudine, nevirapine, and zidovudine nevirapine tablets using the lead-in period dosing for 14 days.

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