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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue lamivudine, nevirapine, and zidovudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.7 ) Exacerbation of anemia has been reported in HIV 1/HCV co infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. ( 5.7 ) Pancreatitis: Use with caution in patients with a history of pancreatitis or other significant risk factors for pancreatitis. Discontinue treatment as clinically appropriate. ( 5.8 ) Immune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. ( 5.9 , 5.12 ) 5.1 Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine, a component of lamivudine, nevirapine, and zidovudine. tablets. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups. The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with nonspecific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction. Patients with signs or symptoms of hepatitis must be advised to discontinue lamivudine, nevirapine, and zidovudine tablets and immediately seek medical evaluation, which should include liver enzyme tests. The first 18 weeks of therapy with nevirapine are a critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [ see Dosage and Administration (2.2) ]. If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue lamivudine, nevirapine, and zidovudine tablets. Do not restart lamivudine, nevirapine, and zidovudine tablets after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 + cell counts. In general, during the first 6 weeks of treatment, women have a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4 + cell counts greater than 250 cells per mm 3 had a 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4 + cell counts less than 250 cells per mm 3 (11% versus 1%). An increased risk was observed in men with CD4 + cell counts greater than 400 cells per mm 3 (6% versus 1% for men with CD4 + cell counts less than 400 cells per mm 3 ). However, all patients, regardless of gender, CD4 + cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 + cell counts. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT. In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated [ see Contraindications (4) ]. Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer lamivudine, nevirapine, and zidovudine tablets to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Contraindications (4) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ]. 5.2 Skin Reactions Nevirapine, a component of lamivudine, nevirapine, and zidovudine tablets, has been associated with severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue lamivudine, nevirapine, and zidovudine tablets and seek medical evaluation immediately. Do not restart lamivudine, nevirapine, and zidovudine tablets following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction. If patients present with a suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue lamivudine, nevirapine, and zidovudine tablets in patients with rash-associated transaminase elevations [ see Warnings and Precautions (5.1) ]. Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg per day (150 mg per m 2 per day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue lamivudine, nevirapine, and zidovudine tablets if a patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase lamivudine, nevirapine, and zidovudine tablets dose to a patient experiencing a mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg per m 2 per day in pediatric patients) until the rash has resolved . The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [ see Dosage and Administration (2.3) ]. Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping lamivudine, nevirapine, and zidovudine tablets treatment after the onset of rash may result in a more serious reaction. Women appear to be at higher risk than men of developing rash with nevirapine. In a clinical trial, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended. 5.3 Hematologic Toxicity/Bone Marrow Suppression Zidovudine, a component of lamivudine, nevirapine, and zidovudine tablets, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Lamivudine, nevirapine, and 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 grams per dL [see Adverse Reactions (6.1) ] . Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with lamivudine, nevirapine, and zidovudine tablets. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed. 5.4 Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, a component of lamivudine, nevirapine, and zidovudine tablets, and therefore may occur with therapy with lamivudine, nevirapine, and zidovudine tablets. 5.5 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, including lamivudine and zidovudine, components of lamivudine, nevirapine, and zidovudine tablets. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Treatment with lamivudine, nevirapine, and zidovudine tablets 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). 5.6 Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis: Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine, a component of lamivudine, nevirapine, and zidovudine tablets. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment. Emergence of Lamivudine-Resistant HBV: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudine containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine). 5.7 Use With Interferon- and Ribavirin-Based Regimens in HIV-1/HCV Co-Infected Patients Patients receiving interferon alfa with or without ribavirin and lamivudine and zidovudine, components of lamivudine, nevirapine, and zidovudine tablets, should be closely monitored for treatment‑associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of lamivudine, nevirapine, and zidovudine tablets 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) (see full prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and lamivudine, nevirapine, and zidovudine tablets is not advised. 5.8 Pancreatitis Lamivudine, nevirapine, and zidovudine tablets should be used with caution in patients with a history of pancreatitis or other significant risk factors for the development of pancreatitis. Treatment with lamivudine, nevirapine, and zidovudine tablets should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1) ]. 5.9 Lipoatrophy Treatment with zidovudine, a component of lamivudine, nevirapine, and zidovudine tablets, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy. 5.10 Drug Interactions See Table 5 for listings of established and potential drug interactions [ see Drug Interactions (7) ]. Concomitant use of St. John's wort ( Hypericum perforatum ) or St. John's wort-containing products and nevirapine, a component of lamivudine, nevirapine, and zidovudine tablets, is not recommended. Co-administration of St. John’s wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. 5.11 Resistance Nevirapine, a component of lamivudine, nevirapine, and zidovudine tablets, must not be used as a single agent to treat HIV-1 or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop [ see Microbiology (12.4) ]. 5.12 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine, zidovudine, and nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, 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.