Nevirapine - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Monitor patients for immune reconstitution syndrome and fat redistribution. ( 5.5 , 5.6 ) 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.

The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy.

The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment.

However, hepatic events may occur at any time during treatment.

In some cases, patients presented with non-specific, 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 patients 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 nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.

The first 18 weeks of therapy with nevirapine extended-release tablets 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 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 extended-release tablets 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 ].

If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine.

Do not restart nevirapine 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 a retrospective analysis of pooled clinical trials with immediate-release nevirapine tablets, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%).

Patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events.