VIRAMUNE SIDE EFFECTS

SIDE EFFECTS

Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Experience In Adult Patients

The most serious adverse reactions associated with VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may 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.

Hepatic Reaction

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received VIRAMUNE and 1% of subjects in control groups. Female gender and higher CD4 cell counts (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in men) place patients at increased risk of these events.

Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received VIRAMUNE and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving VIRAMUNE than in controls (see Table 3).

Skin Reaction

The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening. Rash occurs most frequently within 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 clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving VIRAMUNE compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of VIRAMUNE recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of VIRAMUNE-associated rash.

Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving VIRAMUNE in placebo-controlled trials are shown in Table 1.

Table 1 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials

Laboratory Abnormalities

Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving VIRAMUNE than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 2).

Table 2 Percentage of Adult Subjects with Laboratory Abnormalities

Clinical Trial Experience In Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of VIRAMUNE (n=305) in which pediatric subjects received combination treatment with VIRAMUNE. In this trial two subjects were reported to experience Stevens- Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of VIRAMUNE (n=37) in which subjects were followed for 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 BI 1100.892). The most frequently reported adverse events related to VIRAMUNE in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Cases of allergic reaction, including one case of anaphylaxis, were also reported.

The safety of VIRAMUNE was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with VIRAMUNE 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 experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%).

Safety information on use of VIRAMUNE in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

Post-Marketing Experience

In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal, redistribution/accumulation of 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 associated with skin and/or liver reactions

Neurologic: paraesthesia

Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms (DRESS) plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

SRC: NLM .