REBETRON SIDE EFFECTS

SIDE EFFECTS

The safety of combination REBETOL/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination REBETOL/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination REBETOL/INTRON A therapy. (See Description of Clinical Studies.) Overall, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-2 weeks of therapy (see WARNINGS). Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients treated with REBETOL/INTRON A therapy. (See WARNINGS.)

The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with REBETOL/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. In addition, the following spontaneous adverse events have been reported during the marketing surveillance of REBETOL/INTRON A therapy: hearing disorder and vertigo. Very rarely, combination REBETOL/INTRON A therapy may be associated with aplastic anemia.

Selected treatment-emergent adverse events that occurred in the US studies with ≥ 5% incidence are provided in TABLE 1 by treatment group. In general, the selected treatment-emergent adverse events reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

TABLE 1. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Patients

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during combination REBETOL/INTRON A treatment are described below (see TABLE 2).

Hemoglobin

Hemoglobin decreases among patients on combination therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4 – 8 weeks of cessation of therapy in most patients.

Neutrophils

There were decreases in neutrophil counts in both the combination REBETOL/INTRON A and INTRON A plus placebo dose groups. In previously untreated patients treated for 48 weeks the mean maximum decrease in neutrophil count in the US study was 1.3 x 10⁹ /L and in the International study was 1.5 x 10⁹ /L. In relapse patients the mean maximum decrease in neutrophil count in the US study was 1.3 x 10⁹ /L and in the International study was 1.6 x 10⁹ /L. Neutrophil counts returned to pretreatment levels within 4 weeks of cessation of therapy in most patients.

Platelets

In both previously untreated and relapse patients mean platelet counts generally remained in the normal range in all treatment groups, however, mean platelet counts were 10% to 15% lower in the INTRON A plus placebo group than the REBETOL/INTRON A group. Mean platelet counts returned to baseline levels within 4 weeks after treatment discontinuation.

Thyroid Function

Of patients who entered the previously untreated (24 and 48 week treatment) and relapse (24 week treatment) studies without thyroid abnormalities, approximately 3% to 6% and 1% to 2%, respectively, developed thyroid abnormalities requiring clinical intervention.

Bilirubin and Uric Acid

Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

TABLE 2. Selected Hematologic Values During Treatment with REBETOL plus INTRON A: Previously Untreated and Relapse Patients