Adverse experiences that were reported, regardless of attribution to treatment, in at least 5% of patients in the 9 mcg INFERGEN or 3 MIU IFN (α)-2b groups of the pivotal study are presented in Table 3, listed in decreasing order by the 9 mcg INFERGEN group. The incidence of adverse events is expressed based on the number of patients experiencing each event at least once during treatment or during posttreatment observation.

Most adverse events were mild-to-moderate in severity and abated with cessation of therapy. Flu-like symptoms (ie, headache, fatigue, fever, rigors, myalgia, sweating increased, and arthralgia) were the most frequently reported treatment-related adverse reactions. Most were short-lived and could be treated symptomatically.

Depression, usually mild-to-moderate in severity, was reported in 26% of patients who received 9 mcg INFERGEN and was the most common adverse event resulting in study drug discontinuation.

In patients who had tolerated previous interferon therapy (9 mcg INFERGEN or 3 MIU IFN (alpha)-2b) and failed to normalize ALT, or who had achieved normalization of ALT during the treatment period but who relapsed during the posttreatment observation period, subsequent treatment with 15 mcg TIW of INFERGEN for 24 or 48 weeks was generally tolerated. Adverse experiences of patients receiving subsequent treatment, regardless of attribution to treatment, are reported in Table 3. The higher dose of INFERGEN used in these patients was associated with a greater incidence of leukopenia and granulocytopenia. One or more dose reductions for all causes were required in up to 36% of patients. Patients who do not tolerate initial standard interferon therapy should not receive therapy with 15 mcg TIW of INFERGEN.

Laboratory Values

The following laboratory variables were found to be affected by therapy with Infergen in the 231 patients who received treatment with 9 mcg Infergen.

Hemoglobin and Hematocrit: Treatment with Infergen was associated with gradual decreases in mean values for hemoglobin and hematocrit, which were 4% and 5% below baseline at the end of treatment. Decreases from baseline of 20% or more in hemoglobin or hematocrit were seen in 1% of patients or less.

White Blood Cells: Infergen treatment was associated with decreases in mean values for both total white blood cell (WBC) count and ANC within the first 2 weeks of treatment. By the end of treatment, mean decreases from baseline of 19% for WBCs and 23% for ANC were observed. These effects reversed during the post-treatment observation period. In two Infergen-treated patients in the phase 3 trial, decreases in ANC to levels below 500 x 10⁶ cells/L were seen. In both cases, the ANC returned to clinically acceptable levels with reduction of the dose of Infergen, and these transient decreases in neutrophils were not associated with infections.

Platelets: Infergen treatment was associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of treatment. These decreases were reversed during the post-treatment observation period. Values below normal were common during treatment with 3% of patients developing values less than 50 x 10⁹ cells/L, usually necessitating dose reduction.

Triglycerides: Mean values for serum triglyceride increased shortly after the start of administration of Infergen, with increases of 41%, compared with baseline, at the end of the treatment period. Seven percent of the patients developed values which were at least three times above pretreatment levels during treatment. This effect was promptly reversed after discontinuation of treatment.

Thyroid Function: Infergen treatment was associated with biochemical changes consistent with hypothyroidism including increases in TSH and decreases in T₄ mean values. Increases in TSH to greater than 7 mU/L were seen in 10% of 9 mcg Infergen-treated patients either during the treatment period or the 24-week post-treatment observation period. Thyroid supplements were instituted in approximately one third of these patients.

Laboratory Values for Subsequent Treatment: From a database of 165 patients receiving subsequent treatment with 15 mcg of INFERGEN for 24 weeks, and 168 patients receiving subsequent treatment with 15 mcg of INFERGEN for 48 weeks after failing initial interferon therapy, similar changes in the laboratory values as outlined above were observed. Mean decreases from baseline up to 23% for WBCs and up to 27% for ANC were observed for patients subsequently treated with interferon, which was greater than during initial treatment. Two patients in the 24-week group experienced reversible reductions in ANC to less than 500 10 6 cells/L, which were not associated with infectious complications. No patients discontinued as a result of hematologic toxicity.

No formal drug interaction studies have been conducted with Infergen. Infergen should be used cautiously in patients who are receiving agents that are known to cause myelosuppression or with agents known to be metabolized via the cytochrome P-450 pathway.⁹ Patients taking drugs that are metabolized by this pathway should be monitored closely for changes in the therapeutic and/or toxic levels of concomitant drugs.

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