Interferon, alfacon-1

Interferon alfacon-1 Monotherapy

Pregnancy Category C.

Interferon alfacon-1 has been shown to have embryo lethal or abortifacient effects in golden Syrian hamsters when given at doses >150 mcg/kg/day (135 times the human dose) and in cynomolgus and rhesus monkeys when given at doses of 3 mcg/kg/day and 10 mcg/kg/day (9 to 81 times the human dose), respectively, based on body surface area) the human dose. There are no adequate and well-controlled studies in pregnant women. Interferon alfacon-1 should not be used during pregnancy. If a woman becomes pregnant or plans to become pregnant while taking interferon alfacon-1, she should be informed of the potential hazards to the fetus. Males and females treated with interferon alfacon-1 should be advised to use effective contraception.

Combination Treatment with interferon alfacon-1/Ribavirin

Pregnancy Category X.

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant.

It is not known whether interferon alfacon-1 or ribavirin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if interferon alfacon-1 is administered to a nursing woman. The effect on the nursing neonate of orally ingested interferon alfacon-1 in breast milk has not been evaluated. Because of the potential for serious adverse reactions from the drug in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue ribavirin.

Carcinogenesis

No carcinogenicity data for interferon alfacon-1 are available in animals or humans.

Mutagenesis

Interferon alfacon-1 was not mutagenic when tested in several in vitro assays, including the Ames bacterial mutagenicity assay and an in vitro cytogenetic assay in human lymphocytes, either in the presence or absence of metabolic activation.

Use with Ribavirin

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays and should be considered a potential carcinogen (see ribavirin Full Prescribing Information).

Impairment of Fertility

Interferon alfacon-1 at doses as high as 100 mcg/kg did not selectively affect reproductive performance or the development of the offspring when administered subcutaneous injection to male and female golden Syrian hamsters for 70 and 14 days before mating, respectively, and then through mating and to day 7 of pregnancy.

Interferon alfacon-1 alone or in combination with ribavirin causes a broad range of serious adverse reactions.

Clinical Trials 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.

During clinical development, more than 560 subjects were exposed to 9 mcg or 15 mcg of interferon alfacon-1 monotherapy administered three times per week over a range of 24 to 48 weeks, and more than 480 subjects were exposed to 9 mcg or 15 mcg of interferon alfacon-1, in combination with ribavirin, administered daily up to 48 weeks.

Interferon alfacon-1 Monotherapy Clinical Trials

Adverse reactions that were reported, regardless of attribution to treatment, in >10% of subjects in interferon alfacon-1 monotherapy studies are presented in Table 4.

Flu-like symptoms (i.e., headache, fatigue, fever, rigors, myalgia, arthralgia, and sweating increased) were the most frequently reported treatment-related adverse reactions. In most cases, these events could be treated symptomatically.

Depression of any severity was reported in 26% of subjects who received 9 mcg interferon alfacon-1 monotherapy and was the most common adverse reaction resulting in study drug discontinuation.

Interferon alfacon-1 15 mcg three times a week monotherapy as subsequent treatment was associated with a greater incidence of leukopenia and granulocytopenia. One or more dose reductions for any causes were required in up to 36% of subjects.

Treatment Emergent Adverse Reactions Occurring in >10% of Subjects in interferon alfacon-1 Monotherapy Trials:

Combination Treatment with Interferon alfacon-1/Ribavirin Clinical Trials

The most common adverse reactions in the combination treatment with interferon alfacon-1/ribavirin trial are listed in Table 5 and included fatigue (76%), nausea (45%), flu-like symptoms (40%), headache (42%), arthralgia (31%), and myalgia (29%), neutropenia (40%), leukopenia (29%), insomnia (39%), and depression (26%).

Adverse reactions led to early study discontinuation in 104 (21%) of subjects; more subjects discontinued from the 15 mcg interferon alfacon-1 group (64 versus 40). Fatigue, anemia, and depression were the most common adverse reactions resulting in study drug discontinuation. A higher proportion of subjects who received the recommended starting dose of 15 mcg (52%) than the 9 mcg dose group (40%) required interferon alfacon-1 dose modifications due to adverse reactions, primarily due to neutropenia/leucopenia, thrombocytopenia, and fatigue/weakness. A total of 14% of subjects experienced serious adverse reactions, the most common of which were neutropenia (2%), suicidal ideation (1%), and hyperuricemia (1%).

Treatment Emergent Adverse Reactions Occurring in the >10% of Subjects in Combination Treatment with Interferon alfacon-1/Ribavirin Phase 3 Trial:

Laboratory Values

Hemoglobin and Hematocrit

Treatment with interferon alfacon-1 alone and in combination with ribavirin is associated with decreases in mean values for hemoglobin and hematocrit. In the interferon alfacon-1 monotherapy trials, 4% and 5% of subjects had decreases in hemoglobin and hematocrit levels. Decreases from baseline of 20% or more in hemoglobin or hematocrit were seen in <1% of subjects.

In the combination interferon alfacon-1/ribavirin trial, 88% of subjects had decreases in hemoglobin levels of >2 g/dL from baseline. Of these, 27% had hemoglobin levels decrease to <10 g/dL, and underwent dose reductions of ribavirin. Anemia or hemolytic anemia led to study drug discontinuation in 10 subjects.

White Blood Cells

Interferon alfacon-1 treatment is associated with decreases in mean values for both total white blood cell (WBC) count and ANC. By the end of initial monotherapy 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 interferon alfacon-1-monotherapy treated subjects ANC levels decreased to below 500 × 10³ cells/µL. In both cases, the ANC values returned to clinically acceptable levels with interferon alfacon-1 dose reductions and were not associated with infections.

Mean decreases from baseline up to 23% for WBCs and up to 27% for ANC were observed for subjects subsequently retreated with interferon alfacon-1 monotherapy. Two subjects experienced reversible reductions in ANC to less than 500 × 10⁶ cells/L.

In the combination interferon alfacon-1/ribavirin trial, leukopenia was reported in 24% and 34% of 9 mcg and 15 mcg treated subjects, respectively. More subjects treated with 15 mcg experienced lymphopenia than did those treated with 9 mcg: 14% versus 7%. ANC levels <0.75 × 10⁹/L were observed in 21% of subjects treated with 9 mcg and 27% of those treated with 15 mcg; no subjects experienced significant infections associated with low ANC levels.

Platelets

Interferon alfacon-1 treatment is associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of interferon alfacon-1 monotherapy treatment. These decreases were reversed during the post treatment observation period. Three percent of subjects had platelets decrease to less than 50 × 10⁹ cells/L, which necessitated dose reduction.

More subjects treated with 15 mcg in the interferon alfacon-1/ribavirin combination trial experienced a decrease in platelet counts <40 × 10⁹/L, 3% versus 1% in the 9 mcg dose group. None of the subjects had platelet counts <25 × 10⁹/L. One subject in the 15 mcg group had Grade 4 thrombocytopenia 127 days after the start of treatment, was hospitalized for this event, and treatment with both study drugs was discontinued; the event resolved 8 days later.

Triglycerides

Mean values for serum triglyceride increased shortly after the start of administration of interferon alfacon-1 monotherapy, with increases of 41%, compared with baseline, at the end of the treatment period. Seven percent of the subjects developed values which were at least 3 times above pretreatment levels during treatment. This effect was reversed after discontinuation of treatment.

In the interferon alfacon-1/ribavirin combination trial, 7% of subjects in the 15 mcg dose group experienced increases in triglyceride levels over baseline levels at week 48 compared to 2% in the 9 mcg dose group. There were no differences in the proportion of subjects who had >Grade 3 triglyceride elevations: 2% in both dose groups.

Thyroid Function

Interferon alfacon-1 monotherapy 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 interferon alfacon-1-treated subjects either during the treatment period or the 24-week post treatment observation period. Thyroid supplements were instituted in approximately one-third of these subjects.

In the combination interferon alfacon-1/ribavirin trial, mean increases in TSH levels from baseline were greater for the 15 mcg group compared with the 9 mcg group; 14% and 3%, respectively, at Week 12 and 54% and 0% at Week 48. No serious adverse events, discontinuations or dose modifications were related to abnormalities in thyroid function.

Uric Acid

Grade 4 (>10 mg/dL) uric acid levels were commonly observed in both interferon alfacon-1/ribavirin treatment groups: 23 in the 9 mcg and 26 in the 15 mcg group. One subject in the 9 mcg group and three in the 15 mcg group experienced serious adverse events related to elevated uric acid levels. Four subjects in the 15 mcg had interferon alfacon-1/ribavirin temporarily interrupted due to elevated uric acid levels.