Interferon alfacon-1 adverse reactions

# 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 INFERGEN 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 INFERGEN, in combination with ribavirin, administered daily up to 48 weeks.
INFERGEN Monotherapy Clinical Trials
Adverse reactions that were reported, regardless of attribution to treatment, in  10% of subjects in INFERGEN 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 INFERGEN monotherapy and was the most common adverse reaction resulting in study drug discontinuation.
INFERGEN 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.

## Combination Treatment with INFERGEN/Ribavirin Clinical Trials
The most common adverse reactions in the combination treatment with INFERGEN/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 INFERGEN 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 INFERGEN dose modifications due to adverse reactions, primarily due to neutropenia/leukopenia, 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%).

### Laboratory Values
Hemoglobin and Hematocrit: Treatment with INFERGEN alone and in combination with ribavirin is associated with decreases in mean values for hemoglobin and hematocrit. In the INFERGEN 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 INFERGEN/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: INFERGEN 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 INFERGEN-monotherapy treated subjects ANC levels decreased to below 500  106 cells/L. In both cases, the ANC values returned to clinically acceptable levels with INFERGEN 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 INFERGEN monotherapy. Two subjects experienced reversible reductions in ANC to less than 500  106 cells/L.
In the combination INFERGEN/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 x 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: INFERGEN treatment is associated with alterations in platelet count. Decreases in mean platelet count of 16% compared to baseline were seen by the end of INFERGEN 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 INFERGEN/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 INFERGEN 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 INFERGEN/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: INFERGEN 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 INFERGEN-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 INFERGEN/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 INFERGEN/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 INFERGEN/ribavirin temporarily interrupted due to elevated uric acid levels.

## Immunogenicity
The number of subjects developing positive binding antibody responses was similar in the 9 mcg INFERGEN (11%) and 3 MIU IFN -2b groups (15%) in monotherapy studies. The titer of neutralizing antibodies to interferon was not measured. Following cessation of interferon therapy, the number of subjects with a positive antibody response declined.
In the INFERGEN/ribavirin combination study, approximately 13% of subjects in the 15 mcg and 18% in the 9 mcg arms developed low-titer neutralizing antibodies to INFERGEN. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response was observed. The incidence of binding antibody was approximately 31%.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies for INFERGEN with the incidence of antibodies to other products may be misleading.

## Postmarketing Experience
The following adverse reactions have been identified and reported during post-approval use of INFERGEN. Because these reactions are reported voluntarily and from a population of uncertain size, it is not possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.
Application site
injection site reaction, including injection site necrosis ulcer, and bruising
Ear and Labyrinth
hearing loss, hearing impairment
Gastrointestinal
abdominal distention, gastrointestinal bleeding, gastritis
Hepatobiliary
hepatic enzyme elevations, including ALT and AST elevation, abnormal hepatic function, hyperbilirubinemia, jaundice, ascites, hepatic encephalopathy
Infections
sepsis
Metabolism and Nutritional
dehydration
Musculoskeletal
rhabdomyolysis, arthritis, bone pain
Nervous
speech disorder, ataxia, gait abnormal, convulsions, loss of consciousness, memory impairment, tremors, visual field defect
Psychiatric
delusions, hallucinations
Skin and Subcutaneous
bruising, pyoderma gangrenosum, toxic epidermal necrolysis
Vascular Disorders
Hemorrhage