ADVERSE REACTIONS
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 (i.e., 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 α-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.
Table 3. Patient Incidence of Adverse Events in Phase 3 Clinical Trials Regardless of Attributiona | Initial Treatment b | Subsequent Treatment b |
| INFERGEN | IFN α-2b | INFERGEN | INFERGEN |
| 9 mcg | | 15 mcg | 15 mcg |
| (n = 231) | (n = 236) | 24 wks | 48 wks |
| | | (n = 165) | (n = 168) |
Body System/Preferred Term | % of Patients | % of Patients |
a. Only events that occurred at a frequency of ≥ 5% in any treatment group are included. Patients can appear more than once in Table 3. Because the 2 studies were conducted at different times with nonidentical patient groups, the adverse events profile for the subsequent treatment study is not directly comparable to the initial treatment study. |
b. Adverse events reported in patients during treatment or posttreatment observation in the pivotal initial treatment and subsequent treatment studies are listed regardless of attribution to treatment. |
c. Influenza-like symptoms: presumed viral etiology. |
APPLICATION SITE |
Injection Site Erythema | 23 | 15 | 17 | 22 |
Injection Site Pain | 9 | 3 | 8 | 11 |
Injection Site Ecchymosis | 6 | 7 | 5 | 5 |
BODY AS A WHOLE |
Fatigue | 69 | 67 | 65 | 71 |
Fever | 61 | 45 | 58 | 55 |
Rigors | 57 | 45 | 62 | 66 |
Body Pain | 54 | 45 | 39 | 51 |
Influenza-like Symptomsc | 15 | 11 | 8 | 8 |
Pain Chest | 13 | 14 | 5 | 9 |
Hot Flushes | 13 | 7 | 7 | 4 |
Malaise | 11 | 10 | 2 | 5 |
Asthenia | 9 | 11 | 10 | 7 |
Edema Peripheral | 9 | 8 | 4 | 3 |
Access Pain | 8 | 9 | 1 | 1 |
Allergic Reaction | 7 | 5 | 3 | 4 |
Weight Decrease | 5 | 7 | 5 | 2 |
CARDIOVASCULAR |
Hypertension | 5 | 3 | 2 | 4 |
Palpitation | 3 | 6 | 5 | 2 |
CNS/PNS |
Headache | 82 | 83 | 78 | 80 |
Insomnia | 39 | 30 | 24 | 28 |
Dizziness | 22 | 25 | 18 | 25 |
Paresthesia | 13 | 10 | 9 | 9 |
Hypoesthesia | 10 | 8 | 8 | 10 |
Amnesia | 10 | 6 | 2 | 5 |
Hypertonia | 7 | 10 | 6 | 6 |
Somnolence | 4 | 8 | 6 | 7 |
Confusion | 4 | 6 | 4 | 5 |
Hyperesthesia | 1 | 1 | 1 | 5 |
ENDOCRINE DISORDERS |
Thyroid Test Abnormal | 9 | 5 | 4 | 6 |
GASTROINTESTINAL |
Abdominal Pain | 41 | 40 | 24 | 32 |
Nausea | 40 | 36 | 30 | 36 |
Diarrhea | 29 | 24 | 24 | 22 |
Anorexia | 24 | 17 | 21 | 14 |
Dyspepsia | 21 | 18 | 12 | 10 |
Vomiting | 12 | 11 | 13 | 11 |
Constipation | 9 | 6 | 5 | 6 |
Flatulence | 8 | 9 | 6 | 5 |
Tooth Ache | 7 | 7 | 3 | 7 |
Saliva Decreased | 6 | 7 | 4 | 1 |
Hemorrhoids | 6 | 3 | 1 | 2 |
Stomatitis Ulcerative | 3 | 4 | 2 | 6 |
Gingivitis | 2 | 3 | 1 | 5 |
HEARING/VESTIBULAR |
Tinnitus | 6 | 4 | 4 | 2 |
Earache | 5 | 7 | 5 | 5 |
Otitis | 2 | 5 | 1 | 3 |
HEMATOLOGIC |
Granulocytopenia | 23 | 25 | 42 | 39 |
Thrombocytopenia | 19 | 16 | 18 | 18 |
Leukopenia | 15 | 13 | 19 | 28 |
Lymphadenopathy | 6 | 8 | 4 | 4 |
Ecchymosis | 6 | 4 | 4 | 2 |
Lymphocytosis | 5 | 7 | 11 | 5 |
PT Increased | 3 | 5 | 1 | 0 |
Anemia | 2 | 3 | 2 | 6 |
LIVER AND BILIARY |
Liver Tender | 5 | 3 | 6 | 2 |
Hepatomegaly | 3 | 5 | 5 | 2 |
METABOLIC/NUTRITION |
Hypertriglyceridemia | 6 | 7 | 5 | 5 |
MUSCULO-SKELETAL |
Myalgia | 58 | 56 | 51 | 55 |
Arthralgia | 51 | 44 | 43 | 46 |
Back Pain | 42 | 37 | 29 | 23 |
Limb Pain | 26 | 25 | 13 | 23 |
Skeletal Pain | 14 | 14 | 10 | 12 |
Neck Pain | 14 | 13 | 8 | 5 |
Musculo-skeletal Disorder | 4 | 4 | 7 | 4 |
PSYCHIATRIC DISORDER |
Nervousness | 31 | 29 | 16 | 22 |
Depression | 26 | 25 | 18 | 19 |
Anxiety | 19 | 18 | 9 | 14 |
Emotional Lability | 12 | 11 | 6 | 3 |
Thinking Abnormal | 8 | 12 | 10 | 20 |
Agitation | 6 | 6 | 4 | 4 |
Libido Decreased | 5 | 5 | 5 | 4 |
Apathy | 2 | 3 | 4 | 5 |
REPRODUCTIVE (FEMALE) |
Dysmenorrhea | 9 | 9 | 2 | 7 |
Vaginitis | 8 | 2 | 5 | 5 |
Menstrual Disorder | 6 | 5 | 2 | 5 |
Menorrhagia | 3 | 0 | 2 | 5 |
Moniliasis Genital | 2 | 6 | 2 | 0 |
Breast Mass | 0 | 3 | 0 | 5 |
Breast Pain | 0 | 5 | 2 | 0 |
RESISTANCE MECHANISM |
Infection | 3 | 5 | 2 | 6 |
RESPIRATORY |
Pharyngitis | 34 | 31 | 17 | 21 |
Infection Upper Respiratory | 31 | 34 | 16 | 18 |
Cough | 22 | 17 | 12 | 11 |
Sinusitis | 17 | 22 | 12 | 16 |
Rhinitis | 13 | 16 | 7 | 9 |
Respiratory Tract Congestion | 12 | 7 | 4 | 9 |
Upper Resp. Tract Congestion | 10 | 14 | 7 | 9 |
Epistaxis | 8 | 12 | 6 | 6 |
Dyspnea | 7 | 12 | 8 | 7 |
Bronchitis | 6 | 6 | 2 | 1 |
SKIN AND APPENDAGES |
Alopecia | 14 | 25 | 10 | 13 |
Pruritus | 14 | 14 | 11 | 10 |
Rash | 13 | 15 | 13 | 10 |
Sweating Increased | 12 | 11 | 13 | 11 |
Erythema | 6 | 6 | 7 | 9 |
Skin Dry | 6 | 5 | 2 | 5 |
Wound | 4 | 7 | 3 | 4 |
SPECIAL SENSES |
Taste Perversion | 3 | 6 | 3 | 5 |
VISION DISORDERS |
Conjunctivitis | 8 | 8 | 4 | 6 |
Eye Pain | 5 | 6 | 4 | 2 |
Vision Abnormal | 3 | 5 | 5 | 5 |
Laboratory Values
The following laboratory values 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 posttreatment observation period. In 2 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 posttreatment 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 3 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 posttreatment 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 x 106 cells/L, which were not associated with infectious complications. No patients discontinued as a result of hematologic toxicity.
Postmarketing Experience
In addition, the following potential adverse reactions have been reported during post-approval use of INFERGEN. Because the reports of these adverse events are voluntary and the 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
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