WARNINGS
Treatment with INFERGEN should be administered under the guidance of a qualified physician, and may lead to moderate-to-severe adverse experiences requiring dose reduction, temporary dose cessation, or discontinuation of further therapy.
Withdrawal from study for adverse events occurred in 7% of patients initially treated with 9 mcg INFERGEN (including 4% due to psychiatric events). Withdrawal from study due to adverse events occurred in 5% of patients subsequently treated with 15 mcg INFERGEN for 24 weeks and 11% of patients subsequently treated with 15 mcg INFERGEN for 48 weeks.
Neuropsychiatric Disorders
Severe psychiatric adverse events may manifest in patients receiving therapy with alpha interferons, including INFERGEN. Depression, suicidal ideation, suicide attempt, and suicide may occur. Other prominent psychiatric adverse events may also occur, including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Prior to initiation of INFERGEN therapy, physicians should inform patients of the possible development of depression and patients should be advised to immediately report any sign or symptom of depression and/or suicidal ideation. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted (See DOSAGE AND ADMINISTRATION: Dose Reduction).
Bone Marrow Toxicity
Alpha interferons suppress bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. Alpha interferon therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 109/L) or platelet counts (<50 x 109/L).
Cardiovascular Disorders
Hypertension, tachycardia, palpitation, and tachyarrhythmias have been reported in patients treated with INFERGEN. INFERGEN should be administered with caution to patients with preexisting cardiac disease. Supraventricular arrhythmias, chest pain, and myocardial infarction have been associated with alpha interferon therapies.8
Hypersensitivity
Serious acute hypersensitivity reactions have been reported in rare instances following treatment with alpha interferons. If hypersensitivity reactions occur (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis), INFERGEN should be discontinued immediately and appropriate medical treatment instituted.
Endocrine Disorders
INFERGEN should be administered with caution to patients with a history of endocrine disorders. Occurrence or aggravation of hyperthyroidism or hypothyroidism have been reported with INFERGEN. Hyperglycemia and diabetes mellitus have also been observed in patients treated with INFERGEN. Patients who develop these conditions during treatment that cannot be controlled with medication should not continue INFERGEN therapy.
Autoimmune Disorders
Development of or exacerbation of autoimmune disorders (e.g., autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis) have been reported in patients receiving alpha interferon therapies, including INFERGEN. INFERGEN should not be used in patients with autoimmune hepatitis (see CONTRAINDICATIONS) and should be used with caution in patients with other autoimmune disorders.
Pulmonary Disorder
Pneumonia and interstitial pneumonitis, some resulting in respiratory failure and/or patient deaths, have been induced or aggravated by alpha interferon therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN.
Colitis
Hemorrhagic/ischemic colitis, sometimes fatal, has been observed within 12 weeks of alpha interferon therapies and has been reported in patients treated with INFERGEN. INFERGEN treatment should be discontinued immediately in patients who develop signs and symptoms of colitis.
Pancreatitis
Pancreatitis, sometimes fatal, has been observed in patients treated with alpha interferons, including INFERGEN. INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.
Hepatic Exacerbations and Decompensated Hepatic Disease
Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with alpha interferons, including INFERGEN. During treatment, patients’ clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin, are observed (see CONTRAINDICATIONS).
Ophthalmologic Disorders
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, and papilledema are induced or aggravated by treatment with INFERGEN or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. INFERGEN therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Cerebrovascular Disorders
Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including INFERGEN. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alfa-based therapies and these events is difficult to establish.
PRECAUTIONS
General
While fever may be related to the flu-like symptoms reported in patients treated with INFERGEN, when fever occurs, other possible causes of persistent fever should be ruled out.
Bone Marrow Toxicity
INFERGEN should be used cautiously in patients with abnormally low peripheral blood cell counts or who are receiving agents that are known to cause myelosuppression. Transplantation patients or other chronically immunosuppressed patients should receive alpha interferon therapy with caution.
Renal Impairment
Increases in serum creatinine levels, and rarely renal failure, have been observed in patients receiving INFERGEN. INFERGEN has not been studied in patients with renal insufficiency. Patients with impaired renal function should be closely monitored and INFERGEN should be used with caution in patients with renal insufficiency.
Information for Patients
If home use is determined to be desirable by the physician, instructions on appropriate use should be given by a healthcare professional. The patient must be instructed as to the proper dosage and administration. Information included in the MEDICATION GUIDE should be fully reviewed with the patient; it is not a disclosure of all, or possible, adverse effects. The most common adverse reactions occurring with INFERGEN therapy are flu-like symptoms including fatigue, fever, rigors, headache, arthralgia, myalgia, and increased sweating. Non-narcotic analgesics and bedtime administration of INFERGEN may be used to prevent or lessen some of these symptoms.
Additionally, patients must be thoroughly instructed in the importance of proper disposal procedures and cautioned against the reuse of needles, syringes, or re-entry of the drug product. A puncture-resistant container for the disposal of used syringes and needles should be used by the patient and should be disposed of according to the directions provided by the health care provider (see MEDICATION GUIDE).
Laboratory Tests
Laboratory tests are recommended for all patients on INFERGEN therapy, prior to beginning treatment (baseline), 2 weeks after initiation of therapy, and periodically thereafter during the 24 or 48 weeks of therapy at the discretion of the physician. Following completion of INFERGEN therapy, any abnormal test values should be monitored periodically. The entrance criteria that were used for the clinical study of INFERGEN may be considered as a guideline to acceptable baseline values for initiation of treatment:
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Platelet count ≥ 75 x 109/L
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Hemoglobin concentration ≥ 100 g/L
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ANC ≥ 1500 x 106/L
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Serum creatinine concentration < 180 μmol/L (< 2.0 mg/dL) or creatinine clearance > 0.83 mL/second (> 50 mL/minute)
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Serum albumin concentration ≥ 25 g/L
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Bilirubin within normal limits
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TSH and T4 within normal limits
Neutropenia, thrombocytopenia, hypertriglyceridemia, and thyroid disorders have been reported with administration of INFERGEN (see ADVERSE REACTIONS). Therefore, these laboratory parameters should be monitored closely.
Drug Interactions
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: No carcinogenicity data for INFERGEN are available in animals or humans.
Mutagenesis: INFERGEN 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.
Impairment of Fertility: INFERGEN at doses as high as 100 mcg/kg did not selectively affect reproductive performance or the development of the offspring when administered SC 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.
Pregnancy Category C
INFERGEN has been shown to have embryolethal or abortifacient effects in golden Syrian hamsters when given at 135 times the human dose and in cynomolgus and rhesus monkeys when given at 9 to 81 times (based on body surface area) the human dose. There are no adequate and well-controlled studies in pregnant women. INFERGEN should not be used during pregnancy. If a woman becomes pregnant or plans to become pregnant while taking INFERGEN, she should be informed of the potential hazards to the fetus. Males and females treated with INFERGEN should be advised to use effective contraception.
Nursing Mothers
It is not known whether INFERGEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if INFERGEN is administered to a nursing woman. The effect on the nursing neonate of orallyingested INFERGEN in breast milk has not been evaluated.
Pediatric Use
The safety and effectiveness of INFERGEN have not been established in patients below the age of 18 years. INFERGEN therapy is not recommended in pediatric patients.
Geriatric Use
Clinical studies of INFERGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, treatment with Interferons, including INFERGEN, is associated with psychiatric, cardiac, and systemic (flu-like) adverse effects. Since decreased hepatic, renal or cardiac function, concomitant disease and the use of other drug therapies in elderly patients may produce adverse reactions of greater severity, caution should be exercised in the use of INFERGEN in this population.
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