Patients should be monitored for the following serious conditions, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should be withdrawn from therapy.
Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with and without a previous psychiatric disorder during PEG-Intron treatment and follow-up. Psychoses, hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons. PEG-Intron should be used with extreme caution in patients with a history of psychiatric disorders. Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. In severe cases, PEG-Intron should be stopped immediately and psychiatric intervention instituted. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)
BONE MARROW TOXICITY
PEG-Intron suppresses bone marrow function, sometimes resulting in severe cytopenias. PEG-Intron should be discontinued in patients who develop severe decreases in neutrophil or platelet counts. (See DOSAGE AND ADMINISTRATION: Dose Reduction). Ribavirin may potentiate the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic anemia.
PEG-Intron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed in patients treated with PEG-Intron. Diabetes mellitus has been observed in patients treated with alpha interferons. Patients with these conditions who cannot be effectively treated by medication should not begin PEG-Intron therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should not continue PEG-Intron therapy.
Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina pectoris, and myocardial infarction, have been observed in patients treated with PEG-Intron. PEG-Intron should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial infarction and arrhythmic disorder who require PEG-Intron therapy should be closely monitored (see Laboratory Tests). Patients with a history of significant or unstable cardiac disease should not be treated with PEG-Intron/REBETOL combination therapy. [See REBETOL package insert.]
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by PEG-Intron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PEG-Intron combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.
Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within 12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations. PEG-Intron treatment should be discontinued immediately in patients who develop these symptoms and signs. The colitis usually resolves within 1-3 weeks of discontinuation of alpha interferons.
Fatal and nonfatal pancreatitis have been observed in patients treated with alpha interferon. PEG-Intron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.
Development or exacerbation of autoimmune disorders (e.g. thyroiditis, thrombocytopenia, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, psoriasis) have been observed in patients receiving PEG-Intron. PEG-Intron should be used with caution in patients with autoimmune 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 may be induced or aggravated by treatment with peginterferon alfa-2b 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. Peginterferon alfa-2b treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alpha interferon therapy. If such a reaction develops during treatment with PEG-Intron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.
Use with Ribavirin-(See also REBETOL Package Insert)
REBETOL may cause birth defects and/or death of the unborn child. REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests (See BOX WARNING, CONTRAINDICATIONS and PRECAUTIONS: Information for Patients and REBETOL package insert).
Ribavirin caused hemolytic anemia in 10% of PEG-Intron/REBETOL treated patients within 1-4 weeks of initiation of therapy. Complete blood counts should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of REBETOL may be necessary. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)
PEG-Intron alone or in combination with REBETOL has not been studied in patients who have failed other alpha interferon treatments.
The safety and efficacy of PEG-Intron alone or in combination with REBETOL for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported but a causal association to interferon alpha therapy has not been established.
The safety and efficacy of PEG-Intron/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.
Triglycerides: Elevated triglyceride levels have been observed in patients treated with interferons including PEG-Intron therapy. Elevated triglyceride levels should be managed as clinically appropriate. Hypertriglyceridemia may result in pancreatitis. Discontinuation of PEG-Intron therapy should be considered for patients with persistently elevated triglycerides (eg, triglycerides >1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting.
Patients with renal failure: Increases in serum creatinine levels have been observed in patients with renal insufficiency treated with interferons, including PEG-Intron. Patients with impairment of renal function should be closely monitored for signs and symptoms of interferon toxicity, including increases in serum creatinine, and doses of PEG-Intron should be adjusted accordingly. PEG-Intron should be used with caution in patients with creatinine clearance <50 mL/min; in considering these patients for PEG-Intron therapy, the potential risks must be evaluated against the potential benefits of treatment. REBETOL must not be used in patients with creatinine clearance <50 mL/min. (See DOSAGE AND ADMINISTRATION: Dose Reduction).
Information for Patients: Patients receiving PEG-Intron alone or in combination with REBETOL should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the MEDICATION GUIDES for PEG-Intron and, if applicable, REBETOL (ribavirin, USP).
Patients must be informed that REBETOL may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during treatment with combination PEG-Intron/REBETOL therapy and for 6 months post-therapy. Combination PEG-Intron/REBETOL therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. It is recommended that patients undergo monthly pregnancy tests during therapy and for 6 months post-therapy. (See CONTRAINDICATIONS and REBETOL package insert).
Patients should be informed that there are no data regarding whether PEG-Intron therapy will prevent transmission of HCV infection to others. Also, it is not known if treatment with PEG-Intron will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus.
Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment. "Flu-like" symptoms associated with administration of PEG-Intron may be minimized by bedtime administration of PEG-Intron or by use of antipyretics.
Patients should be advised to use a puncture-resistant container for the disposal of used syringes, needles, and the Redipen. The full container should be disposed of in accordance with state and local laws. Patients should be thoroughly instructed in the importance of proper disposal. Patients should also be cautioned against reusing or sharing needles, syringes, or the Redipen.
Laboratory Tests: PEG-Intron alone or in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g. TSH) and hepatic abnormalities. Transient elevations in ALT (2-5 fold above baseline) were observed in 10% of patients treated with PEG-Intron, and was not associated with deterioration of other liver functions.
Patients on PEG-Intron or PEG-Intron/REBETOL combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the clinical trial CBC (including hemoglobin, neutrophil and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week intervals or more frequently if abnormalities developed. TSH levels were measured every 12 weeks during the treatment period.
HCV RNA should be measured at 6 months of treatment. PEG-Intron or PEG-Intron/REBETOL combination therapy should be discontinued in patients with persistent high viral levels.
Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEG-Intron/REBETOL.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Carcinogenesis and Mutagenesis: PEG-Intron has not been tested for its carcinogenic potential. Neither PEG-Intron, nor its components interferon or methoxypolyethylene glycol caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.
Use with Ribavirin: Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen. See REBETOL package insert for additional warnings relevant to PEG-Intron therapy in combination with ribavirin.
Impairment of Fertility: PEG-Intron may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 µg/m2 PEG-Intron alone every other day for one month, (approximately 345 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of PEG-Intron treatment. Every other day dosing with 262 µg/m2(approximately 21 times the weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of PEG-Intron on male fertility have not been studied.
Pregnancy Category C: PEG-Intron monotherapy: Non-pegylated Interferon alfa-2b, has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg adult). PEG-Intron should be assumed to also have abortifacient potential. There are no adequate and well-controlled studies in pregnant women. PEG-Intron therapy is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Therefore, PEG-Intron is recommended for use in fertile women only when they are using effective contraception during the treatment period.
Nursing Mothers: It is not known whether the components of PEG-Intron are excreted in human milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the treatment, taking into account the importance of the product to the mother.
PREGNANCY CATEGORY X: USE WITH RIBAVIRIN
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. See CONTRAINDICATIONS and the REBETOL Package Insert.
If pregnancy occurs in a patient or partner of a patient during treatment with PEG-Intron and REBETOL during the 6 months after treatment cessation, physicians should report such cases by calling (800) 727-7064.
Pediatric. Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
Geriatric. In general, younger patients tend to respond better than older patients to interferon-based therapies. Clinical studies of PEG-Intron alone or in combination with REBETOL did not include sufficient numbers of subjects aged 65 and over, however, to determine whether they respond differently than younger subjects. Treatment with alpha interferons, including PEG-Intron, is associated with neuropsychiatric, cardiac, pulmonary, GI and systemic (flu-like) adverse effects. Because these adverse reactions may be more severe in the elderly, caution should be exercised in use of PEG-Intron in this population. This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. REBETOL should not be used in patients with creatinine clearance <50 mL/min. When using PEG-Intron/REBETOL therapy, refer also to the REBETOL Medication Guide.