General

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 Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn (see BOXED WARNING).

Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving therapy with PEGASYS and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with and without previous psychiatric illness.

PEGASYS should be used with extreme caution in patients who report a history of depression. Neuropsychiatric adverse events observed with alpha interferon treatment include aggressive behavior, psychoses, hallucinations, bipolar disorders, and mania. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. Patients should be advised to report any sign or symptom of depression or suicidal ideation to their prescribing physicians. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Serious and severe bacterial infections, some fatal, have been observed in patients treated with alpha interferons including PEGASYS. Some of the infections have been associated with neutropenia. PEGASYS should be discontinued in patients who develop severe infections and appropriate antibiotic therapy instituted.

PEGASYS suppresses bone marrow function and may result in severe cytopenias. Ribavirin may potentiate the neutropenia and lymphopenia induced by alpha interferons including PEGASYS. Very rarely alpha interferons may be associated with aplastic anemia. It is advised that complete blood counts (CBC) be obtained pre-treatment and monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests).

PEGASYS and COPEGUS should be used with caution in patients with baseline neutrophil counts <1500 cells/mm3, with baseline platelet counts <90,000 cells/mm3 or baseline hemoglobin <10 g/dL.PEGASYS therapy should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts (see DOSAGE AND ADMINISTRATION: Dose Modifications).

Severe neutropenia and thrombocytopenia occur with a greater incidence in HIV coinfected patients than monoinfected patients and may result in serious infections or bleeding (see ADVERSE REACTIONS).

Hypertension, supraventricular arrhythmias, chest pain, and myocardial infarction have been observed in patients treated with PEGASYS.

PEGASYS should be administered with caution to patients with pre-existing cardiac disease. Because cardiac disease may be worsened by ribavirin-induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS (see WARNINGS: Anemia and COPEGUS Package Insert).

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study 6, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs for the associated risk. During treatment, patients clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score ≥6) is observed (see CONTRAINDICATIONS).

Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. Chronic hepatitis B patients experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation >10-fold higher than the upper limit of normal) during PEGASYS treatment (12% and 18%) and post-treatment (7% and 12%) in HBeAg negative and HBeAg positive patients, respectively. Marked transaminase flares while on PEGASYS therapy have been accompanied by other liver test abnormalities. Patients experiencing ALT flares should receive more frequent monitoring of liver function. PEGASYS dose reduction should be considered in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of PEGASYS dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, PEGASYS should be immediately discontinued (see ADVERSE REACTIONS: Chronic Hepatitis B and DOSAGE AND ADMINISTRATION: Dose Modifications).

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with PEGASYS and COPEGUS should be discontinued and appropriate medical therapy immediately instituted.

PEGASYS causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with PEGASYS. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin PEGASYS therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of PEGASYS therapy.

Autoimmune Disorders

Development or exacerbation of autoimmune disorders including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus have been reported in patients receiving alpha interferon. PEGASYS should be used with caution in patients with autoimmune disorders.

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 PEGASYS or alpha interferon therapy. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with PEGASYS.

Ulcerative and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. PEGASYS should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.

Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. PEGASYS and COPEGUS should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS and COPEGUS should be discontinued in patients diagnosed with pancreatitis.

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 PEGASYS or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre existing 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. PEGASYS treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

The primary toxicity of ribavirin is hemolytic anemia. Hemoglobin <10 g/dL was observed in approximately 13% of COPEGUS and PEGASYS treated patients in chronic hepatitis C clinical trials (see PRECAUTIONS: Laboratory Tests). The anemia associated with COPEGUS occurs within 1 to 2 weeks of initiation of therapy with maximum drop in hemoglobin observed during the first eight weeks. BECAUSE THE INITIAL DROP IN HEMOGLOBIN MAY BE SIGNIFICANT, IT IS ADVISED THAT HEMOGLOBIN OR HEMATOCRIT BE OBTAINED PRE-TREATMENT AND AT WEEK 2 AND WEEK 4 OF THERAPY OR MORE FREQUENTLY IF CLINICALLY INDICATED. Patients should then be followed as clinically appropriate.

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued (see DOSAGE AND ADMINISTRATION: COPEGUS Dosage Modification Guidelines). Because cardiac disease may be worsened by drug- induced anemia, patients with a history of significant or unstable cardiac disease should not use COPEGUS (see COPEGUS Package Insert).

It is recommended that renal function be evaluated in all patients started on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).

General

The safety and efficacy of PEGASYS alone or in combination with COPEGUS have not been established in:

·Patients who have failed alpha interferon treatment with or without ribavirin

·Liver or other organ transplant recipients

·Hepatitis B patients coinfected with HCV or HIV

·Hepatitis C patients coinfected with HBV or coinfected with HIV with a CD4+ cell count <100 cells/mL

Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

A 25% to 45% higher exposure to PEGASYS is seen in subjects undergoing hemodialysis. In patients with impaired renal function, signs and symptoms of interferon toxicity should be closely monitored. Doses of PEGASYS should be adjusted accordingly. PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min (see DOSAGE AND ADMINISTRATION: Dose Modifications).

COPEGUS should not be used in patients with creatinine clearance <50 mL/min (see COPEGUS Package Insert).

Before beginning PEGASYS or PEGASYS and COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed.

After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of PEGASYS may be considered as a guideline to acceptable baseline values for initiation of treatment:

·Platelet count ≥90,000 cells/mm³ (as low as 75,000 cells/mm³ in HCV patients with cirrhosis or 70,000 cells/mm³ in patients with CHC and HIV)

·Absolute neutrophil count (ANC) ≥1500 cells/mm³

·Serum creatinine concentration <1.5 x upper limit of normal

·TSH and T⁴ within normal limits or adequately controlled thyroid function

·CD4+ cell count ≥200 cells/mL or CD4+ cell count ≥100 cells/mL but <200 cells/mL and HIV-1 RNA <5000 copies/mL in patients coinfected with HIV

·Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men in CHC monoinfected patients

·Hemoglobin ≥11 g/dL for women and ≥12 g/dL for men in patients with CHC and HIV

PEGASYS treatment was associated with decreases in WBC, ANC, lymphocytes, and platelet counts often starting within the first 2 weeks of treatment (see ADVERSE REACTIONS). Dose reduction is recommended in patients with hematologic abnormalities (see DOSAGE AND ADMINISTRATION: Dose Modifications).

While fever is commonly caused by PEGASYS therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia (see WARNINGS: Infections).

In chronic hepatitis C, transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, and were not associated with deterioration of other liver function tests. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, PEGASYS therapy should be discontinued (see DOSAGE AND ADMINISTRATION: Dose Modifications).

Unlike hepatitis C, during hepatitis B therapy and follow up, transient elevations in ALT of 5 to 10 x ULN were observed in 25% and 27% and of >10 x ULN were observed in 12% and 18%, of HBeAg negative and HBeAg positive patients, respectively. These ALT elevations have been accompanied by other liver test abnormalities (see WARNINGS: Hepatic Failure and Hepatitis Exacerbations and DOSAGE AND ADMINISTRATION: Dose Modifications). Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

PEGASYS has not been tested for its carcinogenic potential.

Mutagenesis

PEGASYS did not cause DNA damage when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.

Use with Ribavirin

Ribavirin is genotoxic and mutagenic. The carcinogenic potential of ribavirin has not been fully determined. In a p53 (+/-) mouse carcinogenicity study at doses up to the maximum tolerated dose of 100 mg/kg/day ribavirin was not oncogenic. However, on a body surface area basis, this dose was 0.5 times maximum recommended human 24-hour dose of ribavirin. A study in rats to assess the carcinogenic potential of ribavirin is ongoing (see COPEGUS Package Insert).

Impairment of Fertility

PEGASYS may impair fertility in women. Prolonged menstrual cycles and/or amenorrhea were observed in female cynomolgus monkeys given sc injections of 600 mg/kg/dose (7200 mg/m2 /dose) of PEGASYS every other day for one month, at approximately 180 times the recommended weekly human dose for a 60 kg person (based on body surface area). Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17γ¯Â�-estradiol and progesterone levels following administration of PEGASYS to female monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with 100 mg/kg (1200 mg/m2) PEGASYS (equivalent to approximately 30 times the recommended human dose) had no effects on cycle duration or reproductive hormone status.

The effects of PEGASYS on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys treated with non-pegylated interferon alfa-2a for 5 months at doses up to 25 x 106 IU/kg/day.

Use with Ribavirin

Ribavirin has shown reversible toxicity in animal studies of male fertility (see COPEGUS Package Insert).

Pregnancy

Pregnancy: Category C

PEGASYS has not been studied for its teratogenic effect. Non-pegylated interferon alfa- 2a treatment of pregnant Rhesus monkeys at approximately 20 to 500 times the human weekly dose resulted in a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. PEGASYS should be assumed to have abortifacient potential. There are no adequate and well-controlled studies of PEGASYS in pregnant women. PEGASYS is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. PEGASYS is recommended for use in women of childbearing potential only when they are using effective contraception during therapy.

Pregnancy: Category X: Use With Ribavirin (see CONTRAINDICATIONS) Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. COPEGUS therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant (see CONTRAINDICATIONS, WARNINGS, and COPEGUS Package Insert).

Ribavirin Pregnancy Registry

A Ribavirin Pregnancy Registry has been established to monitor maternal and fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593 2214.

Nursing Mothers

It is not known whether peginterferon or ribavirin or its components are excreted in human milk. The effect of orally ingested peginterferon or ribavirin from breast milk on the nursing infant has not been evaluated. Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue PEGASYS and COPEGUS treatment.

Pediatric Use

The safety and effectiveness of PEGASYS, alone or in combination with COPEGUS in patients below the age of 18 years have not been established.

PEGASYS contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal (see CONTRAINDICATIONS).

Geriatric Use

Younger patients have higher virologic response rates than older patients. Clinical studies of PEGASYS alone or in combination with COPEGUS did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects may be more severe in the elderly and caution should be exercised in the use of PEGASYS in this population. PEGASYS and COPEGUS are excreted by the kidney, and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min and COPEGUS should not be administered to patients with creatinine clearance <50 mL/min.

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