INDICATIONS AND USAGE

PEGASYS^® (peginterferon alfa-2a), alone or in combination with COPEGUS^® (ribavirin, USP), is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Efficacy has been demonstrated in subjects with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and in adult subjects with clinically stable HIV disease and CD4 count >100 cells/mm³.

The following points should be considered when initiating therapy with PEGASYS and COPEGUS:

• Use of PEGASYS monotherapy is not recommended for treatment of CHC unless a patient has a contraindication to or significant intolerance to ribavirin. Combination therapy provides substantially better response rates than monotherapy.
• Safety and efficacy have not been demonstrated for treatment longer than 48 weeks.
• The safety and efficacy have not been established in liver or other organ transplant recipients.

PEGASYS is indicated for the treatment of adult patients with HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation.

IMPORTANT SAFETY INFORMATION

Boxed WARNINGS

Alpha interferons, including PEGASYS, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy.

Use with ribavirin. Ribavirin, including COPEGUS, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. [See COPEGUS Package Insert for additional information and other WARNINGS.]

DOSE MODIFICATION

If severe adverse reactions or laboratory abnormalities develop during combination PEGASYS/ribavirin therapy, the dose should be modified until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/ribavirin therapy should be discontinued. Refer to the full prescribing information for guidelines pertaining to dose modifications and discontinuation of PEGASYS/ribavirin based on laboratory abnormalities, patient’s depression status, and cardiac status.

In patients with CrCL less than 30 mL/min, including patients with end-stage renal disease requiring hemodialysis, dose reduction to 135 mcg PEGASYS is recommended. Signs and symptoms of interferon toxicity should be closely monitored. Renal function should be evaluated in all patients on ribavirin. Ribavirin should be reduced for patients with creatinine clearance <50 mL/min. No data are available for pediatric patients with renal impairment.

DISCONTINUATION OF DOSING

Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log₁₀ reduction from baseline in HCV RNA titer by 12 weeks of therapy or undetectable HCV RNA after 24 weeks of therapy.

During treatment, patients’ clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation is observed.

Patients should be monitored for serious adverse events, some of which may become life threatening. Patients with persistently severe or worsening signs or symptoms should have their therapy withdrawn.

CONTRAINDICATIONS

PEGASYS is contraindicated in patients with:

• Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome to alpha interferons, including PEGASYS, or any of its components
• Autoimmune hepatitis
• Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment
• Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment

PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal.

PEGASYS/ribavirin combination therapy is additionally contraindicated in:

• Women who are pregnant (PEGASYS: Category C; ribavirin: Category X)
• Men whose female partners are pregnant
• Patients with known hypersensitivity (urticaria, angioedema, bronchoconstriction, and anaphylaxis) to ribavirin or to any component of the tablet
• Patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia)
• Combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials

WARNINGS AND PRECAUTIONS

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:

Use with ribavirin:

• Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking PEGASYS and ribavirin combination therapy. Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
• The primary toxicity of ribavirin is hemolytic anemia. 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. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin.
• Neuropsychiatric reactions (suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction and drug overdose)
• Cardiovascular disorders (hypertension, supraventricular arrhythmias, chest pain and myocardial infarction)
• Bone marrow suppression (severe cytopenias and, rarely, aplastic anemia). Pancytopenia has been reported with concomitant use of azathioprine
• Autoimmune disorders (including myositis, hepatitis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and systemic lupus erythematosus)
• Endocrine disorders (hypothyroidism, hyperthyroidism, hyperglycemia, hypoglycemia and diabetes mellitus)
• Ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema and serous retinal detachment)
• Cerebrovascular events (ischemic and hemorrhagic cerebrovascular events)
• Hepatic failure and hepatitis exacerbations (chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation and death; exacerbations of hepatitis during hepatitis B therapy)
• Pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths)
• Infections (bacterial, viral, or fungal), some fatal
• Colitis (ulcerative and hemorrhagic/ischemic colitis), sometimes fatal
• Pancreatitis, sometimes fatal
• Hypersensitivity (eg, urticaria, angioedema, bronchoconstriction, and anaphylaxis) and serious skin reactions, including Stevens-Johnson syndrome
• Impact on growth in pediatric patients (delay in weight and height increases after 48 weeks of therapy)
• Peripheral neuropathy (in combination with telbivudine)

ADVERSE REACTIONS

Adult patients:

The most common life-threatening or fatal events induced or aggravated by PEGASYS and ribavirin include depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV subjects.

Chronic Hepatitis C (Adult Patients)

In clinical trials, 98 to 99 percent of subjects experienced one or more adverse events. For hepatitis C subjects, the most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache, and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus.

The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (eg, sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other serious adverse events occurred at a frequency of <1% and included: suicide, suicidal ideation, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (eg, hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

Chronic Hepatitis C (Pediatric Patients)

In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most prevalent adverse events in subjects treated with combination therapy for up to 48 weeks with PEGASYS and ribavirin were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Most of the adverse events reported in the study were mild or moderate in severity. Severe adverse events were reported in 2 subjects in the PEGASYS plus ribavirin combination therapy group (hyperglycemia and cholecystectomy). Pediatric subjects treated with PEGASYS plus ribavirin showed a delay in weight and height increases after 48 weeks of therapy; most had returned to baseline normative growth curve percentiles for weight and height at two years of follow-up.

Chronic Hepatitis C with HIV Coinfection (Adult Patients)

The adverse event profile of HCV/HIV coinfected subjects treated with PEGASYS/ribavirin was generally similar to that shown for monoinfected patients. Events occurring more frequently in coinfected subjects were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Chronic Hepatitis B

In clinical trials of 48-week treatment duration, the adverse event profile of PEGASYS in chronic hepatitis B was similar to that seen in chronic hepatitis C PEGASYS monotherapy use, except for exacerbations of hepatitis. Six percent of PEGASYS treated subjects in the hepatitis B studies experienced one or more serious adverse events.

The most common or important serious adverse events, all of which occurred at a frequency of less than or equal to 1%, in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, and thrombotic thrombocytopenic purpura.

The most commonly observed adverse reactions in patients treated with PEGASYS were pyrexia (54%), headache (27%), fatigue (24%), myalgia (26%), alopecia (18%), and anorexia (16%).

You may report side effects to the FDA at 1-800-FDA-1088 or www.FDA.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see PEGASYS full Prescribing Information for Boxed WARNINGS and additional Important Safety Information.

PEGASYS^® and COPEGUS^® are registered trademarks of Hoffmann-La Roche Inc. All other brands for listed products are trademarks or registered trademarks (as indicated) of their respective owners and are not trademarks of Genentech, Inc. or Hoffmann-La Roche Inc.