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Name:Pegasys
Manufacturer:Genentech, Inc.
Category:Prescription Marketed Drugs


These highlights do not include all the information needed to use PEGASYS safely and effectively. See full prescribing information for PEGASYS.PEGASYS® (peginterferon alfa-2a)Solution for Subcutaneous InjectionInitial U.S. Approval: 2002

PEGASYS - peginterferon alfa-2a injection, solution 
Genentech, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PEGASYS safely and effectively. See full prescribing information for PEGASYS.

PEGASYS® (peginterferon alfa-2a)
Solution for Subcutaneous Injection
Initial U.S. Approval: 2002


WARNING: RISK OF SERIOUS DISORDERS AND

RIBAVIRIN ASSOCIATED EFFECTS
See full prescribing information for complete boxed warning.

  • May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely and withdraw therapy with persistently severe or worsening signs or symptoms of the above disorders (5)

Use with Ribavirin

  • Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients (5.1, 8.1)

RECENT MAJOR CHANGES

Boxed Warning 02/2011
Indications and Usage (1) 02/2011
Dosage and Administration (2.1, 2.4, 2.5, 2.8) 02/2011
Contraindications (4) 02/2011
Warnings and Precautions (5.1, 5.4, 5.16) 02/2011

INDICATIONS AND USAGE

PEGASYS is an antiviral indicated for:

Treatment of Chronic Hepatitis C (CHC) in adults with compensated liver disease not previously treated with interferon alpha, in patients with histological evidence of cirrhosis and compensated liver disease, and in adults with CHC/ HIV coinfection and CD4 count > 100 cells/mm3 (1.1)

  • Combination Therapy with COPEGUS is recommended unless patient has contraindication to or significant intolerance to COPEGUS (1.1)

PEGASYS Monotherapy is indicated for:

  • 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 (1.2)

DOSAGE AND ADMINISTRATION

  • PEGASYS 180 mcg/week is administered by subcutaneous injection
  • The length of PEGASYS treatment depends on indication, genotype, and whether it is co-administered with COPEGUS (2.2, 2.3, 2.4)
  • Dose reduction is recommended in patients experiencing certain laboratory abnormalities, adverse reactions or renal dysfunction (2.5, 12.3)

DOSAGE FORMS AND STRENGTHS

  • 180 mcg/1.0 mL Vial for single use (3)
  • 180 mcg/0.5 mL Prefilled Syringe for single use (3)

CONTRAINDICATIONS

  • Autoimmune hepatitis (4)
  • Hepatic decompensation in patients with cirrhosis (4)
  • Use in neonates/infants (4)
  • Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction and anaphylaxis to alpha interferons or any component of the product (4, 5)

Additional contraindications for use with ribavirin:

  • Pregnant women and men whose female partners are pregnant in combination therapy with COPEGUS (4, 8.1)
  • Hemoglobinopathies (e.g., thalassemia major, sickle cell disease) (4)
  • Coadministration with didanosine

WARNINGS AND PRECAUTIONS

Use with Ribavirin

  • Birth defects and fetal death: patients must have a negative pregnancy test prior to therapy, use 2 or more forms of contraception, and have monthly pregnancy tests (5.1)
  • Hemolytic anemia (5.1)
  • History of significant or unstable cardiac disease (5.3)

Patients exhibiting the following events should be closely monitored and may require dose reduction or discontinuation of therapy:

  • Neuropsychiatric events (5.2)
  • Autoimmune and endocrine disorders (including thyroid disorders; hyperglycemia) (5.5, 5.6)
  • Ophthalmologic disorders (5.7)
  • Cerebrovascular disorders (5.8)
  • Hepatic decompensation in cirrhotic patients. Exacerbation of hepatitis during hepatitis B treatment (5.9)
  • Pulmonary disorders (5.10)
  • Infections (bacterial, viral, fungal) (5.11)
  • Bone marrow suppression (5.4)
  • Colitis and pancreatitis (5.12, 5.13)
  • Hypersensitivity and serious skin reactions including Stevens-Johnson Syndrome (5.14)
  • Peripheral neuropathy when used in combination with telbivudine (5.15)

ADVERSE REACTIONS

The most common adverse reactions (incidence > 40%) are fatigue/asthenia, pyrexia, myalgia, and headache. (6)


To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.


DRUG INTERACTIONS

  • Drugs metabolized by CYP1A2: monitor for increased serum levels of theophylline and adjust dose accordingly (7.2)
  • Methadone: monitor for signs and symptoms of methadone toxicity (7.3)
  • Nucleoside analogues: closely monitor for toxicities and dose reduce or discontinue PEGASYS/COPEGUS or both should event worsen (7.4)
  • Zidovudine: monitor for worsening neutropenia and/or anemia with PEGASYS/COPEGUS (7.4)
  • Azathioprine (7.4)

USE IN SPECIFIC POPULATIONS

  • Ribavirin Pregnancy Registry (8.1)
  • Pediatrics: safety and efficacy have not been established (8.4)
  • Geriatric patients: Neuropsychiatric, cardiac, and systemic (flu-like) adverse reactions may be more severe (8.5)
  • Hepatic patients: Clinical status and hepatic function should be closely monitored and treatment should be immediately discontinued if decompensation occurs (8.6)
  • Renal Impairment increases exposure to PEGASYS; monitor for interferon toxicity and adjust dose accordingly (8.7)
  • Organ transplant: safety and efficacy have not been studied (8.8)
  • Chronic Hepatitis B: safety and efficacy have not been established in hepatitis B patients coinfected with HCV or HIV (8.9)


See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised: 02/2011

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C

1.2 Chronic Hepatitis B

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Hepatitis C

2.2 Chronic Hepatitis C with HIV Coinfection

2.3 Chronic Hepatitis B

2.4 Dose Modifications

2.5 Renal Function

2.6 Liver Function

2.7 Discontinuation of Dosing

2.8 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Use with Ribavirin including COPEGUS

5.2 Neuropsychiatric

5.3 Cardiovascular Disorders

5.4 Bone Marrow Suppression

5.5 Autoimmune Disorders

5.6 Endocrine Disorders

5.7 Ophthalmologic Disorders

5.8 Cerebrovascular Disorders

5.9 Hepatic Failure and Hepatitis Exacerbations

5.10 Pulmonary Disorders

5.11 Infections

5.12 Colitis

5.13 Pancreatitis

5.14 Hypersensitivity

5.15 Peripheral Neuropathy

5.16 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

6.3 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Metabolized by Cytochrome P450

7.2 Theophylline

7.3 Methadone

7.4 Nucleoside Analogues

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic impairment

8.7 Renal impairment

8.8 Organ Transplant Recipients

8.9 Chronic Hepatitis B

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Studies 1, 2, and 3: PEGASYS Monotherapy

14.2 Chronic Hepatitis C Studies 4 and 5: PEGASYS/COPEGUS Combination Therapy

14.3 Chronic Hepatitis C and Coinfection with HIV (CHC/HIV) Study 6: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy

14.4 Chronic Hepatitis B Studies 7 and 8: PEGASYS Monotherapy

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Information for patients


FULL PRESCRIBING INFORMATION

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

Alpha interferons, including PEGASYS (peginterferon alfa-2a), 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 [see Warnings and Precautions (5.2, 5.5, 5.8, 5.11, 5.14, 5.16), Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)].

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].

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C

 PEGASYS, peginterferon alfa-2a, alone or in combination with COPEGUS, is indicated for the treatment of adults 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 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 [see Clinical Studies (14)].
  • Safety and efficacy has not been demonstrated for treatment longer than 48 weeks.
  • The safety and efficacy have not been established in liver or other organ transplant recipients [see Use in Specific Populations (8.7)].

1.2 Chronic Hepatitis B

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.

2 DOSAGE AND ADMINISTRATION

Pegasys is administered by subcutaneous injection in the abdomen or thigh.

2.1 Chronic Hepatitis C

 PEGASYS Monotherapy:

The recommended dose of PEGASYS monotherapy for chronic hepatitis C is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks.

PEGASYS/COPEGUS Combination Therapy:

The recommended dose of PEGASYS when used in combination with ribavirin for chronic hepatitis C is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly. The recommended dose of COPEGUS and duration for PEGASYS/COPEGUS therapy is based on viral genotype (see Table 1).

The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses.

COPEGUS should be taken with food.

Table 1 PEGASYS and COPEGUS Dosing Recommendations
Hepatitis C virus Genotype PEGASYS Dose COPEGUS Dose Duration
Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 8).
Data on genotypes 5 and 6 are insufficient for dosing recommendations.
Genotypes 1, 4 180 mcg <75 kg = 1000 mg
≥75 kg = 1200 mg
48 weeks
48 weeks
Genotypes 2, 3 180 mcg 800 mg 24 weeks

2.2 Chronic Hepatitis C with HIV Coinfection

PEGASYS Monotherapy: The recommended dose of PEGASYS monotherapy for chronic hepatitis C in patients coinfected with HIV is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks.

PEGASYS/COPEGUS Combination Therapy: The recommended dose when used in combination with ribavirin is PEGASYS 180 mcg once weekly and COPEGUS 800 mg orally daily given in two divided doses for a total of 48 weeks, regardless of genotype.

Since COPEGUS absorption increases when administered with a meal, patients are advised to take COPEGUS with food.

2.3 Chronic Hepatitis B

PEGASYS Monotherapy: The recommended dose of PEGASYS monotherapy for hepatitis B is 180 mcg (1.0 mL vial or 0.5 mL prefilled syringe) once weekly for 48 weeks.

2.4 Dose Modifications

 If severe adverse reactions or laboratory abnormalities develop during combination PEGASYS/COPEGUS therapy, the dose should be modified until the adverse reactions abate. If intolerance persists after dose adjustment, PEGASYS/COPEGUS therapy should be discontinued. Table 2, Table 3, and Table 4 provide guidelines for dose modifications and discontinuation of PEGASYS/COPEGUS based on laboratory abnormalities, patient's depression status, and cardiac status.

When dose modification of PEGASYS is required for adverse reactions (clinical and/or laboratory), initial dose reduction to 135 mcg (which is 0.75 mL for the vials or adjustment to the corresponding graduation mark for the syringes) is recommended. Dose reduction to 90 mcg (which is 0.5 mL for the vials or adjustment to the corresponding graduation mark for the syringes) may be needed if the adverse reaction persists or recurs. Following improvement of the adverse reaction, re-escalation of the dose may be considered [see Warnings and Precautions (5), and Adverse Reactions (6)].

Table 2 PEGASYS Hematological Dose Modification Guidelines
Laboratory Values Recommended Dose

ANC <750/mm3

ANC <500/mm3

Reduce to 135 mcg

Discontinue treatment until ANC values return to more than 1000/mm3. Reinstitute at 90 mcg and monitor ANC

Platelet <50,000/mm3

Platelet <25,000/mm3

Reduce to 90 mcg

Discontinue treatment
Table 3 Guidelines for Modification or Discontinuation of PEGASYS and for Scheduling Visits for Patients with Depression
Depression Severity Initial Management
(4-8 weeks)
Depression Status
Dose
modification
Visit
schedule
Remains
stable
Improves Worsens
Mild No change Evaluate once weekly by visit and/or phone Continue weekly visit schedule Resume normal visit schedule (See moderate or severe depression)
Moderate Decrease PEGASYS dose to 135 mcg (in some cases dose reduction to 90 mcg may be needed) Evaluate once weekly (office visit at least every other week) Consider psychiatric consultation. Continue reduced dosing If symptoms improve and are stable for 4 weeks, may resume normal visit schedule. Continue reduced dosing or return to normal dose (See severe depression)
Severe Discontinue PEGASYS permanently Obtain immediate psychiatric consultation Psychiatric therapy necessary
Table 4 COPEGUS Dose Modification Guidelines
Laboratory Values Reduce COPEGUS Dose to 600 mg/day* if: Discontinue COPEGUS if:
*
One 200 mg tablet in the morning and two 200 mg tablets in the evening.
Hemoglobin in patients with no cardiac disease <10 g/dL <8.5 g/dL
Hemoglobin in patients with history of stable cardiac disease ≥2 g/dL decrease in hemoglobin during any 4 week period treatment <12 g/dL despite 4 weeks at reduced dose

Once COPEGUS has been withheld due to a laboratory abnormality or clinical adverse event, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that COPEGUS be increased to the original dose (1000 mg or 1200 mg).

2.5 Renal Function

 In 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 COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].

2.6 Liver Function

If ALT increases are progressive despite dose reduction or accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be immediately discontinued.

In chronic hepatitis C patients with progressive ALT increases above baseline values, the dose of PEGASYS should be reduced to 135 mcg and more frequent monitoring of liver function should be performed. After PEGASYS dose reduction or withholding, therapy can be resumed after ALT flares subside.

In chronic hepatitis B patients with elevations in ALT (>5 x ULN), more frequent monitoring of liver function should be performed and consideration should be given to either reducing the dose of PEGASYS to 135 mcg or temporarily discontinuing treatment. After PEGASYS dose reduction or withholding, therapy can be resumed after ALT flares subside.

In patients with persistent, severe (ALT >10 times above the upper limit of normal) hepatitis B flares, consideration should be given to discontinuation of treatment.

2.7 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 [see Clinical Studies (14)].

During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation is observed [see Contraindications (4)].

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 [see Boxed Warning].

2.8 Preparation and Administration

 A patient should self-inject PEGASYS only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique [see illustrated FDA Approved Medication Guide for directions on injection site preparation and injection instructions].

PEGASYS should be inspected visually for particulate matter and discoloration before administration, and not used if particulate matter is visible or product is discolored. Vials and prefilled syringes with particulate matter or discoloration should be returned to the pharmacist.

Discard unused portion of PEGASYS in single-use vials or prefilled syringes in excess of the labeled volume. Use only one vial or prefilled syringe per dose.

3 DOSAGE FORMS AND STRENGTHS

  • Vial for single use: 180 mcg/1.0 mL
  • Prefilled Syringe for single use: 180 mcg/0.5 mL

4 CONTRAINDICATIONS

 PEGASYS is contraindicated in patients with:

  • 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/COPEGUS combination therapy is additionally contraindicated in:

  • Women who are pregnant
  • Men whose female partners are pregnant
  • Patients with known hypersensitivity (urticaria, angioedema, bronchoconstriction, and anaphylaxis) to COPEGUS or to any component of the tablet
  • Patients with hemoglobinopathies (e.g., 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 [see Drug Interactions (7.4)].

5 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 [see Boxed Warning].

5.1 Use with Ribavirin including COPEGUS

 Pregnancy

COPEGUS 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 COPEGUS combination therapy. COPEGUS 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 for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time [see Boxed Warning, Contraindications (4), Patient Counseling Information (17) and COPEGUS Package Insert].

Anemia

The primary toxicity of COPEGUS is hemolytic anemia. Hemoglobin <10 g/dL was observed in approximately 13% of COPEGUS and PEGASYS treated subjects in chronic hepatitis C clinical trials. 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. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by COPEGUS. Patients should be assessed for underlying cardiac disease before initiation of COPEGUS 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 (2.6)]. 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].

5.2 Neuropsychiatric

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 (6.1) and Dosage and Administration (2.5)].

5.3 Cardiovascular Disorders

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 receive PEGASYS/COPEGUS [see Warnings and Precautions (5.15) and COPEGUS Package Insert].

5.4 Bone Marrow Suppression

 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 Warnings and Precautions (5.1)].

PEGASYS/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 (2.6)].

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 (6.1)].

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PEGASYS, COPEGUS, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions (7)].

5.5 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.

5.6 Endocrine Disorders

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.

5.7 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 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.

5.8 Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. 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.

5.9 Hepatic Failure and Hepatitis Exacerbations

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 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic subjects receiving HAART, 14 (11%) of these subjects across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 subjects 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/COPEGUS treatment should be immediately discontinued in patients with hepatic decompensation [see Contraindications (4)].

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 subjects 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 subjects, 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 (6.1) and Dosage and Administration (2.5)].

5.10 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by PEGASYS or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. PEGASYS combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored.

5.11 Infections

While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, or fungal), some fatal, have been reported during treatment with alpha interferons including PEGASYS. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

5.12 Colitis

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.

5.13 Pancreatitis

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

5.14 Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with PEGASYS/COPEGUS should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving PEGASYS with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

5.15 Peripheral Neuropathy

Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and PEGASYS as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated.

5.16 Laboratory Tests

 Before beginning PEGASYS or PEGASYS/COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEGASYS/COPEGUS.

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 subjects with cirrhosis or 70,000 cells/mm3 in subjects with CHC and HIV)
  • Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
  • Serum creatinine concentration < 1.5 × upper limit of normal
  • TSH and T4 within normal limits or adequately controlled thyroid function
  • CD4+ cell count ≥ 200 cells/mcL or CD4+ cell count ≥ 100 cells/mcL but < 200 cells/mcL and HIV-1 RNA <5000 copies/mL in subjects coinfected with HIV
  • Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected subjects
  • Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in subjects with CHC and HIV

6 ADVERSE REACTIONS

In clinical trials, a broad variety of serious adverse reactions were observed in 1,010 subjects who received PEGASYS at doses of 180 mcg for 48 weeks, alone or in combination with COPEGUS [see Boxed Warning and Warnings and Precautions (5)]. The most common life-threatening or fatal events induced or aggravated by PEGASYS and COPEGUS 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 [see Warnings and Precautions (5.9)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in clinical practice.

In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with COPEGUS. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs 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 (e.g., 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.

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. Table 5 displays pooled rates of adverse events occurring in > 5% of subjects in the PEGASYS monotherapy and PEGASYS/COPEGUS combination therapy clinical trials.

Overall 11% of CHC monoinfected subjects receiving 48 weeks of therapy with PEGASYS either alone or in combination with COPEGUS discontinued therapy; 16% of CHC/HIV coinfected subjects discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic, and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of subjects with CHC or CHC/HIV required modification of PEGASYS and/or COPEGUS therapy. The most common reason for dose modification of PEGASYS in CHC and CHC/HIV subjects was for laboratory abnormalities, neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of COPEGUS in CHC and CHC/HIV subjects was anemia (22% and 16%, respectively). PEGASYS dose was reduced in 12% of subjects receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of subjects receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of subjects receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of subjects receiving 800 mg COPEGUS for 24 weeks.

Chronic hepatitis C monoinfected subjects treated for 24 weeks with PEGASYS and 800 mg COPEGUS were observed to have lower incidence of serious adverse events (3% vs. 10%), Hgb <10 g/dL (3% vs. 15%), dose modification of PEGASYS (30% vs. 36%) and COPEGUS (19% vs. 38%) and of withdrawal from treatment (5% vs. 15%) compared to subjects treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg COPEGUS. The overall incidence of adverse events appeared to be similar in the two treatment groups.

Table 5 Adverse Reactions Occurring in ≥5% of Subjects in Chronic Hepatitis C Clinical Trials (Pooled Studies 1, 2, 3, and Study 4)
CHC Monotherapy (Pooled Studies 1-3) CHC Combination Therapy
Study 4
Body System PEGASYS 180 mcg
48 week*
ROFERON-A Either 3 MIU or 6/3 MIU of ROFERON-A
48 week*
PEGASYS 180 mcg +
1000 mg or 1200 mg COPEGUS
48 week
Intron® A +
1000 mg or 1200 mg Rebetol ®
48 week
N=559 N=554 N=451 N=443
% % % %
*
Pooled studies 1, 2, and 3
An induction dose of 6 million international units (MIU) three times a week for the first 12 weeks followed by 3 million international units three times a week for 36 weeks given subcutaneously.
Study 4
§
Severe hematologic abnormalities (lymphocyte <0.5 × 109/L; hemoglobin <10 g/dL; neutrophil <0.75 × 109/L; platelet <50 × 109/L).
Application Site Disorders
Injection site reaction 22 18 23 16
Endocrine Disorders
Hypothyroidism 3 2 4 5
Flu-like Symptoms and Signs
Fatigue/Asthenia 56 57 65 68
Pyrexia 37 41 41 55
Rigors 35 44 25 37
Pain 11 12 10 9
Gastrointestinal
Nausea/Vomiting
Diarrhea
Abdominal pain
Dry mouth
Dyspepsia

24
16
15
6
<1

33
16
15
3
1

25
11
8
4
6

29
10
9
7
5
Hematologic§
Lymphopenia 3 5 14 12
Anemia 2 1 11 11
Neutropenia 21 8 27 8
Thrombocytopenia 5 2 5 <1
Metabolic and Nutritional
Anorexia 17 17 24 26
Weight decrease 4 3 10 10
Musculoskeletal, Connective Tissue and Bone
Myalgia 37 38 40 49
Arthralgia 28 29 22 23
Back pain 9 10 5 5
Neurological
54
16
5
Headache 58 43 49
Dizziness (excluding vertigo) 12 14 14
Memory impairment 4 6 5
Resistance Mechanism Disorders
Overall 10 6 12 10
Psychiatric
Irritability/Anxiety/
Nervousness
Insomnia
Depression
Concentration impairment
Mood alteration

19

19
18
8
3

22

23
19
10
2

33

30
20
10
5

38

37
28
13
6
Respiratory, Thoracic and Mediastinal
Dyspnea 4 2 13 14
Cough 4 3 10 7
Dyspnea exertional <1 <1 4 7
Skin and Subcutaneous Tissue
Alopecia 23 30 28 33
Pruritus 12 8 19 18
Dermatitis 8 3 16 13
Dry skin 4 3 10 13
Rash 5 4 8 5
Sweating increased 6 7 6 5
Eczema 1 1 5 4
Visual Disorders
Vision blurred 4 2 5 2

CHC with HIV Coinfection

The adverse event profile of coinfected subjects treated with PEGASYS/COPEGUS in Study 6 was generally similar to that shown for monoinfected subjects in Study 4 (Table 5). 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 CHC PEGASYS monotherapy use, except for exacerbations of hepatitis [see Warnings and Precautions (5.9)]. 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 ≤ 1%, in the hepatitis B studies were infections (sepsis, appendicitis, tuberculosis, influenza), hepatitis B flares, and thrombotic thrombocytopenic purpura.

One serious adverse event of anaphylactic shock occurred in a dose ranging study of 191 subjects in a subject taking a higher than approved dose of PEGASYS.

The most commonly observed adverse reactions in the PEGASYS and lamivudine groups, respectively, were pyrexia (54% vs. 4%), headache (27% vs. 9%), fatigue (24% vs. 10%), myalgia (26% vs. 4%), alopecia (18% vs. 2%), and anorexia (16% vs. 3%).

Overall 5% of hepatitis B subjects discontinued PEGASYS therapy and 40% of subjects required modification of PEGASYS dose. The most common reason for dose modification in subjects receiving PEGASYS therapy was for laboratory abnormalities including neutropenia (20%), thrombocytopenia (13%), and ALT elevation (11%).

Laboratory Values

The laboratory test values observed in the hepatitis B trials (except where noted below) were similar to those seen in the PEGASYS monotherapy CHC trials.

Neutrophils

In the hepatitis C studies, decreases in neutrophil count below normal were observed in 95% of all subjects treated with PEGASYS either alone or in combination with COPEGUS. Severe potentially life-threatening neutropenia (ANC <0.5 × 109/L) occurred in 5% of CHC subjects and 12% of CHC/HIV subjects receiving PEGASYS either alone or in combination with COPEGUS. Modification of PEGASYS dose for neutropenia occurred in 17% of subjects receiving PEGASYS monotherapy and 22% of subjects receiving PEGASYS/COPEGUS combination therapy. In the CHC/HIV subjects 27% required modification of interferon dosage for neutropenia. Two percent of subjects with CHC and 10% of subjects with CHC/HIV required permanent reductions of PEGASYS dosage and <1% required permanent discontinuation. Median neutrophil counts return to pre-treatment levels 4 weeks after cessation of therapy [see Dosage and Administration (2.5)].

Lymphocytes

Decreases in lymphocyte count are induced by interferon alpha therapy. PEGASYS plus COPEGUS combination therapy induced decreases in median total lymphocyte counts (56% in CHC and 40% in CHC/HIV, with median decrease of 1170 cells/mm3 in CHC and 800 cells/mm3 in CHC/HIV). In the hepatitis C studies, lymphopenia was observed during both monotherapy (81%) and combination therapy with PEGASYS and COPEGUS (91%). Severe lymphopenia (<0.5 × 109/L) occurred in approximately 5% of all monotherapy subjects and 14% of all combination PEGASYS and COPEGUS therapy recipients. Dose adjustments were not required by protocol. The clinical significance of the lymphopenia is not known.

In CHC with HIV coinfection, CD4 counts decreased by 29% from baseline (median decrease of 137 cells/mm3) and CD8 counts decreased by 44% from baseline (median decrease of 389 cells/mm3) in the PEGASYS plus COPEGUS combination therapy arm. Median lymphocyte CD4 and CD8 counts return to pre-treatment levels after 4 to 12 weeks of the cessation of therapy. CD4% did not decrease during treatment.

Platelets

In the hepatitis C studies, platelet counts decreased in 52% of CHC subjects and 51% of CHC/HIV subjects treated with PEGASYS alone (respectively median decrease of 41% and 35% from baseline), and in 33% of CHC subjects and 47% of CHC/HIV subjects receiving combination therapy with COPEGUS (median decrease of 30% from baseline). Moderate to severe thrombocytopenia (<50,000/mm3) was observed in 4% of CHC and 8% of CHC/HIV subjects. Median platelet counts return to pre-treatment levels 4 weeks after the cessation of therapy.

Hemoglobin

In the hepatitis C studies, the hemoglobin concentration decreased below 12 g/dL in 17% (median Hgb reduction of 2.2 g/dL) of monotherapy and 52% (median Hgb reduction of 3.7 g/dL) of combination therapy subjects. Severe anemia (Hgb <10 g/dL) was encountered in 13% of all subjects receiving combination therapy and in 2% of CHC subjects and 8% of CHC/HIV subjects receiving PEGASYS monotherapy. Dose modification for anemia in COPEGUS recipients treated for 48 weeks occurred in 22% of CHC subjects and 16% of CHC/HIV subjects [see Dosage and Administration (2.6)].

Triglycerides

Triglyceride levels are elevated in subjects receiving alfa interferon therapy and were elevated in the majority of subjects participating in clinical studies receiving either PEGASYS alone or in combination with COPEGUS. Random levels ≥400 mg/dL were observed in about 20% of CHC subjects. Severe elevations of triglycerides (>1000 mg/dL) occurred in 2% of CHC monoinfected subjects.

In HCV/HIV coinfected subjects, fasting levels ≥400 mg/dL were observed in up to 36% of subjects receiving either PEGASYS alone or in combination with COPEGUS. Severe elevations of triglycerides (>1000 mg/dL) occurred in 7% of coinfected subjects.

ALT Elevations

Chronic Hepatitis C

One percent of subjects in the hepatitis C trials experienced marked elevations (5- to 10-fold above the upper limit of normal) in ALT levels during treatment and follow-up. These transaminase elevations were on occasion associated with hyperbilirubinemia and were managed by dose reduction or discontinuation of study treatment. Liver function test abnormalities were generally transient. One case was attributed to autoimmune hepatitis, which persisted beyond study medication discontinuation [see Dosage and Administration (2.5)].

Chronic Hepatitis B

Transient ALT elevations are common during hepatitis B therapy with PEGASYS. Twenty-five percent and 27% of subjects experienced elevations of 5 to 10 × ULN and 12% and 18% had elevations of >10 × ULN during treatment of HBeAg negative and HBeAg positive disease, respectively. Flares have been accompanied by elevations of total bilirubin and alkaline phosphatase and less commonly with prolongation of PT and reduced albumin levels. Eleven percent of subjects had dose modifications due to ALT flares and <1% of subjects were withdrawn from treatment [see Warnings and Precautions (5.9) and Dosage and Administration (2.5)].

ALT flares of 5 to 10 × ULN occurred in 13% and 16% of subjects, while ALT flares of >10 × ULN occurred in 7% and 12% of subjects in HBeAg negative and HBeAg positive disease, respectively, after discontinuation of PEGASYS therapy.

Thyroid Function

PEGASYS alone or in combination with COPEGUS was associated with the development of abnormalities in thyroid laboratory values, some with associated clinical manifestations. In the hepatitis C studies, hypothyroidism or hyperthyroidism requiring treatment, dose modification or discontinuation occurred in 4% and 1% of PEGASYS treated subjects and 4% and 2% of PEGASYS and COPEGUS treated subjects, respectively. Approximately half of the subjects, who developed thyroid abnormalities during PEGASYS treatment, still had abnormalities during the follow-up period [see Warnings and Precautions (5.6)].

6.2 Immunogenicity

Chronic Hepatitis C

Nine percent (71/834) of subjects treated with PEGASYS with or without COPEGUS developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Three percent of subjects (25/835) receiving PEGASYS with or without COPEGUS, developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL).

Chronic Hepatitis B

Twenty-nine percent (42/143) of hepatitis B subjects treated with PEGASYS for 24 weeks developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. Thirteen percent of subjects (19/143) receiving PEGASYS developed low-titer neutralizing antibodies (using an assay with a sensitivity of 100 INU/mL).

The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The percentage of subjects whose test results were considered positive for antibodies is highly dependent on the sensitivity and specificity of the assays.

Additionally, the observed incidence of antibody positivity in these assays may be influenced by several factors including sample timing and handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to PEGASYS with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of PEGASYS therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders

 
pure red cell aplasia

Ear and Labyrinth Disorders

 
hearing impairment, hearing loss

Immune system disorders

 
Liver graft rejection and renal graft rejection [see Warnings and Precautions (5.9) and Use in Specific Populations (8.8)].

Metabolism and Nutrition Disorders

 
dehydration

Skin and subcutaneous tissue disorders

 
serious skin reactions

Neurological

 
seizures

7 DRUG INTERACTIONS

7.1 Drugs Metabolized by Cytochrome P450

There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC.

7.2 Theophylline

Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS.

7.3 Methadone

In a PK study of HCV subjects concomitantly receiving methadone, treatment with PEGASYS once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of methadone toxicity.

The pharmacokinetics of concomitant administration of methadone and PEGASYS were evaluated in 24 PEGASYS naive chronic hepatitis C (CHC) subjects (15 male, 9 female) who received 180 mcg PEGASYS subcutaneously weekly. All subjects were on stable methadone maintenance therapy (median dose 95 mg, range 30 mg to 150 mg) prior to receiving PEGASYS. Mean methadone PK parameters were 10% to 15% higher after 4 weeks of PEGASYS treatment as compared to baseline. Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C subjects not receiving methadone.

7.4 Nucleoside Analogues

In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected subjects.

NRTIs

In Study 6 among the CHC/HIV coinfected cirrhotic subjects receiving NRTIs cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.9)].

Patients receiving PEGASYS/COPEGUS and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3, 5.9), Dosage and Administration (2.5, 2.6)].

Didanosine

Co-administration of COPEGUS and didanosine is contraindicated. In vitro, Didanosine and its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4)].

Zidovudine

In Study 6, subjects who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar subjects not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of PEGASYS, COPEGUS or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6).

Azathioprine

The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.1)].

Please refer to the Full Prescribing Information for ribavirin for full details on ribavirin's drug interaction potential.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: PEGASYS Monotherapy

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 (4)].

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 (4), Warnings and Precautions (5.1), 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.

8.3 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.

8.4 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 (4)].

8.5 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.

8.6 Hepatic impairment

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. 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 (4)]. Chronic hepatitis B subjects 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 subjects, respectively.

8.7 Renal impairment

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 (2.5)].

It is recommended that renal function be evaluated in all patients on COPEGUS. COPEGUS should not be administered to patients with creatinine clearance <50 mL/min [see Clinical Pharmacology (12.3) and COPEGUS Package Insert].

8.8 Organ Transplant Recipients

The safety and efficacy of PEGASYS and COPEGUS treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on PEGASYS, alone or in combination with COPEGUS [see Adverse Reactions (6.3)].

8.9 Chronic Hepatitis B

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

  • 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/mcL

10 OVERDOSAGE

There is limited experience with overdosage. The maximum dose received by any patient was 7 times the intended dose of PEGASYS (180 mcg/day for 7 days). There were no serious reactions attributed to overdosages. Weekly doses of up to 630 mcg have been administered to patients with cancer. Dose-limiting toxicities were fatigue, elevated liver enzymes, neutropenia, and thrombocytopenia. There is no specific antidote for PEGASYS. Hemodialysis and peritoneal dialysis are not effective.

11 DESCRIPTION

PEGASYS, peginterferon alfa-2a, is a covalent conjugate of recombinant alfa-2a interferon (approximate molecular weight [MW] 20,000 daltons) with a single branched bis-monomethoxy polyethylene glycol (PEG) chain (approximate MW 40,000 daltons). The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli.

PEGASYS is a sterile, preservative-free, colorless to light yellow injectable solution administered subcutaneously.

180 mcg/1.0 mL Vial: Each vial contains approximately 1.2 mL of solution to deliver 1.0 mL of drug product. Subcutaneous (sc) administration of 1.0 mL of 180 mcg of drug product (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.05 mg), benzyl alcohol (10.0 mg), polysorbate 80 (0.05 mg), sodium acetate trihydrate (2.62 mg), and sodium chloride (8.0 mg) at pH 6.0 ± 0.5.

180 mcg/0.5 mL Prefilled Syringe: Each syringe contains 0.6 mL of solution to deliver 0.5 mL of drug product. Subcutaneous (sc) administration of 0.5 mL delivers 180 mcg of drug product (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.0231 mg), benzyl alcohol (5.0 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4.0 mg) at pH 6.0 ± 0.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Clinical Pharmacology (12.4)].

12.2 Pharmacodynamics

PEGASYS stimulates the production of effector proteins such as serum neopterin and 2', 5'-oligoadenylate synthetase.

12.3 Pharmacokinetics

Maximal serum concentrations (Cmax) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of PEGASYS. Maximal serum concentrations (Cmax) occur between 72 to 96 hours post-dose.

Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON®-A). The mean terminal half-life after subcutaneous dosing in subjects with chronic hepatitis C was 160 hours (range 84 to 353 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.

Special Populations

Gender and Age

PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng∙h/mL in subjects older than 62 years taking 180 mcg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years.

Pediatric Patients

In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child x 180 mcg/1.73m2). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults.

Steady-state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 mcg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing. The safety and effectiveness of PEGASYS in patients below the age of 18 years have not been established [see Use in Specific Populations (8.4)].

Renal Dysfunction

In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance [see Use in Specific Populations (8.7)].

The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with COPEGUS [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

12.4 Microbiology

Mechanism of Action

The biological activity of PEGASYS is derived from its recombinant human interferon α-2a moiety. Peginterferon α-2a binds to the human type 1 interferon receptor leading to receptor dimerization. Receptor dimerization activates multiple intracellular signal transduction pathways initially mediated by the JAK/STAT pathway. Given the diversity of cell types that respond to interferon α-2a, and the multiplicity of potential intracellular responses to interferon receptor activation, peginterferon α-2a is expected to have pleiotropic biological effects in the body.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with an effective concentration (EC) value of 11-21 µm. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC value of 0.1 - 3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN-α and ribavirin has not been observed.

13 NONCLINICAL TOXICOLOGY

13.1 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 in in vitro and in vivo assays, and therefore, potential carcinogenic risk to humans cannot be excluded. In a p53 (+/-) mouse carcinogenicity study at doses up to 100 mg/kg/day ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogencity study at doses 60 mg/kg/day. On a body surface area basis, these doses were 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin respectively [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 subcutaneous injections of 600 mcg/kg/dose (7200 mcg/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 17β-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 mcg/kg (1200 mcg/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 × 106 IU/kg/day.

Use with Ribavirin: Ribavirin has shown reversible toxicity in animal studies of male fertility [see COPEGUS Package Insert].

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Studies 1, 2, and 3: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of hepatitis C virus infection were assessed in three randomized, open-label, active-controlled clinical studies. All subjects were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All subjects received therapy by subcutaneous injection for 48 weeks, and were followed for an additional 24 weeks to assess the durability of response. In studies 1 and 2, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 3 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In Study 1 (n=630), subjects received either ROFERON-A (interferon alfa-2a) 3 MIU three times a week, PEGASYS 135 mcg once weekly or PEGASYS 180 mcg once weekly. In Study 2 (n=526), subjects received either ROFERON-A 6 MIU three times a week for 12 weeks followed by 3 MIU three times a week for 36 weeks or PEGASYS 180 mcg once weekly. In Study 3 (n=269), subjects received ROFERON-A 3 MIU three times a week, PEGASYS 90 mcg once weekly or PEGASYS 180 mcg once each week.

In all three studies, treatment with PEGASYS 180 mcg resulted in significantly more subjects who experienced a sustained response (defined as undetectable HCV RNA [<50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2.0 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A. In Study 1, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 3, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A.

Table 6 Sustained Response to Monotherapy Treatment
Study 1 Study 2 Study 3
Roferon-A
3 MIU
(N=207)
PEGASYS
180 mcg
(N=208)
Diff*
(95% CI)
Roferon-A
6/3 MIU
(N=261)
PEGASYS
180 mcg
(N=265)
Diff*
(95% CI)
Roferon-A
3 MIU
(N=86)
PEGASYS
180 mcg
(N=87)
Diff*
(95% CI)
*
Percent difference between PEGASYS and ROFERON-A treatment.
An induction dose of 6 million international units (MIU) three times a week for the first 12 weeks followed by 3 million international units three times a week for 36 weeks given subcutaneously.
Defined as undetectable HCV RNA [<50 IU/mL] using the COBAS AMPLICOR® HCV Test, version 2.0 and normalization of ALT on or after study week 68
Combined Virologic and Biologic Sustained Response 11% 24% 13 (6, 20) 17% 35% 18 (11, 25) 7% 23% 16 (6, 26)
Sustained Virologic Response 11% 26% 15 (8, 23) 19% 38% 19 (11, 26) 8% 30% 22 (11, 33)

Matched pre- and post-treatment liver biopsies were obtained in approximately 70% of subjects. Similar modest reductions in inflammation compared to baseline were observed in all treatment groups.

Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2log10 drop in HCV RNA titer from baseline by 12 weeks of PEGASYS 180 mcg therapy, 2% (3/156) achieved a sustained virologic response [see Dosage and Administration (2.2)].

Averaged over Study 1, Study 2, and Study 3, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% in subjects with other viral genotypes. The treatment response rates were similar in men and women.

14.2 Chronic Hepatitis C Studies 4 and 5: PEGASYS/COPEGUS Combination Therapy

The safety and effectiveness of PEGASYS in combination with COPEGUS for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of subjects in both studies had compensated cirrhosis (Child-Pugh class A). Subjects coinfected with HIV were excluded from these studies.

In Study 4, subjects were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS 180 mcg once weekly with COPEGUS 1000 mg by mouth (body weight <75 kg) or 1200 mg by mouth (body weight ≥75 kg) or Rebetron® (interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth). All subjects received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. PEGASYS in combination with COPEGUS resulted in a higher SVR compared to PEGASYS alone or interferon alfa-2b and ribavirin (Table 7). In all treatment arms, subjects with viral genotype 1, regardless of viral load, had a lower response rate.

Table 7 Sustained Virologic Response to Combination Therapy (Study 4)
Interferon alfa-2b +
Ribavirin 1000 mg or 1200 mg
PEGASYS +
Placebo
PEGASYS +
COPEGUS 1000 mg or 1200 mg
*
Difference in overall treatment response (PEGASYS/COPEGUS – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).
All subjects 197/444 (44%)* 65/224 (29%) 241/453 (53%)*
Genotype 1 103/285 (36%) 29/145 (20%) 132/298 (44%)
Genotypes 2-6 94/159 (59%) 36/79 (46%) 109/155 (70%)

In Study 5 (see Table 8), all subjects received PEGASYS 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a COPEGUS dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg / ≥75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Subjects with genotype 1 and high viral titer (defined as >2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

HCV Genotypes

HCV 1 and 4 – Irrespective of baseline viral titer, treatment for 48 weeks with PEGASYS and 1000 mg or 1200 mg of COPEGUS resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg COPEGUS.

HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS and 800 mg of COPEGUS resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of COPEGUS (see Table 8).

The numbers of subjects with genotype 5 and 6 were too few to allow for meaningful assessment.

Table 8 Sustained Virologic Response as a Function of Genotype (Study 5)
24 Weeks Treatment 48 Weeks Treatment
PEGASYS +
COPEGUS
800 mg
(N=207)
PEGASYS +
COPEGUS
1000 mg or 1200 mg*
(N=280)
PEGASYS +
COPEGUS
800 mg
(N=361)
PEGASYS +
COPEGUS
1000 mg or 1200 mg*
(N=436)
*
1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg.
Genotype 1 29/101 (29%) 48/118 (41%) 99/250 (40%) 138/271 (51%)
Genotypes 2, 3 79/96 (82%) 116/144 (81%) 75/99 (76%) 117/153 (76%)
Genotype 4 0/5 (0%) 7/12 (58%) 5/8 (63%) 9/11 (82%)

Other Treatment Response Predictors

Treatment response rates are lower in subjects with poor prognostic factors receiving pegylated interferon alpha therapy. In studies 4 and 5, treatment response rates were lower in subjects older than 40 years (50% vs. 66%), in subjects with cirrhosis (47% vs. 59%), in subjects weighing over 85 kg (49% vs. 60%), and in subjects with genotype 1 with high vs. low viral load (43% vs. 56%). African-American subjects had lower response rates compared to Caucasians.

Paired liver biopsies were performed on approximately 20% of subjects in studies 4 and 5. Modest reductions in inflammation compared to baseline were seen in all treatment groups.

In studies 4 and 5, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of subjects who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of subjects who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

14.3 Chronic Hepatitis C and Coinfection with HIV (CHC/HIV) Study 6: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy

In Study 6, subjects with CHC/HIV were randomized to receive either PEGASYS 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS 180 mcg once weekly plus COPEGUS 800 mg by mouth daily or ROFERON-A (interferon alfa-2a), 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All subjects received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. COPEGUS or placebo treatment assignment was blinded in the PEGASYS treatment arms. All subjects were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Subjects also had CD4+ cell count ≥200 cells/mcL or CD4+ cell count ≥100 cells/mcL but <200 cells/mcL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Table 9.

Table 9 Sustained Virologic Response in Subjects with Chronic Hepatitis C Coinfected with HIV (Study 6)
ROFERON-A +
COPEGUS 800 mg
(N=289)
PEGASYS +
Placebo
(N=289)
PEGASYS +
COPEGUS 800 mg
(N=290)
All subjects 33 (11%) 58 (20%) 116 (40%)
Genotype 1 12/171 (7%) 24/175 (14%) 51/176 (29%)
Genotypes 2, 3 18/89 (20%) 32/90 (36%) 59/95 (62%)

Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.

Of the subjects who did not demonstrate either undetectable HCV RNA or at least a 2log10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and COPEGUS combination therapy, 2% (2/85) achieved an SVR.

In CHC subjects with HIV coinfection who received 48 weeks of PEGASYS alone or in combination with COPEGUS treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

14.4 Chronic Hepatitis B Studies 7 and 8: PEGASYS Monotherapy

The safety and effectiveness of PEGASYS for the treatment of chronic hepatitis B were assessed in controlled clinical trials in HBeAg positive (Study 7) and HBeAg negative (Study 8) subjects with chronic hepatitis B.

Subjects were randomized to PEGASYS 180 mcg subcutaneous once weekly, PEGASYS 180 mcg subcutaneous once weekly combined with lamivudine 100 mg once daily by mouth or lamivudine 100 mg once daily by mouth. All subjects received 48 weeks of their assigned therapy followed by 24 weeks of treatment-free follow-up. Assignment to receipt of PEGASYS or no PEGASYS was not masked.

All subjects were adults with compensated liver disease, had chronic hepatitis B virus (HBV) infection, and evidence of HBV replication (serum HBV >500,000 copies/mL for Study 7 and >100,000 copies/mL for Study 8) as measured by PCR (COBAS AMPLICOR® HBV Assay). All subjects had serum alanine aminotransferase (ALT) between 1 and 10 times the upper limit of normal (ULN) and liver biopsy findings compatible with the diagnosis of chronic hepatitis.

The results observed in the PEGASYS and lamivudine monotherapy groups are shown in Table 10.

Table 10 Percentage of Subjects with Serological, Virological, Biochemical, and Histological Response
Study 7
HBeAg positive
Study 8
HBeAg negative
Lamivudine

N = 272
PEGASYS

N = 271
Lamivudine

N = 181
PEGASYS

N = 177
*
End of Treatment (week 48)
End of follow-up – 24 weeks post-treatment (week 72)
<100,000 copies/mL for HBeAg positive and <20,000 copies/mL for HBeAg negative subjects
§
≥2 point decrease in Ishak necro-inflammatory score from baseline with no worsening of the Ishak fibrosis score. Not all subjects provided both initial and end of follow-up biopsies (missing biopsy rates: 19% to 24% in the PEGASYS and 31% to 32% in the Lamivudine arms)
Change of 1 point or more in Ishak fibrosis score
EOT* EOF EOF EOT* EOF EOF
HBeAg Seroconversion (%) 20 19 32 NA NA NA
HBV DNA Response (%) 62 22 32 85 29 43
ALT Normalization (%) 62 28 41 73 44 59
HBsAg Seroconversion (%) 0 0 3 1 0 3
N = 184 N = 207 N = 125 N = 143
Histological Improvement (%)§ ND 40 41 ND 41 48
Changes in Ishak fibrosis score compared to baseline (%):
- Improved
- Unchanged
- Worsened


ND


32
20
16


25
25
26


ND



31
23
15


32
30
19

PEGASYS co-administered with lamivudine did not result in any additional sustained response when compared to PEGASYS monotherapy.

Conclusions regarding comparative efficacy of PEGASYS and lamivudine treatment based upon the end of follow-up results are limited by the different mechanisms of action of the two compounds. Most treatment effects of lamivudine are unlikely to persist 24 weeks after therapy is withdrawn.

16 HOW SUPPLIED/STORAGE AND HANDLING

Single Use Vial: Each PEGASYS (peginterferon alfa-2a) 180 mcg single use, clear glass vial provides 1.0 mL containing 180 mcg peginterferon alfa-2a for subcutaneous injection. Each package contains 1 vial (NDC 0004-0350-09).

Prefilled Syringes Monthly Convenience Pack: Four prefilled syringes of PEGASYS (peginterferon alfa-2a), 180 mcg single use, graduated, clear glass prefilled syringes, in a box with 4 needles and 4 alcohol swabs (NDC 0004-0352-39). Each syringe is a 0.5 mL (½ cc) volume syringe supplied with a 27-gauge, ½-inch needle with needle-stick protection device.

Storage and Handling

Store in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Vials and prefilled syringes are for single use only. Discard any unused portion.

Disposal Instructions

If home use is prescribed, a puncture-resistant container for the disposal of used needles and syringes should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of any needles and syringes. The full container should be disposed of according to the directions provided by the physician [see FDA Approved Medication Guide].

17 PATIENT COUNSELING INFORMATION

17.1 Information for patients

Patients receiving PEGASYS alone or in combination with COPEGUS should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the PEGASYS and, if applicable, COPEGUS (ribavirin) MEDICATION GUIDES.

Pregnancy

PEGASYS and COPEGUS combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. COPEGUS therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during COPEGUS therapy and for 6 months post-therapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy [see Contraindications (4) and Warnings and Precautions (5.1)].

Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has been stopped; routine monthly pregnancy tests must be performed during this time [see Contraindications (4) and COPEGUS Package Insert].

To monitor maternal and fetal outcomes of pregnant women exposed to COPEGUS, the Ribavirin Pregnancy Registry has been established. Patients should be encouraged to register by calling 1-800-593-2214.

Laboratory Evaluations and Hydration

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter [see Warnings and Precautions (5.16)]. Patients should be instructed to remain well hydrated, especially during the initial stages of treatment. Patients should be advised to take COPEGUS with food.

General Information

Patients should be questioned about prior history of drug abuse before initiating COPEGUS/PEGASYS; as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.

Patients should be informed that it is not known if therapy with PEGASYS alone or in combination with COPEGUS will prevent transmission of HCV or HBV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV or HBV infection. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Patients should be advised to avoid drinking alcohol to reduce the chance of further injury to the liver.

Patients should not switch to another brand of interferon without consulting their healthcare provider.

Dosing Instructions

Patients should be advised to take their prescribed dose of PEGASYS on the same day and approximately same time each week. Patients should also be advised that if they miss a dose, but remember within 2 days, to take their missed dose as soon as they remember and then to take their next dose on the day they normally do. If they remember when more than 2 days have passed, patients should be advised to consult their healthcare provider.

Patients must be instructed on the use of aseptic techniques when administering PEGASYS. Appropriate training for preparation using the vial or syringe must be given by a healthcare provider, including a careful review of the PEGASYS Medication Guide and Medication Guide Appendix: Instructions for Preparing and Giving a Dose with a PEGASYS® Prefilled Syringe and Appendix: Instructions for Use PEGASYS® Solution for Injection Vial.

Patients should be instructed to allow the vial or prefilled syringe to come to room temperature and for condensation on the outside of the syringe to disappear before use. Patients should be advised not to shake the vial or prefilled syringe as foaming may occur.

Patients should be advised to choose a different place on either the thigh or abdomen each time an injection is made.

Medication Guide

PEGASYS®

(PEG-ah-sis)

(peginterferon alfa-2a)

Solution for Subcutaneous Injection

Read this Medication Guide before you start taking PEGASYS, and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

If you are taking PEGASYS with COPEGUS, also read the Medication Guide for COPEGUS (ribavirin) Tablets.

What is the most important information I should know about PEGASYS?

1.
COPEGUS in combination with PEGASYS may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant or plans to become pregnant, do not take PEGASYS/COPEGUS combination therapy. You or your sexual partner should not become pregnant while you take PEGASYS/COPEGUS combination therapy and for 6 months after treatment is over. You must use 2 forms of birth control one of which should be a condom with spermicide when you take PEGASYS/COPEGUS combination therapy and for the 6 months after treatment.
  • Females must have a pregnancy test before starting PEGASYS/COPEGUS combination therapy, every month while being treated, and every month for the 6 months after treatment with PEGASYS/COPEGUS combination therapy.
  • If you or your female sexual partner becomes pregnant while taking PEGASYS/COPEGUS or within 6 months after you stop taking PEGASY/COPEGUS, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes PEGASYS/COPEGUS while she is pregnant.
2.
Mental health problems and suicide. PEGASYS therapy may cause you to develop mood or behavioral problems, including:
  • irritability (getting upset easily)
  • depression (feeling low, feeling bad about yourself or feeling hopeless), and anxiety.
  • aggressive behavior
  • former drug addicts may fall back into drug addiction or overdose
  • thoughts of hurting yourself or others, or suicide
3.
Heart problems. Some people who take PEGASYS may get heart problems, including:
  • high blood pressure
  • fast heart rate or abnormal heart beat
  • chest pain
  • heart attacks
4.
Stroke or symptoms of a stroke. Symptoms may include weakness, loss of coordination, and numbness. Stroke or symptoms of a stroke may happen in people who have some risk factors or no known risk factors for a stroke.
5.
New or worsening autoimmune problems. Some people taking PEGASYS develop autoimmune problems (a condition where the body's immune cells attack other cells or organs in the body), such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. In some people who already have an autoimmune problem, it may get worse during your treatment with PEGASYS.
6.
Infections. Some people who take PEGASYS may get an infection. Symptoms may include:
  • fever
  • chills
  • burning and painful urination
  • urinating often
  • coughing up yellow or pink mucus (phlegm)

Before taking PEGASYS, tell your healthcare provider if you:

  • have or ever had any problems with your heart, including heart attack or have high blood pressure
  • are being treated for a mental illness or had treatment in the past for any mental illness, including depression and suicidal behavior.
  • have any kind of autoimmune disease (where the body's immune system attacks the body's own cells), such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis
  • have or ever had low blood cells counts
  • have or had blood disorders (bleeding problems or a blood clot, thalassemia major or sickle-cell anemia).
  • have ever been addicted to drugs or alcohol

Call your healthcare provider right away if you get any of these problems while taking PEGASYS:

  • new or worse mental health problems, such as thoughts of hurting yourself or others, or suicide
  • trouble breathing or chest pain
  • any new weakness, loss of coordination, or numbness
  • symptoms of infection including: fever, chills, burning or pain with urination, urinating often, tiredness, or coughing up yellow or pink mucus (phlegm)

During treatment with PEGASYS you will need to see your healthcare provider regularly and have blood tests to make sure that your treatment is working and to check for side effects.

PEGASYS can cause serious side effects. Some of these side effects may cause death. Tell your healthcare provider right away if you have any of these symptoms while taking PEGASYS. Other serious side effects are listed in "What are the possible side effects of PEGASYS?"

What is PEGASYS?

PEGASYS is a prescription medicine that is:

  • used alone or with COPEGUS to treat adults who have chronic (lasting a long time) hepatitis C infection and certain types of liver problems, and who have not taken alpha interferon
  • if you have chronic hepatitis C, you should not take PEGASYS by itself unless you are not able to take COPEGUS
  • used to treat adults with chronic hepatitis B.

It is not known if PEGASYS is safe and will work in children under 18 years age.

Who should not take PEGASYS?

Do not take PEGASYS if you:

  • have certain other liver problems
  • have certain types of hepatitis caused by your immune system attacking your liver (autoimmune hepatitis)
  • have had a serious allergic reaction to another alpha interferon medicine or to any of the ingredients in PEGASYS. Symptoms of a serious allergic reaction to alpha-interferon may include: itching, swelling of your face, tongue, throat, trouble breathing, feeling dizzy or faint, and chest pain. See the end of this Medication Guide for a list of the ingredients in PEGASYS.

Do not take PEGASYS in combination with COPEGUS if you:

  • are pregnant, or planning to get pregnant during treatment or during the 6 months after treatment
  • are a male patient with a female sexual partner who is pregnant or plans to become pregnant at any time while you are being treated with COPEGUS or during the 6 months after your treatment has ended
  • have certain blood disorders such as thalassemia major or sickle-cell anemia.
  • take didanosine (Videx or Videx EC)

Talk to your healthcare provider before taking PEGASYS if you have any of these conditions.

Do not give PEGASYS to a baby under 1 year of age. PEGASYS contains benzyl alcohol. Benzyl alcohol can cause nervous system problems and other problems which may lead to death.

What should I tell my healthcare provider before taking PEGASYS?

  • Before taking PEGASYS, See "What is the most important information I should know about PEGASYS?" and tell your healthcare provider if you have:
  • liver problems (other than hepatitis B or C) or had lung problems
  • thyroid problems
  • diabetes
  • colitis (inflammation of your intestine)
  • cancer
  • hepatitis B or C infection
  • HIV infection (the virus that causes AIDS)
  • kidney problems
  • high blood triglyceride levels (fat in your blood)
  • an organ transplant
  • any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if PEGASYS will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with PEGASYS.
  • are breast-feeding or plan to breast-feed. It is not known if PEGASYS passes into your breast milk. You and your healthcare provider should decide if you will use PEGASYS or breast-feed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. PEGASYS and certain other medicines may affect each other and cause side effects.

Especially tell your healthcare provider if you take:

  • the anti-hepatitis B medicine telbivudine (Tyzeka).
  • theophylline (Theo-24, Elixophyllin, Uniphyl, Theolair). Your healthcare provider may need to monitor the amount of theophylline in your body and make changes to your theophylline dose.
  • any anti-HIV medicines
  • methadone hydrochloride (Methadose, Dolophine hydrochloride)
  • azathioprine (Azasan, Imuran)

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take PEGASYS?

  • PEGASYS is given by injection under the skin (subcutaneous injection).
  • Your healthcare provider will decide on your dose of PEGASYS and when you will take it. PEGASYS is usually injected one time each week.
  • If your healthcare provider decides that you can inject PEGASYS for your condition, inject it exactly as prescribed.
  • Your healthcare provider may change your dose of PEGASYS if needed. Do not change your dose unless your healthcare provider tells you to change it.
  • Do not switch to another brand of interferon without talking to your healthcare provider
  • Take your prescribed dose of PEGASYS 1 time each week, on the same day of each week and at approximately the same time.
  • Do not take more than your prescribed dose.
  • If you miss your dose
    • If you remember within 2 days of when you should have taken PEGASYS, give yourself an injection of PEGASYS as soon as you remember. Take your next dose on the day you would usually take it.
    • If more than 2 days have passed, ask your healthcare provider what you should do.
  • Your healthcare provider should show you how to prepare and measure your dose of PEGASYS, and how to inject yourself before you use PEGASYS for the first time.
  • PEGASYS comes as a liquid:
    • in a single use vial
    • in a prefilled syringe

    Your healthcare provider will decide which one is best for you. See the Instructions for Use at the end of this Medication Guide for detailed instructions for preparing and injecting a dose of PEGASYS.

  • Do not re-use PEGASYS single use vials, prefilled syringes, and needles.
  • If you take more than the prescribed amount of PEGASYS, call your healthcare provider right away. Your healthcare provider may want to examine you and do blood tests.
  • During treatment with PEGASYS you will need to see your healthcare provider regularly and have blood tests to make sure that your treatment is working and to check for side effects.
  • It is not known whether PEGASYS, alone or in combination with COPEGUS, will prevent an infected person from spreading the hepatitis B or C virus to another person.

What should I avoid while taking PEGASYS, or PEGASYS with COPEGUS?

  • If you are pregnant do not start taking or continue taking PEGASYS alone or in combination with COPEGUS. (See "What is the most important information I should know about PEGASYS?"). COPEGUS in combination with PEGASYS may cause birth defects or death of your unborn baby.
  • Avoid becoming pregnant while taking PEGASYS, alone or in combination with COPEGUS. PEGASYS, alone or in combination with COPEGUS, may harm your unborn child (death or serious birth defects) or cause you to lose your baby (miscarry). (See "What is the most important information I should know about PEGASYS?").
  • Do not breast-feed your baby while on PEGASYS, alone or in combination with COPEGUS.
  • Drinking alcohol, including beer, wine and liquor. This may make your liver disease worse.
  • Taking other medicines. Take only medicines prescribed or approved by your healthcare provider. These include prescription and nonprescription medicines and herbal supplements.

What are the possible side effects of PEGASYS?

PEGASYS can cause serious side effects including:

  • See "What is the most important information I should know about PEGASYS?"
  • Blood problems. PEGASYS can affect your bone marrow and cause low red blood cell, low white blood cell and platelet counts. In some people, these blood counts may fall to dangerously low levels. If your blood cell counts become very low, you can get anemia, infections or have problems with bleeding and bruising.
  • Thyroid problems. Some people develop changes in the function of their thyroid. Symptoms of thyroid changes include feeling cold or hot all the time, a change in your weight, and changes to your skin, trouble concentrating.
  • Blood sugar problems. Some people may develop high blood sugar or diabetes. If you have high blood sugar or diabetes before starting PEGASYS, talk to your healthcare provider before you take PEGASYS. If you develop high blood sugar or diabetes while taking PEGASYS, your healthcare provider may tell you to stop PEGASYS and prescribe a different medicine for you. Symptoms of high blood sugar or diabetes may include:
    • Increased thirst
    • Tiredness
    • Urinating more often than normal
    • Increased appetite
    • Weight loss
    • Your breath smells like fruit
  • Serious eye problems. PEGASYS may cause eye problems that may lead to vision loss or blindness. You should have an eye exam before your start taking PEGASYS. If you have eye problems or have had them in the past, you may need eye exams while taking PEGASYS. Tell your healthcare provider or eye doctor right away if you have any vision changes while taking PEGASYS.
  • Serious liver problems, worsening of liver problems including liver failure and death. Symptoms may include:
    • nausea
    • loss of appetite
    • tiredness
    • diarrhea
    • yellowing of your skin or the white part of your eyes
    • bleeding more easily than normal
    • swelling of your stomach area (abdomen)
    • confusion
    • sleepiness
    • you cannot be awakened (coma)
  • Lung problems including:
    • trouble breathing
    • pneumonia
    • inflammation of lung tissue
    • new or worse high blood pressure of the lungs (pulmonary hypertension). This can be severe and may lead to death.

You may need to have a chest X-ray or other tests if you develop fever, cough, shortness of breath or other symptoms of a lung problem during treatment with PEGASYS.

  • Inflammation of your pancreas (pancreatitis). Symptoms of inflammation of your pancreas (pancreatitis) may include:
    • severe stomach (abdomen) pain
    • severe back pain
    • nausea
    • vomiting
    • fever
  • Inflammation of your intestines (colitis). Symptoms of inflammation of your intestines (colitis) may include:
    • severe stomach area (abdomen) pain
    • bloody diarrhea or bloody bowel movements
  • Serious allergic reactions and skin reactions. Symptoms may include:
    • itching
    • swelling of your face, eyes, lips, tongue, or throat
    • trouble breathing
    • anxiousness
    • chest pain
    • feeling faint
    • skin rash, hives, sores in your mouth, or your skin blisters and peels
  • Nerve problems. People who take PEGASYS or other alpha interferon products with telbivudine (Tyzeka) for hepatitis B can develop nerve problems such as continuing numbness, tingling, or burning sensation in the arms or legs (peripheral neuropathy). Call your healthcare provider if you have any of these symptoms.

Tell your healthcare provider right away if you have any of the symptoms listed above.

The most common, but less serious side effects of PEGASYS include:

  • flu-like symptoms. Symptoms may include: fever, chills, muscle aches, joint pain, and headaches. Some of these symptoms may be decreased by injecting your PEGASYS dose in the evening. Talk to your healthcare provider about which over-the-counter medicines you can take to help prevent or decrease some of the symptoms.
  • tiredness and weakness: Many people become very tired or feel weak while taking PEGASYS.
  • stomach problems: Nausea and vomiting may happen with PEGASYS.
  • loss of appetite
  • skin reactions: Some people may develop redness, swelling, dry or itchy skin at the site of injection. If after several days these symptoms do not disappear, contact your healthcare provider.
  • hair thinning: Temporary hair loss is not uncommon during treatment with PEGASYS.
  • trouble sleeping

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the side effects of PEGASYS. For more information; ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.

How should I store PEGASYS?

  • Store PEGASYS single use vials and prefilled syringes in a refrigerator, at 36°F to 46°F (2°C to 8°C).
  • Do not freeze or shake PEGASYS.
  • Protect PEGASYS from light.

Keep PEGASYS vials, prefilled syringes, and all medicines out of the reach of children.

General information about PEGASYS

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PEGASYS for a condition for which it was not prescribed. Do not give PEGASYS to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about PEGASYS. If you would like more information about PEGASYS, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information that is written for health professionals.

What are the ingredients in PEGASYS?

Active ingredient: interferon alfa-2a

Inactive ingredients: acetic acid, benzyl alcohol, polysorbate 80, sodium acetate trihydrate, and sodium chloride

Keep PEGASYS and all medicines out of the reach of children.

This Medication Guide has been approved by the US Food and Drug Administration.

MG Revised: February 2011

Medication Guide Appendix: Instructions for Use

Solution for Injection Prefilled Syringe

Be sure that you read, understand and follow these instructions before injecting PEGASYS. Your healthcare provider should show you how to prepare, measure and inject PEGASYS properly before you use it for the first time. Ask your healthcare provider if you have any questions.

PEGASYS prefilled syringes come in a Monthly Convenience Pack that contains 4 prefilled syringes of PEGASYS in a box with 4 needles and 4 alcohol pads. Each needle has a needle-stick protection device.

Before starting, collect all of the supplies that you will need to use for preparing and injecting PEGASYS. You will need the following supplies:

  • 1 single-use disposable prefilled syringe of PEGASYS
  • 1 needle with needle-stick protection device
  • 1 alcohol pad

You will also need a puncture-proof disposable container to throw away used prefilled syringes and needles.

Important:

  • Never re-use disposable prefilled syringes and needles.
  • Throw away the prefilled syringe of PEGASYS after you use it 1 time
  • Do not shake PEGASYS. If shaken, PEGASYS may not work properly.

How should I prepare a dose of PEGASYS?

  1. Find a well lit, clean flat working surface such as a table.
  2. Take a carton containing PEGASYS out of the refrigerator. Check the date on the carton the PEGASYS comes in. Make sure the expiration date has not passed. Do not use if the expiration date has passed (see Figure 1).
    Figure 1:

    Figure

  3. Remove the prefilled syringe of PEGASYS from the carton. Look at the prefilled syringe of PEGASYS. The solution should be clear and colorless to light yellow, without particles (see Figure 2), if there is foam in the solution, put it back in the refrigerator for use at a later time and use another syringe.
    Figure 2:

    Figure

    Do not use the prefilled syringe of PEGASYS if:
    • the medicine remains cloudy after a few minutes at room temperature
    • has particles
    • the medicine is not colorless to light yellow
    • the expiration date has passed (see Figure 3).
    Figure 3:

    Figure

  4. Wash your hands well with soap and warm water. Keep your work area, your hands, and injection site clean to decrease the risk of infection.
  5. Lay the syringe on a flat clean surface and wait a few minutes until it reaches room temperature. If you notice condensation water on the outside of the syringe, wait another few minutes until it disappears.

How do I attach the needle to the PEGASYS prefilled syringe?

6.
Remove the needle from its package. Do not remove the needle shield yet. Keep the needle covered until just before you give the injection (see Figure 4).
Figure 4:

Figure

7.
Remove and throw away the rubber cap from the tip of the syringe barrel (see Figure 5).
Figure 5:

Figure

8.
With one hand, hold the syringe by the barrel. With your other hand, hold the needle close to the hub where the green needle cover connects to the syringe (see Figure 6).
Figure 6:

Figure

9.
Push the needle onto the syringe and tighten by using an easy twisting motion in the direction of the arrow (see Figure 7).
Figure 7:

Figure

 
Here is a picture of what the syringe will look like after you finish attaching the needle (see Figure 8).
Figure 8:

Figure

10.
Lay the syringe and needle down on your clean work surface. Be sure that the plastic needle shield covers the needle. Never let the needle touch any surface.

How should I choose a site for injection?

11.
You can inject PEGASYS under the skin on your stomach or thigh (see Figure 9). Avoid your navel and waistline. You should use a different place each time you give yourself an injection.
Figure 9:

Figure

12.
Clean the area using the alcohol pad. Let the skin air dry.

How do I prepare the PEGASYS prefilled syringe for injection?

13.
Pull the green needle cover back from the needle toward the syringe barrel. The green needle cover will stay in the position you set. Do not remove it. This is the needle-stick protection device (see Figure 10).
Figure 10:

Figure

14.
Hold the syringe and needle tightly at the hub. Gently rock the plastic needle shield back and forth to prepare for removal. Remove the plastic needle shield by pulling it straight off (see Figure 11).
Figure 11:

Figure

15.
Remove air bubbles from the syringe.
  • Hold the syringe with the needle pointing up to the ceiling.
  • Using your thumb and finger, gently tap the syringe to bring air bubbles to the top (see Figure 12).
  • Press the plunger in slightly to push air bubbles out of the syringe.
    Figure 12:

    Figure

16.
Depending on the dose of PEGASYS that your healthcare provider prescribes, you may have to get rid of (discard) some of the medicine from the prefilled syringe before you inject the medicine. The syringe has markings for 180 mcg, 135 mcg, and 90 mcg. Your healthcare provider will tell you which mark to use (see Figure 13 and Figure 14).
Figure 13: Figure 14:

Figure

Figure


Do not decrease or increase your dose of PEGASYS unless your healthcare provider tells you to.

How Do I Give the Injection of PEGASYS

17.
Position the point of the needle (the bevel) so it is facing up (see Figure 15).
Figure 15:

Figure

18.
Pinch a fold of skin on your stomach or thigh firmly with your thumb and forefinger (see Figure 16).
Figure 16:

Figure

19.
Hold the syringe like a pencil at a 45° to 90° angle to your skin. With a quick "dart-like" motion, push the needle into the skin as far as it will go (see Figure 17).
Figure 17:

Figure

20.
After the needle is inserted, remove the hand used to pinch the skin and use it to hold the syringe barrel.
  • Pull the plunger of the syringe back slightly.
  • If blood comes into the syringe, the needle has entered a blood vessel.
    • Do not inject PEGASYS. Withdraw the needle and throw away the syringe and needle in the puncture-proof container. See "How should I dispose of used syringes and needles?"
    • Then, repeat steps 1 through 16 with a new prefilled syringe and prepare a new injection site.
  • If no blood is present in the syringe, inject the medicine by gently pressing the plunger all the way down the syringe barrel, until the syringe is empty.
21.
When the syringe is empty, pull the needle out of the skin. Wipe the area with an alcohol pad.
22.
To prevent needle-stick injuries, before you dispose of the syringe and needle, push the green needle cover toward the needle (see Figure 18). Then place the free end of the green cap on a flat surface and push gently down on it until it clicks and covers over the needle (see Figure 19).
Figure 18: Figure 19:

Figure

Figure

23.
Throw away the used syringe and needle. See "How should I dispose of used syringes and needles?"

How should I dispose of used syringes and needles?

  • Do not re-use needles and syringes
  • Throw away used syringes and needles in a puncture-proof container, sharps container
  • Check with your healthcare provider for instructions about the right way to throw away used needles and syringes. There may be local or state laws about how to throw away used needles and syringes.
  • Do not throw away used needles and syringes or the puncture-proof container in household trash and do not recycle them.
  • Dispose of the full container as instructed by your healthcare provider or pharmacist.

Always keep the puncture-proof container out of the reach of children.

How should I store PEGASYS?

  • Store PEGASYS prefilled syringes in a refrigerator, at 36°F to 46°F (2°C to 8°C).
  • Do not freeze or shake PEGASYS.
  • Protect PEGASYS from light.

MG Appendix: Prefilled Syringe revision date: February 2011

Medication Guide Appendix: Instructions for Use
Solution for Injection Vial

Be sure that you read, understand and follow these instructions before injecting PEGASYS. Your healthcare provider should show you how to prepare, measure, and inject PEGASYS properly before you use it for the first time. Ask your healthcare provider if you have any questions.

Before starting, collect all of the supplies that you will need to use for preparing and injecting PEGASYS. You will need the following supplies:

  • 1 vial of PEGASYS
  • 1 single-use disposable syringe and needle
  • several alcohol pads

You will also need a puncture-proof container to throw away used syringes, needles, and vials.

Important:

  • Never re-use disposable syringes and needles.
  • Throw away the vial of PEGASYS after you use it 1 time even if there is medicine left in the vial.
  • Make sure you have the right syringe and needle to use with PEGASYS. Your healthcare provider should tell you what syringes and needles you should use and where to buy them.
  • Do not shake PEGASYS. If shaken, PEGASYS may not work properly.

How should I prepare a dose of PEGASYS?

1.
Find a well lit, clean flat working surface such as a table.
2.
Take a carton containing PEGASYS out of the refrigerator. Check the date on the carton the PEGASYS comes in. Make sure the expiration date has not passed. Do not use if the expiration date has passed (see Figure 1).
Figure 1:

Figure

3.
Wash your hands well with soap and warm water. Keep your work area, your hands, and injection site clean to decrease the risk of infection.
4.
Remove the vial of PEGASYS from the carton. Look at the vial of PEGASYS. The solution should be clear and colorless, without particles (see Figure 2).
Figure 2:

Figure


Do not use the vial of PEGASYS if
  • the medicine is cloudy
  • has particles
  • the medicine is not colorless to light yellow.
  • the expiration date has passed
5.
Warm the refrigerated medicine by gently rolling it in the palms of your hands for about one minute. Do not shake PEGASYS.
6.
Remove (flip off) the plastic cap from the top of the PEGASYS vial (see Figure 3). Clean the rubber stopper on the top of the vial with an alcohol pad (see Figure 4).
Figure 3: Figure 4:
Figure

Figure

If you are not sure how much medicine to use or which mark on the syringe to use, stop and call your healthcare provider right away.

7.
Open the package for the syringe you are using and if it does not have a needle attached, then attach a new needle to the syringe.
8.
Remove the protective cap from the needle on the syringe. Never let the needle touch any surface. Fill the syringe with air by pulling back on the plunger to the mark on the syringe barrel that matches the dose prescribed by your healthcare provider (see Figure 5).
Figure 5:

Figure

9.
Hold the vial of PEGASYS on your flat working surface. Do not touch the cleaned rubber stopper.
10.
Push the needle straight down through the middle of the rubber stopper on the vial. Slowly inject all the air from the syringe into the air space above the solution. Do not inject air into the fluid (see Figure 6).
Figure 6:

Figure

11.
Keep the needle in the vial. Turn the vial upside down.
  • Make sure the tip of the needle is in the PEGASYS solution.
  • Slowly pull the plunger back to fill the syringe with PEGASYS solution to the dose (mL or cc markings on the syringe) that matches the dose prescribed by your healthcare provider (see Figure 7).
    Figure 7:

    Figure

12.
Do not remove the needle from the vial. Lay the vial and syringe on its side on your flat work surface until you are ready to inject the PEGASYS solution (see Figure 8).
Figure 8:

Figure

How should I choose a site for injection?

13.
You can inject PEGASYS under the skin on your stomach or thigh (see Figure 9). Avoid your navel and waistline. You should use a different place each time you give yourself an injection.
Figure 9:

Figure

14.
Clean the area using an alcohol pad Let the skin air dry.

How should I give an injection?

15.
Pick up the vial and syringe from your flat work surface. Remove the syringe and needle from the vial.
  • Hold the syringe in the hand that you will use to inject PEGASYS.
  • Do not touch the needle or allow it to touch the work surface.
16.
Remove air bubbles from the syringe.
  • Hold the syringe with the needle pointing up to the ceiling.
  • Using your thumb and finger, tap the syringe to bring air bubbles to the top (see Figure 10).
  • Press the plunger in slightly to push air bubbles out of the syringe.
    Figure 10:

    Figure

17.
Position the point of the needle (the bevel) so it is facing up (see Figure 11).
Figure 11:

Figure

18.
Pinch a fold of skin on your stomach or thigh firmly between your thumb and forefinger (see Figure 12).
Figure 12:

Figure

19.
Hold the syringe like a pencil at a 45° to 90° angle to your skin. With a quick "dart-like" motion, push the needle into the skin as far as it will go (see Figure 13).
Figure 13:

Figure

20.
After the needle is inserted, remove the hand used to pinch the skin and use it to hold the syringe barrel.
  • Pull the plunger of the syringe back slightly.
  • If blood comes into the syringe, the needle has entered a blood vessel.
    • Do not inject PEGASYS. Withdraw the needle and throw away the syringe, needle, and vial in the puncture-proof container. See "How should I dispose of used syringes, needles, and vials?"
    • Then, repeat steps 1 through 19 with a new vial of PEGASYS and inject the medicine at a new injection site.
  • If no blood is present in the syringe, inject the medicine by gently pressing the plunger all the way down the syringe barrel, until the syringe is empty.
21.
When the syringe is empty, pull the needle out of the skin. Wipe the area with an alcohol pad.
22.
Throw away the used syringe, needle, and vial. See "How should I dispose of used syringes, needles, and vials?"

How should I dispose of used syringes, needles, and vials?

  • Do not re-use needles, syringes, or vials.
  • Throw away used syringes, needles, and vials in a puncture-proof container, sharps container.
  • Check with your healthcare provider for instructions about the right way to throw away used needles and syringes. There may be local or state laws about how to throw away used needles and syringes.
  • Do not throw away used needles, syringes, vials, or the puncture-proof container in household trash and do not recycle them.
  • Dispose of the full container as instructed by your healthcare provider or pharmacist.
  • Always keep the puncture-proof container out of the reach of children.

How should I store PEGASYS?

  • Store PEGASYS single use vials in a refrigerator, at 36°F to 46°F (2°C to 8°C).
  • Do not freeze or shake PEGASYS.
  • Protect PEGASYS from light.

MG Appendix: Vial revision date: February 2011

COPEGUS and PEGASYS are trademarks of Hoffmann-La Roche Inc.

PI Revised: February 2011

Manufactured by:

Hoffmann-La Roche Inc.

340 Kingsland Street

Nutley, NJ 07110-1199

(US Govt. Lic. No. 0136)

Distributed by:

Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

PSVS_258310_PI_2011_13_K

© 2011 Genentech, Inc. All rights reserved.

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 180 µg/1 mL Vial Carton

NDC 0004-0350-09

Pegasys®
(peginterferon alfa-2a)

180 µg/1 mL

For Subcutaneous Use
For Single Use
Sterile

ATTENTION PHARMACIST: Each
patient is required to receive the
enclosed Medication Guide.

Refrigerate Immediately

Vial contains: 180 µg/1 mL

Rx only

Genentech

PRINCIPAL DISPLAY PANEL - 180 µg/1 mL Vial Carton

PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Carton

NDC 0004-0352-30

Pegasys®
(peginterferon alfa-2a)

NOT FOR INDIVIDUAL SALE
ATTENTION PHARMACISTS: Each patient is required
to receive the enclosed Medication Guide.
Refrigerate Immediately

Rx only

180 µg/0.5 mL

For Subcutaneous Injection Only

Sterile

Each Carton Contains:
4 Single-Use Prefilled Syringes

Each Prefilled Syringe Contains:
180 µg/0.5 mL

Genentech

PRINCIPAL DISPLAY PANEL - 0.5 mL Syringe Carton

PRINCIPAL DISPLAY PANEL - 0.5 mL 4 Syringe Monthly Convenience Pack

NDC 0004-0352-39

Pegasys®
(peginterferon alfa-2a)

180 µg/0.5 mL

For Subcutaneous Injection Only

Sterile

Prefilled Syringes Monthly Convenience Pack Package Contains:
4 Single-Use Prefilled Syringes Pegasys® 180 µg/0.5 mL, NDC 0004-0352-30
4 Needles (27-gauge, 1/2-inch)
4 Alcohol Swabs

Each Prefilled Syringe Contains:
180 µg/0.5 mL

ATTENTION PHARMACIST: Each patient is required
to receive the enclosed Medication Guide.

Refrigerate Immediately

Rx only

Genentech

PRINCIPAL DISPLAY PANEL - 0.5 mL 4 Syringe Monthly Convenience Pack

PEGASYS 
peginterferon alfa-2a injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0004-0350
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
peginterferon alfa-2a (peginterferon alfa-2a) peginterferon alfa-2a 180 ug  in 1 mL
Inactive Ingredients
Ingredient Name Strength
polysorbate 80  
benzyl alcohol  
acetic acid  
sodium acetate  
talc  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0004-0350-09 1 VIAL, SINGLE-USE ( VIAL) in 1 BOX contains a VIAL, SINGLE-USE
1 1 mL in 1 VIAL, SINGLE-USE This package is contained within the BOX (0004-0350-09)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103964 10/16/2002

PEGASYS 
peginterferon alfa-2a injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0004-0352
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
peginterferon alfa-2a (peginterferon alfa-2a) peginterferon alfa-2a 180 ug  in 0.5 mL
Inactive Ingredients
Ingredient Name Strength
polysorbate 80  
benzyl alcohol  
acetic acid  
sodium acetate  
talc  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0004-0352-39 1 PACKET ( PACKET) in 1 BOX contains a PACKET (0004-0352-30)
1 NDC:0004-0352-30 4 SYRINGE, GLASS ( SYRINGE) in 1 PACKET This package is contained within the BOX (0004-0352-39) and contains a SYRINGE, GLASS
1 0.5 mL in 1 SYRINGE, GLASS This package is contained within a PACKET (0004-0352-30) and a BOX (0004-0352-39)
2 NDC:0004-0352-98 1 PACKET ( PACKET) in 1 BOX contains a PACKET (0004-0352-30)
2 NDC:0004-0352-30 4 SYRINGE, GLASS ( SYRINGE) in 1 PACKET This package is contained within the BOX (0004-0352-98) and contains a SYRINGE, GLASS
2 0.5 mL in 1 SYRINGE, GLASS This package is contained within a PACKET (0004-0352-30) and a BOX (0004-0352-98)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103964 10/16/2002

Labeler - Genentech, Inc. (080129000)
Establishment
Name Address ID/FEI Operations
F. Hoffmann-La Roche Ltd 482242971 MANUFACTURE
Establishment
Name Address ID/FEI Operations
Roche Diagnostics GmbH 323105205 API MANUFACTURE
Establishment
Name Address ID/FEI Operations
F. Hoffmann-La Roche Ltd 485244961 PACK, LABEL

Revised: 02/2011 Genentech, Inc.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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