1.1 Chronic Hepatitis C (CHC)

1.2 Chronic Hepatitis B (CHB)

2.1 Dosage Overview

Administer PEGASYS by subcutaneous injection once weekly in the abdomen or thigh for the treatment of:

• Adult patients with CHC without or with HIV coinfection [see Dosage and Administration (2.2)];
• Pediatric patients with CHC [see Dosage and Administration (2.3)] ;
• Adult patients with CHB [see Dosage and Administration (2.4)] ; and
• Pediatric patients with CHB [see Dosage and Administration (2.5)].

For treatment of CHC, use PEGASYS in combination with other HCV antiviral drugs. For information about the recommended dosage and administration and the safe and effective use of these other HCV antiviral drugs, refer to their prescribing information. PEGASYS monotherapy is only indicated in the treatment of CHC if there are contraindications to or significant intolerance to other HCV antiviral drugs.

For dosage modifications in patients with CHC or CHB:

• Due to neutropenia, thrombocytopenia, ALT elevation, and depression [see Dosage and Administration (2.6)] .
• In patients with severe renal impairment (creatinine clearance less than 30 mL/minute) and in patients with creatinine clearance between 30 and 50 mL/minute [see Dosage and Administration (2.6)] .

For important administration instructions for all the PEGASYS injection presentations (i.e., vial and prefilled syringe) [see Dosage and Administration (2.7)].

2.2 Recommended Dosage for Adults with CHC

2.3 Recommended Dosage for Pediatric Patients with CHC

PEGASYS is administered as 180 mcg/1.73 m 2 × BSA subcutaneously once weekly, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for pediatric patients with HCV genotype 2 or 3 is 24 weeks and for other HCV genotypes is 48 weeks. Patients who initiate treatment prior to their 18 th birthday should maintain the recommended pediatric dosage (not the adult dosage) through the completion of therapy. Refer to the prescribing information of ribavirin for the recommended dosage and duration.

2.4 Recommended Dosage for Adults with CHB

The recommended PEGASYS dosage in adults with CHB is 180 mcg subcutaneously once weekly in the thigh or abdomen for 48 weeks.

2.5 Recommended Dosage for Pediatrics Patients with CHB

The recommended PEGASYS dosage in pediatric patients for HBeAg-positive CHB is 180 mcg/1.73 m 2 × BSA subcutaneously once weekly to a maximum dose of 180 mcg. The recommended duration of therapy is 48 weeks.

Maintain the recommended pediatric dosage through the entire duration of therapy in patients who turn 18 years of age during therapy.

2.6 Dosage Modifications

2.7 Preparation and Administration

5.1 Pregnancy: Use with Ribavirin

Ribavirin may cause birth defects and/or death of the exposed fetus. Patients must avoid pregnancy (female patients or female partners of male patients) while taking PEGASYS and ribavirin combination therapy. Ribavirin therapy should not be started unless a confirmed 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 Contraindications (4), Patient Counseling Information (17) and ribavirin labeling] .

5.2 Neuropsychiatric Reactions

Life-threatening or fatal neuropsychiatric reactions may manifest in all 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 all 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 Boxed Warning, Adverse Reactions (6.1) and Dosage and Administration (2.6)] .

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/ribavirin [see ribavirin prescribing information].

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 ribavirin prescribing information].

PEGASYS/ribavirin should be used with caution in patients with baseline neutrophil counts less than 1,500 cells/mm 3, with baseline platelet counts less than 90,000 cells/mm 3 or baseline hemoglobin less than 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, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.

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 [see Boxed Warning] .

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 [see Boxed Warning] .

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 7 [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/ribavirin 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 greater than 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 (2.6)] .

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 [see Boxed Warning] .

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/ribavirin should be suspended if symptoms or signs suggestive of pancreatitis are observed. PEGASYS/ribavirin 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/ribavirin 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 Impact on Growth in Pediatric Patients

Growth inhibition was observed in CHC pediatric subjects 5 to 17 years of age during combination therapy for up to 48 weeks with PEGASYS plus ribavirin. At the end of treatment, 43% of subjects were more than 15 percentiles below their baseline weight curve, and 25% of subjects were more than 15 percentiles below their baseline height curve. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height; 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.

The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Trials Experience (6.1)] .

Growth inhibition was also observed in CHB pediatric subjects 3 to 17 years of age during therapy with PEGASYS lasting up to 48 weeks. At Week 48 of treatment 11% of subjects were more than 15 percentiles below their baseline weight curve and 6% were more than 15 percentiles below their baseline height curve. At 24 weeks after the end of treatment, 12% of subjects were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentiles below their baseline height curve. No data are available on longer term follow-up post-treatment in these patients [see Clinical Trials Experience (6.1)].

5.16 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 CHB have not been demonstrated.

5.17 Laboratory Tests

Before beginning PEGASYS or PEGASYS 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/ribavirin.

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 adult 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. In a pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. 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 greater than or equal to 90,000 cells/mm 3 (as low as 75,000 cells/mm 3 in HCV subjects with cirrhosis or 70,000 cells/mm 3 in subjects with CHC and HIV)
• Absolute neutrophil count (ANC) greater than or equal to 1,500 cells/mm 3
• Serum creatinine concentration less than 1.5 × upper limit of normal
• TSH and T 4 within normal limits or adequately controlled thyroid function
• CD4+ cell count greater than or equal to 200 cells/mm 3 or CD4+ cell count greater than or equal to 100 cells/mm 3 but less than 200 cells/mm 3 and HIV-1 RNA less than 5,000 copies/mL in subjects coinfected with HIV
• Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected subjects
• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in subjects with CHC and HIV

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.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to peginterferon alfa-2a in the studies described below with the incidence of antibodies in other studies or 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

Gastrointestinal disorders: tongue pigmentation

Immune system disorders: liver graft rejection and renal graft rejection [see Use in Specific Populations (8.8)]

Infections and infestations: limb abscess

Metabolism and nutrition disorders: dehydration

Skin and subcutaneous tissue disorders: serious skin reactions

Neurological: seizures

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 naïve 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

8.1 Pregnancy

8.2 Lactation

There is no information regarding the presence of peginterferon alfa-2a in human milk, the effects on the breastfed infant, or the effects on milk production. 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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PEGASYS and any potential adverse effects on the breastfed child from PEGASYS or from the underlying maternal condition.

The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential transmission of HIV; therefore, CHC- and CHB-infected mothers coinfected with HIV should not breastfeed their infants.

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

PEGASYS is indicated for the treatment of CHC in pediatric patients 5 to 17 years of age and for the treatment of CHB in pediatric patients 3 to 17 years of age [see Indications and Usage (1.1), (1.2), Dosage and Administration (2.3), (2.5), Clinical Studies (14.1), (14.4)].

The use of PEGASYS for the treatment of pediatric patients 5 to 17 years of age with CHC is based on one clinical trial in 114 previously untreated CHC subjects 5 to 17 years of age with compensated liver disease and detectable HCV RNA [see Clinical Trials Experience (6.1), Clinical Studies (14.1)] . The safety and efficacy of PEGASYS in pediatric patients with CHC below the age of 5 years have not been established.

The use of PEGASYS for the treatment of pediatric patients 3 to 17 years of age with CHB is based on one clinical trial in 161 previously untreated CHB subjects 3 to 17 years of age of whom 111 were assigned to treatment with PEGASYS [see Clinical Trials Experience (6.1), Clinical Studies (14.4)] . PEGASYS has not been studied in pediatric CHB patients with liver cirrhosis and the safety and efficacy of PEGASYS in pediatric patients with CHB below the age of 3 years have not been established.

PEGASYS contains benzyl alcohol. In neonates and infants, benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications which are sometimes fatal in neonates and infants [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 is 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 less than or equal to 50 mL/min. The dose of PEGASYS should be reduced for patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.6) and Use in Specific Populations (8.7)] .

8.6 Hepatic Impairment

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 greater than or equal to 6) is observed [see Contraindications (4)] . Chronic hepatitis B subjects experienced transient acute exacerbations (flares) of hepatitis B (ALT elevation greater than 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

Renal function should be evaluated in all patients prior to initiation of PEGASYS by estimating the patient's creatinine clearance.

A clinical trial evaluated treatment with PEGASYS and COPEGUS in 50 CHC subjects with moderate (creatinine clearance 30 – 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). In 18 subjects with ESRD receiving chronic HD, PEGASYS was administered at a dose of 135 mcg once weekly. Dose reductions and temporary interruptions of PEGASYS (due to PEGASYS-related adverse reactions, mainly anemia) were observed in up to 22% ESRD/HD subjects during treatment; and 17% of these subjects discontinued PEGASYS due to PEGASYS-related adverse reactions. Only one-third of ESRD/HD subjects received PEGASYS for 48 weeks. Subjects with severe (n=14) or moderate (n=17) renal impairment received PEGASYS 180 mcg once weekly. PEGASYS discontinuation rates were 36% and 0% in subjects with severe and moderate renal impairment, respectively, compared to 0% discontinuation rate in subjects with normal renal function.

Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS. In addition, patients with any degree of renal impairment should be carefully monitored for laboratory abnormalities (especially decreased hemoglobin) and adverse reactions, and should undergo careful monitoring of creatinine clearance. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)] . Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for information on use in patients with renal impairment.

8.8 Organ Transplant Recipients

The safety and efficacy of PEGASYS 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.

8.9 Chronic Hepatitis B

The safety and efficacy of PEGASYS 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 less than 100 cells/mm 3

12.1 Mechanism of Action

Pegylated recombinant human interferon alfa-2a is an inducer of the innate antiviral immune response [see Microbiology (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 (C max) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mcg of PEGASYS. Maximal serum concentrations (C max) 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.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Chronic Hepatitis C Studies 1, 2, and 3: PEGASYS/COPEGUS Combination Therapy

14.2 Chronic Hepatitis C and Coinfection with HIV (CHC/HIV) Study 4: PEGASYS Monotherapy and PEGASYS/COPEGUS Combination Therapy

In Study 4, 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 greater than or equal to 200 cells/mm 3 or CD4+ cell count greater than or equal to 100 cells/mm 3 but less than 200 cells/mm 3 and HIV-1 RNA less than 5,000 cells/mm 3, and stable status of HIV. Approximately 15% of subjects in the study had cirrhosis. Results are shown in Table 13.

Treatment response rates are lower in CHC/HIV subjects with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 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 2 log 10 reduction from baseline in HCV RNA titer by 12 weeks of PEGASYS and ribavirin 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 ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

14.3 Chronic Hepatitis C Studies 5, 6, and 7: 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 5 and 6, approximately 20% of subjects had cirrhosis or bridging fibrosis. Study 7 enrolled subjects with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

In Study 5 (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 6 (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 7 (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 [less than 50 IU/mL] using the COBAS AMPLICOR ® HCV Test, version 2 and normalization of ALT on or after study week 68) compared to treatment with ROFERON-A.

In Study 5, response to PEGASYS 135 mcg was not different from response to 180 mcg. In Study 7, response to PEGASYS 90 mcg was intermediate between PEGASYS 180 mcg and ROFERON-A.

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 2 log 10 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 5, Study 6, and Study 7, response rates to PEGASYS were 23% among subjects with viral genotype 1 and 48% among subjects with other viral genotypes. The treatment response rates were similar in men and women.

14.4 Chronic Hepatitis B Studies 8, 9 and 10: PEGASYS Monotherapy

Storage and Handling

Store in the refrigerator at 2°C to 8°C (36°F to 46°F). Do not leave PEGASYS out of the refrigerator for more than 24 hours. Do not freeze or shake. Protect from light. Vials and prefilled syringes are for single use only. Discard any unused portion remaining in the vial, prefilled syringe.

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] .

Pregnancy

Patients must be informed that ribavirin must not be used by women who are pregnant or by men whose female partners are pregnant. Ribavirin 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 ribavirin 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), Warnings and Precautions (5.1), Use in Specific Populations (8.1), and ribavirin prescribing information] .

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

Flu-like symptoms

Inform patients that flu-like symptoms are very common in patients taking PEGASYS. Symptoms may include tiredness, weakness, fever, chills, muscle aches, joint pain, and headaches. Inform patients that some of these symptoms may be decreased by injecting PEGASYS in the evening. Also inform patients which over-the-counter medicines can be taken to help prevent or decrease some of the symptoms.

Laboratory Evaluations and Hydration

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter [see Warnings and Precautions (5.17)] . Patients should be instructed to remain well hydrated, especially during the initial stages of treatment.

General Information

Patients should be questioned about prior history of drug abuse before initiating 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 will prevent transmission of HBV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HBV infection.

Patients should be informed that the effect of treatment of hepatitis C infection on transmission is not known, and that appropriate precautions to prevent transmission of the hepatitis C virus during treatment or in the event of treatment failure should be taken.

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 should also be advised to consult their healthcare provider if the full dose is not received (e.g., leakage around the injection site).

Patients must be instructed on the use of aseptic techniques when administering PEGASYS. Appropriate training for preparation using the vial and prefilled syringe must be given by a healthcare provider, including a careful review of the PEGASYS Medication Guide and Instructions for Use for the vial and prefilled syringe.

Patients should be instructed to allow the vial and prefilled syringe to come to room temperature and for condensation on the outside of the prefilled syringe to disappear before use. The following instructions should be given:

• Vial: warm the refrigerated medicine by gently rolling in the palms of the hands for about one minute.
• Pre-filled syringe: lay the syringe on a flat clean surface and wait a few minutes until it reaches room temperature. If condensation water is observed on the outside of the syringe, wait another few minutes until it disappears.

Patients should be advised not to shake the vial and 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.