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 supplied as an injectable solution in vials and prefilled syringes.

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

180 µg/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 µg of drug product (expressed as the amount of interferon alfa-2a), 4.0 mg sodium chloride, 0.025 mg polysorbate 80, 5.0 mg benzyl alcohol, 1.3085 mg sodium acetate trihydrate, and 0.0231 mg acetic acid. The solution is colorless to light yellow and the pH is 6.0 ± 0.5.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation and immunomodulation. The clinical relevance of these in vitro activities is not known.

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

Pharmacokinetics

Maximal serum concentrations (Cmax) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 µg 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 sc dosing in patients 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 µg 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 × 180 µg/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 µg 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 µg fixed dosing. The safety and effectiveness of PEGASYS in patients below the age of 18 years have not been established (see PRECAUTIONS: Pediatric Use).

Renal Dysfunction

In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance (see PRECAUTIONS: Renal Impairment).

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 WARNINGS and DOSAGE AND ADMINISTRATION).

Effect of Food on Absorption of Ribavirin

Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when COPEGUS was taken with a high-fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION).

Drug Interactions

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 patients (see PRECAUTIONS: Drug Interactions).

In vitro, didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin (see PRECAUTIONS: Drug Interactions).

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 (see PRECAUTIONS: Drug Interactions).

Methadone

The pharmacokinetics of concomitant administration of methadone and PEGASYS were eva luated in 24 PEGASYS naive chronic hepatitis C (CHC) patients (15 male, 9 female) who received 180 µg PEGASYS subcutaneously weekly. All patients 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 (see PRECAUTIONS: Drug Interactions). Methadone did not significantly alter the PK of PEGASYS as compared to a PK study of 6 chronic hepatitis C patients not receiving methadone.

CLINICAL STUDIES

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 patients were adults, had compensated liver disease, detectable hepatitis C virus (HCV), liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. All patients received therapy by sc 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 patients with a histological diagnosis of cirrhosis (78%) or bridging fibrosis (22%).

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

In all three studies, treatment with PEGASYS 180 µg resulted in significantly more patients 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 µg was not different from response to 180 µg. In Study 3