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 (T_max was doubled) and the AUC_0-192h and C_max increased by 42% and 66%, respectively, when COPEGUS was taken with a high- fat meal compared with fasting conditions (see DOSAGE AND ADMINISTRATION).

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 evaluated in 24 PEGASYS naïve chronic hepatitis C (CHC) patients (15 male, 9 female) who received 180 mg 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.

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 mg once each week (qw) or PEGASYS 180 mg 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 γ¯µg qw. In Study 3 (n=269), patients received ROFERON-A 3 MIU tiw, PEGASYS 90 mg qw or PEGASYS 180 mg once each week.

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