Peginterferon alfa-2a

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. Reduce or discontinue the dose of PEGASYS or ribavirin or both should the events worsen ( 7.4 ) Zidovudine: monitor for worsening neutropenia and/or anemia with PEGASYS and/or ribavirin ( 7.4 )

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 NRTIs In Study 7 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/ribavirin in combination with other HCV antiviral drugs and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for other HCV antiviral drugs and the respective NRTIs for guidance regarding toxicity management.

In addition, dose reduction or discontinuation of PEGASYS, ribavirin or both, should also be considered if worsening toxicities are observed [see Warnings and Precautions (5.3 , 5.9) and Dosage and Administration (2.6) ] . Zidovudine In Study 7, subjects who were administered zidovudine in combination with PEGASYS/ribavirin developed severe neutropenia (ANC less than 500 cells/mm 3 ) and severe anemia (hemoglobin less than 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, ribavirin or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Refer to the prescribing information for specific HCV antiviral drugs used in combination with PEGASYS for information on drug interaction potential.

8.1 Pregnancy Pregnancy Exposure Registry – Use with ribavirin 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 pregnancy or who become pregnant within 6 months following cessation of treatment with ribavirin. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214. Risk Summary There are no adequate and well-controlled studies of PEGASYS in pregnant women to inform a drug-associated risk. Based on animal reproduction studies, PEGASYS can cause fetal harm and should be assumed to have abortifacient potential.

Non-pegylated interferon alfa-2a treatment caused abortion when given to pregnant rhesus monkeys (see Data ). The background risk of major birth defects and miscarriage in the indicated population is 3% and 4-22%, respectively. In the U.S. general population, the estimated background risk for major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively. PEGASYS combination treatment with ribavirin 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 ribavirin labeling] .

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin [see ribavirin labeling]. Data Animal Data – Groups of 8 or 9 pregnant rhesus monkeys were given non-pegylated interferon alfa-2a by daily intramuscular injection over days 22 to 70 of gestation at doses of 1, 5 and 25 million IU/day. Two, 3 and 6 monkeys aborted in the low, mid and high dose groups compared with 1 in the control group. Maternal toxicity, characterized by transient body weight loss, was seen at all dose levels. There were too few remaining pregnancies to assess teratogenic potential but no developmental abnormalities were observed in surviving fetuses.