2.1 Chronic Hepatitis C Monoinfection

2.2 Chronic Hepatitis C with HIV Coinfection

2.3 Dose Modifications

2.4 Renal Impairment

The total daily dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of PEGASYS should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS Package Insert].

The dose of COPEGUS should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, COPEGUS should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting COPEGUS, COPEGUS/PEGASYS therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

2.5 Discontinuation of Dosing

Discontinuation of PEGASYS/COPEGUS therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

PEGASYS/COPEGUS therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].

5.1 Pregnancy

COPEGUS may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin.

COPEGUS therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during COPEGUS therapy and for 6 months after therapy has stopped [see Boxed Warning, Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17)].

5.2 Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all COPEGUS/PEGASYS-treated subjects in clinical trials. Anemia associated with COPEGUS occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see Dosage and Administration (2.3)].

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 ribavirin 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 (2.3)]. 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 Boxed Warning and Dosage and Administration (2.3)].

5.3 Hepatic Failure

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 NR15961 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients' clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with PEGASYS/COPEGUS should be discontinued immediately in patients with hepatic decompensation [see Contraindications (4)].

5.4 Hypersensitivity

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with PEGASYS and COPEGUS should be discontinued immediately and appropriate medical therapy 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)].

5.5 Pulmonary Disorders

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination COPEGUS/PEGASYS treatment should be discontinued.

5.6 Bone Marrow Suppression

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 (7.3)].

5.7 Pancreatitis

COPEGUS and PEGASYS therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

5.8 Impact on Growth in Pediatric Patients

During combination therapy for up to 48 weeks with PEGASYS plus ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric 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 Studies Experience (6.1)].

5.9 Laboratory Tests

Before beginning 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 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 the 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 COPEGUS and 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/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
• Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm3
• TSH and T4 within normal limits or adequately controlled thyroid function
• CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5,000 copies/mL in patients 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 patients
• Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of PEGASYS/COPEGUS combination 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

Eye disorders

Serous retinal detachment

Immune disorders

Liver and renal graft rejection

Metabolism and Nutrition disorders

Dehydration

Skin and Subcutaneous Tissue disorders

Stevens-Johnson Syndrome (SJS)

Toxic epidermal necrolysis (TEN)

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

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.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.3)].

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, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions (5.3) and Dosage and Administration (2.3)].

7.2 Drugs Metabolized by Cytochrome P450

In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 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 (5.6)].

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with COPEGUS, based on the importance of the therapy to the mother.

8.4 Pediatric Use

Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and effectiveness of COPEGUS have not been established in patients below the age of 5 years.

8.5 Geriatric Use

Clinical studies of COPEGUS and PEGASYS did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. The dose of COPEGUS should be reduced in patients with creatinine clearance less than or equal to 50 mL/min; and the dose of PEGASYS should be reduced in patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.4); Use in Specific Populations (8.7)].

8.6 Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

8.7 Renal Impairment

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

A clinical trial evaluated treatment with COPEGUS and PEGASYS 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, COPEGUS was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of COPEGUS (due to COPEGUS-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received COPEGUS for 48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg COPEGUS daily dose.

Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or 400 mg daily doses of COPEGUS, respectively, due to COPEGUS-related adverse reactions, mainly anemia, and exhibited 20% to 30% higher ribavirin plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of COPEGUS. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation indicate that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma ribavirin exposure similar to patients with normal renal function receiving the approved regimen of COPEGUS. These doses have not been studied in patients [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

Based on the pharmacokinetic and safety results from this trial, patients with creatinine clearance less than or equal to 50 mL/min should receive a reduced dose of COPEGUS; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving COPEGUS should be carefully monitored. Patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening should have therapy withdrawn [see Dosage and Administration (2.4), Clinical Pharmacology (12.3), and PEGASYS Package Insert].

8.8 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of COPEGUS has not been evaluated. The clinical trials of COPEGUS were restricted to patients with Child-Pugh class A disease.

8.9 Gender

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.

Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

8.10 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 (6.2)].

12.1 Mechanism of Action

Ribavirin is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC0-12hr was 25,361±7110 ng∙hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight greater than 75 kg).

The terminal half-life of ribavirin following administration of a single oral dose of COPEGUS is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of COPEGUS is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.

12.4 Microbiology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology

In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin).

Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

14.1 Chronic Hepatitis C Patients

14.2 Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of patients 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 patients 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/HIV Coinfected Patients

In Study NR15961, patients 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 interferon alfa-2a, 3 MIU subcutaneous three times a week plus COPEGUS 800 mg by mouth daily. All patients 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 patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count greater than or equal to 200 cells/mm3 or CD4+ cell count greater than or equal to 100 cells/mm3 but less than 200 cells/mm3 and HIV-1 RNA less than 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 12.

Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.

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

In CHC patients 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.

Storage and Handling

Store the COPEGUS® Tablets bottle at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

Pregnancy

Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. COPEGUS therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking COPEGUS therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking COPEGUS therapy and for 6 months post therapy. COPEGUS therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months post 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)].

Anemia

The most common adverse event associated with ribavirin is anemia, which may be severe [see Boxed Warning, Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. Patients should be advised that laboratory evaluations are required prior to starting COPEGUS therapy and periodically thereafter [see Warnings and Precautions (5.9)]. It is advised that patients be well hydrated, especially during the initial stages of treatment.

Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

Patients should be advised to take COPEGUS with food.

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 advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection.

Patients should be informed about what to do in the event they miss a dose of COPEGUS. The missed doses should be taken as soon as possible during the same day. Patients should not double the next dose. Patients should be advised to call their healthcare provider if they have questions.

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

Patients should be informed regarding the potential benefits and risks attendant to the use of COPEGUS. Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.

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