COPEGUS® (ribavirin) tablets
COPEGUS, ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-Dribofuranosyl-1H-1,2,4-triazole-3-carboxamide. The empirical formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin is a white to offwhite powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.
Indications and usage
COPEGUS is a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with PEGASYS in patients 5 years of age and older with compensated liver disease not previously treated with interferon alpha, and in adult CHC patients coinfected with HIV.
Mechanism of Action
The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction.
Antiviral Activity in Cell Culture
In the stable HCV cell culture model system (HCV replicon), ribavirin inhibited autonomous HCV RNA replication with a 50% effective concentration (EC50) value of 11-21 mcM. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC50 value of 0.1-3 ng/mL. The combination of PEG-IFN α-2a and ribavirin was more effective at inhibiting HCV RNA replication than either agent alone.
Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified.
Dosage and and administration
COPEGUS should be taken with food. COPEGUS should be given in combination with PEGASYS; it is important to note that COPEGUS should never be given as monotherapy. See PEGASYS Package Insert for all instructions regarding PEGASYS dosing and administration.
Chronic Hepatitis C Monoinfection
Adult Patients: The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks. The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen
|Hepatitis C Virus (HCV) Genotype||PEGASYS Dose* (once weekly)||COPEGUS Dose (daily)||Duration|
|Genotypes 1, 4||180 mcg||<75 kg = 1000 mg ≥75 kg = 1200 mg||48 weeks 48 weeks|
|Genotypes 2, 3||180 mcg||800 mg||24 weeks|
*See PEGASYS Package Insert for further details on PEGASYS dosing and administration, including dose modification in patients with renal impairment.
Pediatric Patients: PEGASYS is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.
COPEGUS should be given in combination with PEGASYS. COPEGUS is available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient.
|Body Weight in kilograms (kg)||COPEGUS Daily Dose*||COPEGUS Number of Tablets|
|23 – 33||400 mg/day||1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.|
|34 – 46||600 mg/day||1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.|
|47 – 59||800 mg/day||2 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.|
|60 – 74||1000 mg/day||2 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.|
|≥75||1200 mg/day||3 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.|
*approximately 15 mg/kg/day
Chronic Hepatitis C with HIV Coinfection
Adult Patients: The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS 180 mcg subcutaneous once weekly and COPEGUS 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.
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
COPEGUS (ribavirin) is contraindicated in:
- Women who are pregnant. COPEGUS may cause fetal harm when administered to a pregnant woman. COPEGUS is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Men whose female partners are pregnant.
- Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
- In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials
COPEGUS and PEGASYS combination therapy is contraindicated in patients with:
- Autoimmune hepatitis.
- Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment.
- Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment
Warnings and precautions
Significant adverse reactions associated with COPEGUS/PEGASYS combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.
The PEGASYS Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.
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.
Anemia: 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)
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.
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
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.
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
Pancreatitis: COPEGUS and PEGASYS therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.
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.
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)
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.
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.
Didanosine: Co-administration of COPEGUS and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities.
Zidovudine: In Study NR15961, patients who were administered zidovudine in combination with PEGASYS/COPEGUS developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.
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
Use in specific populations
Pregnancy: Category X
Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced.
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.
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.
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.
No cases of overdose with COPEGUS have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.