Drug: Copegus

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 and has the following structural formula: The empirical formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. COPEGUS (ribavirin) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin and the following inactive ingredients: pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, cornstarch, and magnesium stearate. The coating of the tablet contains Chromatone-P® or Opadry® Pink (made by using hydroxypropyl methyl cellulose, talc, titanium dioxide, synthetic yellow iron oxide, and synthetic red iron oxide), ethyl cellulose (ECD-30), and triacetin.

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PEGASYS in combination with COPEGUS causes a broad variety of serious adverse reactions [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. The most common serious or life-threatening adverse reactions induced or aggravated by COPEGUS/PEGASYS include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see WARNINGS AND PRECAUTIONS]. 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. Adult Patients In the pivotal registration trials NV15801 and NV15942, 886 patients received COPEGUS for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with COPEGUS. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination. The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 5 shows rates of adverse events occurring in greater than or equal to 5% subjects receiving pegylated interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801. Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS in combination with COPEGUS discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia). Overall 39% of patients with CHC or CHC/HIV required modification of PEGASYS and/or COPEGUS therapy. The most common reason for dose modification of PEGASYS in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of COPEGUS in CHC and CHC/HIV patients was anemia (22% and 16%, respectively). PEGASYS dose was reduced in 12% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 7% of patients receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of patients receiving 800 mg COPEGUS for 24 weeks. Chronic hepatitis C monoinfected patients treated for 24 weeks with PEGASYS and 800 mg COPEGUS were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10 g/dL (3% vs. 15%), dose modification of PEGASYS (30% vs. 36%) and COPEGUS (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with PEGASYS and 1000 mg or 1200 mg COPEGUS. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups. Table 5 : Adverse Reactions Occurring in greater than or equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801)
Body System CHC Combination Therapy
Study NV15801 PEGASYS 180 mcg + 1000 mg or 1200 mg COPEGUS
48 weeks
N=451
% Intron A + 1000 mg or 1200 mg Rebetol®
48 weeks
N=443
% Application Site Disorders   Injection site reaction 23 16 Endocrine Disorders   Hypothyroidism 4 5 Flu-like Symptoms and Signs   Fatigue/Asthenia 65 68   Pyrexia 41 55   Rigors 25 37   Pain 10 9 Gastrointestinal   Nausea/Vomiting 25 29   Diarrhea 11 10   Abdominal pain 8 9   Dry mouth 4 7   Dyspepsia 6 5 Hematologic*   Lymphopenia 14 12   Anemia 11 11   Neutropenia 27 8   Thrombocytopenia 5 < 1 Metabolic and Nutritional   Anorexia 24 26   Weight decrease 10 10 Musculoskeletal, Connective Tissue and Bone   Myalgia 40 49   Arthralgia 22 23   Back pain 5 5 Neurological   Headache 43 49   Dizziness (excluding vertigo) 14 14   Memory impairment 6 5 Psychiatric   Irritability/Anxiety/Nervousness 33 38   Insomnia 30 37   Depression 20 28   Concentration impairment 10 13   Mood alteration 5 6 Resistance Mechanism Disorders   Overall 12 10 Respiratory, Thoracic and Mediastinal   Dyspnea 13 14   Cough 10 7   Dyspnea exertional 4 7 Skin and Subcutaneous Tissue   Alopecia 28 33   Pruritus 19 18   Dermatitis 16 13   Dry skin 10 13   Rash 8 5   Sweating increased 6 5   Eczema 5 4 Visual Disorders   Vision blurred 5 2 * Severe hematologic abnormalities (lymphocyte less than 500 cells/mm³; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm³; platelet less than 50,000 cells/mm³). Pediatric Subjects In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS alone or in combination with COPEGUS, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy PEGASYS and COPEGUS for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination PEGASYS and COPEGUS treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the PEGASYS plus COPEGUS combination therapy group (hyperglycemia and cholecystectomy). Growth inhibition was observed in pediatric subjects. During combination therapy for up to 48 weeks with PEGASYS and COPEGUS, negative changes in weight for age z-score and height for age z-score after 48 weeks of therapy compared with baseline were observed [see WARNINGS AND PRECAUTIONS]. Table 6 : Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects)
System Organ Class Study NV17424 PEGASYS 180 mcg/1.73 m² x BSA + COPEGUS 15 mg/kg
(N=55)
% PEGASYS 180 mcg/1.73 m² x BSA + Placebo**
(N=59)
% General disorders and administration site conditions   Influenza like illness 91 81   Injection site reaction 44 42   Fatigue 25 20   Irritability 24 14 Gastrointestinal disorders   Gastrointestinal disorder 49 44 Nervous system disorders   Headache 51 39 Skin and subcutaneous tissue disorders   Rash 15 10   Pruritus 11 12 Musculoskeletal, connective tissue and bone disorders   Musculoskeletal pain 35 29 Psychiatric disorders   Insomnia 9 12 Metabolism and nutrition disorders   Decreased appetite 11 14 * Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.
**Subjects in the PEGASYS plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions were similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment. Common Adverse Reactions in CHC with HIV Coinfection (Adults) The adverse event profile of coinfected patients treated with PEGASYS/COPEGUS in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 5). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%). Laboratory Test Abnormalities Adult Patients Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all COPEGUS and PEGASYS combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see DOSAGE AND ADMINISTRATION]. Table 7 : Selected Laboratory Abnormalities During Treatment With COPEGUS in Combination With Either PEGASYS or Intron A
Laboratory Parameter PEGASYS + Ribavirin 1000/1200 mg 48 wks
(N=887) Intron A + Ribavirin 1000/1200 mg 48 wks
(N=443) Neutrophils (cells/mm³) 1,000 < 1,500 34% 38% 500 < 1,000 49% 21% < 500 5% 1% Platelets (cells/mm³) 50,000 - < 75,000 11% 4% 20,000 - < 50,000 5% < 1% < 20,000 0 0 Hemoglobin (g/dL) 8.5 -9.9 11% 11% < 8.5 2% < 1% Pediatric Patients Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment. Table 8 : Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects
Laboratory Parameter PEGASYS 180 mcg/1.73 m² x BSA + COPEGUS 15 mg/kg
(N=55) PEGASYS 180 mcg/1.73 m² x BSA + Placebo*
(N=59) Neutrophils (cells/mm³) 1,000 - < 1,500 31% 39% 750 - < 1,000 27% 17% 500 - < 750 25% 15% < 500 7% 5% Platelets (cells/mm³) 75,000 - < 100,000 4% 2% 50,000 - < 75,000 0% 2% < 50,000 0% 0% Hemoglobin (g/dL) 8.5 - < 10 7% 3% < 8.5 0% 0% * Subjects in the PEGASYS plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm³ and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment. 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) Read the Copegus (ribavirin) Side Effects Center for a complete guide to possible side effectsLearn More »

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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 dose of COPEGUS tablets is provided in Table 1. 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 (see Table 1). Table 1 : PEGASYS and COPEGUS Dosing Recommendations
Hepatitis C Virus (HCV) Genotype PEGASYS Dose* (once weekly) COPEGUS Dose (daily) Duration Genotypes 1, 4 180 mcg < 75 kg = 1000 mg 48 weeks ≥ 75 kg = 1200 mg 48 weeks Genotypes 2, 3 180 mcg 800 mg 24 weeks Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10).
Data on genotypes 5 and 6 are insufficient for dosing recommendations.
*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. The recommended doses for COPEGUS are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy. Table 2 : COPEGUS Dosing Recommendations for Pediatric Patients
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. Dose Modifications Adult and Pediatric Patients If severe adverse reactions or laboratory abnormalities develop during combination COPEGUS/PEGASYS therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, COPEGUS/PEGASYS therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status. COPEGUS should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see WARNINGS AND PRECAUTIONS]. Table 3 : COPEGUS Dose Modification Guidelines in Adults and Pediatrics
Body weight in kilograms (kg) Laboratory Values Hemoglobin < 10 g/dL in patients with no cardiac disease, or
Decrease in hemoglobin of ≥ 2 g/dL during any 4 week period in patients with history of stable cardiac disease Hemoglobin < 8.5 g/dL in patients with no cardiac disease, or
Hemoglobin < 12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease Adult Patients older than 18 years of age   Any weight 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M. Discontinue COPEGUS Pediatric Patients 5 to 18 years of age   23 – 33 kg 1 x 200 mg tablet A.M. Discontinue COPEGUS   34 – 46 kg 1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.   47 – 59 kg 1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.   60 – 74 kg 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.    ≥ 75 kg 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M. The guidelines for COPEGUS dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values. Adult Patients Once COPEGUS has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that COPEGUS be increased to the original assigned dose (1000 mg to 1200 mg). Pediatric Patients Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in COPEGUS dose to the original dose may be attempted depending upon the physician's judgment. If COPEGUS has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at one-half the full dose. 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, Pharmacokinetics, and PEGASYS Package Insert]. Table 4 : Dosage Modification for Renal Impairment
Creatinine Clearance PEGASYS Dose (once weekly) COPEGUS Dose (daily) 30 to 50 mL/min 180 mcg Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 135 mcg 200 mg daily Hemodialysis 135 mcg 200 mg daily 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. 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].

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Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS (peginterferon alfa-2a) and ribavirin. 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]. 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 and DOSAGE AND ADMINISTRATION]. 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. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see CONTRAINDICATIONS]. 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. Drugs Metabolized by Cytochrome P450 In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. 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]. Read the Copegus Drug Interactions Center for a complete guide to possible interactions Learn More »

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COPEGUS in combination with PEGASYS (peginterferon alfa-2a) is indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. The following points should be considered when initiating COPEGUS combination therapy with PEGASYS:
  • This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm³.
  • This indication is based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
  • Safety and efficacy data are not available for treatment longer than 48 weeks.
  • The safety and efficacy of COPEGUS and PEGASYS therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.
  • The safety and efficacy of COPEGUS therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. COPEGUS should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.

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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 [see WARNINGS AND PRECAUTIONS, Use in Specific Populations, and PATIENT INFORMATION].
  • 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 [see DRUG INTERACTIONS].
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 [see WARNINGS AND PRECAUTIONS].
  • Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see WARNINGS AND PRECAUTIONS].
Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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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.

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Dosage Forms And Strengths COPEGUS (ribavirin) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin. COPEGUS® (ribavirin) is available as tablets for oral administration. Each tablet contains 200 mg of ribavirin and is light pink to pink colored, flat, oval-shaped, film-coated, and engraved with RIB 200 on one side and ROCHE on the other side. They are packaged as bottle of 168 tablets (NDC 0004-0086-94). 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 WARNINGS AND PRECAUTIONS]. Keep bottle tightly closed. Distributed by: Genentech USA, INC. A Member of the Roche Group 1 DNA Way, South San Francisco, CA 94080-4990. Revised: 02/2013 Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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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. 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, Use in Specific Populations, and PATIENT INFORMATION]. 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]. 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]. 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]. 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], 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]. 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]. 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 [see DRUG INTERACTIONS]. Pancreatitis COPEGUS and PEGASYS therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis. Impact on Growth in Pediatric Patients Pediatric subjects treated with PEGASYS plus COPEGUS combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Both weight and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative growth curve percentiles for weight and height (mean weight for age percentile was 64% at baseline and 60% at 2 years posttreatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of subjects experienced a weight percentile decrease of 15 percentiles or more, and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years post-treatment, 16% of subjects remained 15 percentiles or more below their baseline weight curve and 11% remained 15 percentiles or more below their baseline height curve. 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 cells/mm³ 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
Patient Counseling Information
  • “See FDA-approved patient labeling (Medication Guide)”
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 and WARNINGS AND PRECAUTIONS]. Anemia The most common adverse event associated with ribavirin is anemia, which may be severe [see BOXED WARNING, WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory evaluations are required prior to starting COPEGUS therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS]. 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively. Mutagenesis Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Impairment of Fertility In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive COPEGUS unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t½) of ribavirin of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for ribavirin). No reproductive toxicology studies have been performed using PEGASYS in combination with COPEGUS. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents. Use In Specific Populations Pregnancy Pregnancy: Category X [see CONTRAINDICATIONS]. 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 [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]. In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended daily human dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin). Treatment and Post treatment: Potential Risk to the Fetus Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners. COPEGUS should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive COPEGUS unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see CONTRAINDICATIONS]. Ribavirin Pregnancy Registry A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214. 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. 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]. 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. 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 indicates 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, and CLINICAL PHARMACOLOGY]. 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, CLINICAL PHARMACOLOGY, and PEGASYS Package Insert]. 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. 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. 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]. Last reviewed on RxList: 3/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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