Copegus (Tablet, Film Coated)
CHC Monoinfection: The recommended dose of COPEGUS tablets is provided in Table 5. 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 5). In the pivotal clinical trials, patients were instructed to take COPEGUS with food; therefore, patients are advised to take COPEGUS with food.<br/>CHC with HIV Coinfection: The recommended dose for hepatitis C in HCV/HIV coinfected patients is PEGASYS 180��g sc once weekly and COPEGUS 800 mg po daily for a total of 48 weeks, regardless of genotype.<br/>Dose Modifications: 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. If intolerance persists after dose adjustment, COPEGUS/PEGASYS therapy should be discontinued. COPEGUS should be administered with caution to patients with pre-existing cardiac disease (see Table 6). 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 . Once COPEGUS has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily depending upon the physician's judgment. However, it is not recommended that COPEGUS be increased to its original assigned dose (1000 mg to 1200 mg).<br/>Renal Impairment: COPEGUS should not be used in patients with creatinine clearance<50 mL/min (see WARNINGS and CLINICAL PHARMACOLOGY: Special Populations).
COPEGUS, the Hoffmann-La Roche brand name for ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-��-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula: The empirical formula of ribavirin is CHNOand 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 hydroxypropylmethyl cellulose, talc, titanium dioxide, synthetic yellow iron oxide, and synthetic red iron oxide), ethyl cellulose (ECD-30), and triacetin.<br/>Mechanism of Action: Ribavirin is a synthetic nucleoside analogue. The mechanism by which the combination of ribavirin and an interferon product exerts its effects against the hepatitis C virus has not been fully established.
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>75 kg) AUCwas 25,361��7110 ng���hr/mL and Cwas 2748��818 ng/mL. The average time to reach Cwas 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>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 Cat steady state was four-fold higher than that of a single dose.<br/>Effect of Food on Absorption of Ribavirin: Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Twas doubled) and the AUCand Cincreased by 42% and 66%, respectively, when COPEGUS was taken with a high-fat meal compared with fasting conditions .<br/>Elimination and Metabolism: The contribution of renal and hepatic pathways to ribavirin elimination after administration of COPEGUS is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.<br/>Special Populations:<br/>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.<br/>Renal Dysfunction: The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance<50 mL/min. Therefore, patients with creatinine clearance<50 mL/min should not be treated with COPEGUS .<br/>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.<br/>Pediatric Patients: Pharmacokinetic evaluations in pediatric patients have not been performed.<br/>Elderly Patients: Pharmacokinetic evaluations in elderly patients have not been performed.<br/>Gender: Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.<br/>Drug Interactions: In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.<br/>Nucleoside Analogues: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients (see PRECAUTIONS: Drug Interactions). In vitro, didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities .<br/>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 .
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).<br/>Storage Conditions: 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. REBETRONis a trademark of Schering Corporation.
COPEGUS (ribavirin) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication . The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin . Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Information for Patients, and Pregnancy: Category X).
dailymed-ingredient:Chromatone-P, dailymed-ingredient:Opadry, dailymed-ingredient:cornstarch, dailymed-ingredient:ethyl_cellulose_(ECD-30), dailymed-ingredient:magnesium_stearate, dailymed-ingredient:microcrystalline_cellulose, dailymed-ingredient:pregelatinized_starch, dailymed-ingredient:sodium_starch_glycolate, dailymed-ingredient:triacetin
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.
Copegus (Tablet, Film Coated)
PEGASYS in combination with COPEGUS causes a broad variety of serious adverse reactions . The most common life-threatening or fatal events induced or aggravated by PEGASYS and COPEGUS were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of<1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV patients (see WARNINGS: Hepatic Failure). In all studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients and in 19% of CHC/HIV patients 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 SAEs occurred at a frequency of<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. Nearly all patients in clinical trials experienced one or more adverse events. 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. 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, andanemia). 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<10g/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. Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.<br/>Common Adverse Reactions in CHC With HIV Coinfection: The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 4). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).<br/>Laboratory Test Values: Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin<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: Dose Modifications).<br/>Postmarketing Experience: The following adverse reactions have been identified and reported during post-approval use of PEGASYS therapy: dehydration, hearing impairment, hearing loss, and serious skin reactions .
COPEGUS in combination with PEGASYS (peginterferon alfa-2a) is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy).