Copegus Information
Copegus () Indications And Usage
The following points should be considered when initiating Copegus () combination therapy with PEGASYS:
Copegus () Dosage 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.
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 .
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 PEGASYS/Copegus () therapy should be considered if the patient has failed to demonstrate at least a 2 log 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 () 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 () Contraindications
Copegus () (ribavirin) is contraindicated in:
Copegus () and PEGASYS combination therapy is contraindicated in patients with:
Copegus () Warnings And Precautions
The PEGASYS Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.
Copegus () Adverse Reactions
PEGASYS in combination with Copegus () causes a broad variety of serious adverse reactions . 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 .
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
Ear and Labyrinth disorders
Eye disorders
Immune disorders
Metabolism and Nutrition disorders
Skin and Subcutaneous Tissue disorders
Copegus () Drug Interactions
Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS (peginterferon alfa-2a) and ribavirin.
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 .
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) .
Copegus () Use In Specific Populations
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.
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 .
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 .
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.
Copegus () Overdosage
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 () Description
Copegus () , ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide and has the following structural formula:
The empirical formula of ribavirin is CHNO 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.
Copegus () Clinical Pharmacology
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) AUC was 25,361±7110 ng∙hr/mL and C was 2748±818 ng/mL. The average time to reach C 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 C at steady state was four-fold higher than that of a single dose.
Copegus () Nonclinical 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.
Copegus () Clinical Studies
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 log 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.
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/mmor CD4+ cell count greater than or equal to 100 cells/mmbut less than 200 cells/mmand 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
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 log 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.
Copegus () How Supplied/storage And Handling
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).
Copegus () Patient Counseling Information
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 .
Anemia
The most common adverse event associated with ribavirin is anemia, which may be severe . Patients should be advised that laboratory evaluations are required prior to starting Copegus () therapy and periodically thereafter . 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 ()
Copegus ()
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