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© Hepatitis C Online PDF created October 15, 2016, 2:15 am Ribavirin (Copegus, Rebetol, Ribasphere) Drug Summary Table of Contents Ribavirin (Copegus, Rebetol, Ribasphere) Class and Mechanism Manufacturer for United States FDA Status Indications Dosing Clinical Use Cost and Medication Access Adverse Effects Major Drug Interactions Resistance Full Prescribing Information Summary Class and Mechanism Ribavirin is a purine nucleoside analog that has an incompletely understood mechanism of action against hepatitis C virus. Investigators have proposed four main potential sites of ribavirin action against hepatitis C virus: (1) augmentation of host T-cell immune clearance of HCV, (2) inhibition of the host enzyme inosine monophosphate dehydrogenase (IMPDH) that results in depleted pools of guanosine triphosphate, an essential substrate for viral RNA synthesis (3) direct inhibition of HCV replication, and (4) induction of RNA virus mutagenesis that drives HCV to an abonormally high error rate. Manufacturer for United States Ribavirin is manufactured by multiple companies in the United States: Copegus (Figure 1) is produced by Genentech (member of the Roche group), Rebetol by Merck Sharp & Dome, a subsidary of Merck & Co., Inc., and Ribasphere by Kadmon Pharmaceuticals (orginally by Three Rivers Pharmaceuticals which was acquired by Kadmon Pharmaceuticals). In addition, several companies, including Sandoz (Figure 3) and Teva (Figure 4) pharmaceuticals, produce generic ribavirin. FDA Status 1 / 12 In 1998, ribavirin (Rebetol) received initial United States FDA approval for use with interferon alfa-2b and in 2001 for use with peginterferon alfa-2b. Additional FDA approvals occurred for ribavirin in 2003 (Copegus), in 2005 (Ribasphere), and the first generic versions of ribavirin in 2005. Indications The indications for ribavirin depend on the brand of ribavirin used, with the major distinction whether ribavirin is approved for use with peginterferon alfa-2a or peginterferon alfa-2b. Ribavirin (Copegus) is approved for use withpeginterferon alfa-2a (Pegasys) for the treatment of chronic hepatitis C with compensated liver disease. Ribavirin (Rebetol) tablet forumation is approved for use with peginterferon alfa-2a (Pegasys) for the treatment of chronic hepatitis C with compensated liver disease. Ribavirin (Ribasphere) capsule formulation is approved for use with interferon alfa-2b (Intron A) and peginterferon alfa-2b (PegIntron) for the treatment of chronic hepatitis C.Ribavirin (Ribasphere) is approved for use with interferon alfa-2b (Intron A) and peginterferon alfa-2b (PegIntron) for the treatment of chronic hepatitis C. Recently, the NS5a polymerase inhibitor sofosbuvir (Sovaldi) was approved by the FDA for use with ribavirin to treat chronic hepatitis C genotype 2 and 3 infection, and for patients with genotype 1 who are interferon ineligible. Ribavirin should never be used as monotherapy for the treatment of hepatitis C virus. For all preparations, ribavirin is contraindicated in (1) pregnant women and male partners of females who are pregnant, (2) patients with hemoglobinopathies, and (3) coadministration with didanosine (Videx). Dosing Ribavirin is available in 200 mg, 400 mg, 500 mg, and 600 mg capsules and tablets. In addition, ribavirin is available in an oral (liquid) solution. The availability of specific strength depends on the brand of the ribavirin. Ribavirin (Copegus) is available in 200 mg tablets (Figure 2) and should be taken with food. The daily dose when given as fixed dosing is 800 mg per day in two divided doses. When given as weight-based, the dose is 1000 mg/day for persons less than 75 kg and 1200 mg/day for those 75 kg or greater. Ribavirin (Rebetol) is available in 200 mg capsules and oral solution (40 mg/ml) taken with food. The daily dose of ribavirin ranges from 800 to 1400 mg given in two divided doses. The daily dose when given as fixed dosing is 800 mg in two divided doses. When given as weightbased, the dose is 800 mg/day for body weight less than 66 kg, 1000 mg/day for 66 to 80 kg, 1200 mg/day for 81 to 105 kg, and 1400 mg/day for those greater than 105 kg; in all instances, the ribavirin is given in two divided doses. Ribavirin (Ribasphere) is available in 200 mg, 400 mg, and 600 mg tablets and 200 mg capsules and should be taken with food. The daily dose of ribavirin ranges from 800 mg to 1200 mg/day when given with peginterferon alfa-2a. If given with peginterferon alfa-2b, the dose of ribavirin ranges from 800 mg to 1400 mg/day. The levels of ribavirin increase significantly in patients with renal insufficiency. Patients with a creatinine clearance 30 to 60 mL/min have a twofold increase in ribavirin area under the curve (AUC) and those with a creatinine clearance 10 to 30 mL/min have a threefold increase in ribavirin AUC. Ribavirin is not significantly removed by dialysis. 2 / 12 Ribavirin requires doseage modification in patients who have a creatinine clearance less than 50 mL/min and the exact doseage adjustment should be made based on the prescribing information for the specific brand of ribavirin used. Ribavirin levels are not significantly impacted by mild, moderate, or severe hepatic dysfunction. Clinical Use The specific dose and duration of ribavirin therapy depends on the hepatitis C genotype, the patient's prior treatment experience, degree of liver fibrosis, and the concomitant medications used for hepatitis C therapy. Ribavirin should never be used alone for the Ribavirin has been used in combination with Ribavirin has been used in combination with boceprevir, simeprevir, or sofosbuvir. Ribavirin has been used in combination with treatment of hepatitis C virus. peginterferon alfa 2a and peginterferon alfa 2b. peginterferon alfa plus either telaprevir, sofosbuvir as dual therapy. Cost and Medication Access The wholesale acquisition cost (WAC) for ribavirin is difficult to report, given the multiple brand and generic preparation and given the variable doses used with weight-based dosing. In general, the generic preparations are less expensive than the brand drugs. As a rough estimate, a 12-week course of generic ribavirin is in the range of $550 to $850. Accordingly, the ribavirin component of a 48-week treatment course costs approximately $1100 to $1700. Rebetol Patient Assistance: For information regarding reimbursement support services for ribavirin (Rebetol), see the ACT Program website or call 866-363-6379. This is the same patient assistance program for peginterferon alfa-2b (Pegintron). Copegus Patient Assistance: For information regarding coverage, reimbursement, and patient assistance for Copegus), visit the Access Solutions website or call 888-941-3331. This is the same patient assistance program for peginterferon alfa-2a (Pegasys). Ribasphere, RibapakPatient Assistance: For information regarding reimbursement support services for ribavirin (Rebetol), contact the Kadmon Enabling Your Success (K.E.Y.S.) Program at 888-668-3393. Adverse Effects Two potentially serious ribavivirn-associated adverse effects are listed as black box warnings. Hemolytic Anemia: Ribavirin can cause a potentially severe hemolytic anemia. The hemolytic anemia can occur suddenly and can result in worsening of cardiac disease, even leading to myocardial infarction. The hemolytic anemia most often occurs within 1 to 2 weeks after 3 / 12 starting therapy. Accordingly, patients should have a hematocrit and/or hemoglobin checked prior to starting therapy and at week 2 and 4 of therapy. Birth Defects: Ribavirin can cause significant teratogenic and embyocidal effects, including potential birth defects and fetal death. Ribavirin should not be used by women during pregnancy or in male partners of women who are pregnant. For women who will recieve treatment with ribavirin, a documented negative pregnancy test is required immediately prior to starting ribavirin therapy and women should use two or more forms of birth control and have monthly pregnancy testing during treatment and for 6 months thereafter. Further, pregnancy should be avoided for at least 6 months after completing ribavirin therapy (for females who have taken ribavirin and for females partners of males who have taken ribavirin). Other less serious adverse effects have been observed with ribavirin, including fatigue, nausea, rash, and itching. To report suspected adverse reactions, contact (1) the ribavirin manufactuer or (2) the FDA at 1-800-FDA-1088. Major Drug Interactions Ribavirin, when given with didanosine, causes significant increases didanosine levels which can potentially cause life-threatening toxicities. Ribavirin may also adversely interact with other HIV nuceloside analog reverse transcriptase inhibitors. The concomitant use of ribavirin and azathiaprine may lead to an accumulation in an azathioprine metabolite, which may result in azathioprine-related myelotoxicity. Resistance In vitro resistance of hepatitis C virus to ribavirin has been demonstrated, but clinical resistance to ribavirin remain poorly defined. Testing for ribavirin resistance is not commercially available. Full Prescribing Information Full Prescribing Information for Rebetol capsules and oral soluation. Prescribing Information for Copegus tablets. Full Prescribing Information for Ribasphere tablets Full Prescribing Information for Ribasphere capsules Summary 4 / 12 Ribavirin has been an integral component of hepatitis C therapy. When used with interferon or peginterferon, ribavirin significatly reduces relapse rates and significant improves sustained virologic responses. Currently, ribavirin plays a significant role in the treatment of all hepatitis C genotypes. Dosing of ribavirin is somewhat complicated and includes fixed-dose and weight-based ribavirin, with dosing depending on the genotype and brand of ribavirin used. In addition, ribavirin can cause severe anemia and dose adjustement is required in some patients who develop anemia. Ribavirin will likely continue to play an important role in the treatment of hepatitis C, but eventually will likely be replaced by highly effective, better tolerated combinations of direct acting agents. 5 / 12 Clinical Trials Interferon alfa-2b Alone or in Combination with Ribavirin In this investigators randomized 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or combined with ribavirin (weight-based) for either 24 or 48 weeks. Patients treated with interferon alfa-2b alone had SVR24 rates of 6% with 24 weeks of therapy and 13% with 48 weeks of therapy. Those treated with interferon and ribavirin had significantly higher SVR24 rates: 31% with 24 weeks of therapy and 38% with 48 weeks of therapy This trial demonstrated that treatment with interferon and ribavirin generates significantly higher SVR24 rates than with interferon alone, regardless of duration of therapy. View Clinical Trial: In your Browser | Download PDF Peginterferon alfa-2a with or without Ribavirin In this trial, investigators examined the efficacy of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, or peginterferon alone in treatment-naive patients with chronic hepatitis C. The ribavirin was given as weight based dosing. The end of treatment response was higher in the peginterferon alfa-2a plus ribavirin than the other two groups, but notably the sustained virologic response rate was markedly higher in patients who received peginterferon alfa-2a plus ribavirin group than those who received peginterferon alone (56% versus 44%). In addition, the investigators demonstrated the 12 week HCV RNA response clearly predicted a subsequent sustained virologic response. This trial established the benefit of adding ribavirin to peginterferon: patients receiving peginterferon plus ribavirin had lower virologic relapse rates after end of treatment and greater SVR24 rates than patients who received peginterferon alone. View Clinical Trial: In your Browser | Download PDF Duration and Dose-Finding Study of Peginterferon alfa-2a and Ribavirin This multicenter, phase 3, randomized, double-blind trial used a 2 x 2 factorial design to examine the efficacy of 24 versus 48 weeks of peginterferon alfa-2a plus ribavirin, as well as the difference between fixed low dose (800 mg/day) versus weight-based (1000 or 1200 mg/day) dosing of ribavirin in patients with chronic HCV infection. Investigators enrolled 1311 patients, among whom 740 had genotype 1 infection. In patients with genotype 1, significantly higher SVR) rates were observed with weight-based ribavirin dosing (compared with fixed low dose ribavirin) and with 48 versus 24 weeks of therapy. Among patients with genotypes 2 or 3 infection, ribavirin dosing and duration of therapy did not significantly affect SVR rates. This study clearly established that treatment of genotype 1 HCV with peginterferon alfa-2a plus ribavirin generates significantly higher SVR24 rates with higher ribavirin dose longer treatment duration. View Clinical Trial: In your Browser | Download PDF Peginterferon alfa-2b and Weight-Based or Flat-Dose Ribavirin (WINRTrial) This very large, prospective, open-label trial enrolled 5207 hepatitis C treatment-naive patients at 236 sites in the United States to examine the impact of weight-based or flat-dose ribavirin given with 6 / 12 peginterferon alfa-2b. Patients in the study were randomized on a 1:1 basis to receive peginterferon alfa-2b plus flat-dose ribavirin or peginterferon alfa-2b plus weight-based ribavirin. At the beginning of the trial, all patients were scheduled to recieve 48 weeks of therapy, but the protocol was amended so that patients with genotype 2 or 3 were randomized to receive either 24 or 48 weeks of therapy. Overall, SVR24 rates were higher in patients who received weight based ribavirin compared with flat-dose ribavirin. When analyzing for gentoype 1 patients, those who received weight based ribavirin compared with flat-dose ribavirin (34% versus 29%). WIth genotype 2 and 3 patients, no significant differences were observed with weight-based versus flat-dose ribavirin and extending treatment to 48 weeks did not significantly improve SVR rates. This study demonstrated a benefit of using weight-based ribavirin in combination with peginterferon alfa-2b when treating patients with gentoype 1 HCV, but not with genotype 2 or 3. View Clinical Trial: In your Browser | Download PDF 7 / 12 Figures Figure 1 Bottle - Ribavirin (Copegus) Photo: Andrew Karpenko, University of Washington 8 / 12 Figure 2 Tablets - Ribavirin (Copegus) Photo: Andrew Karpenko, University of Washington 9 / 12 Figure 3 Tablets - Ribavirin (Generic from Sandoz) Photo: Andrew Karpenko, University of Washington 10 / 12 Figure 4 Capsules - Ribavirin (Generic from Teva) Photo: Andrew Karpenko, University of Washington 11 / 12 References Brok J, Gluud LL, Gluud C. Meta-analysis: ribavirin plus interferon vs. interferon monotherapy for chronic hepatitic C - an updated Cochrane review. Aliment Pharmacol Ther. 2010;32:840-50. [PubMed Abstract] Chemello L, Cavalletto L, Bernardinello E, Guido M, Pontisso P, Alberti A. The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. J Hepatol. 1995;23 Suppl 2:8-12. [PubMed Abstract] Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature. 2005;436:967-72. [PubMed Abstract] Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82. [PubMed Abstract] Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alfa2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55. [PubMed Abstract] Ibarra KD, Jain MK, Pfeiffer JK. Host-based ribavirin resistance influences hepatitis C virus replication and treatment response. J Virol. 2011;85:7273-83. [PubMed Abstract] Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:971-81. [PubMed Abstract] Lai MY, Kao JH, Yang PM, et al. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology. 1996;111:1307-12. [PubMed Abstract] Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology. 2002;35:1002-9. [PubMed Abstract] McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-92. [New England Journal of Medicine] Reichard O, Norkrans G, Frydén A, Braconier JH, Sönnerborg A, Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet. 1998;351:83-7. [PubMed Abstract] Schalm SW, Hansen BE, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. Meta-analysis of individual patient data from European centers. J Hepatol. 1997;26:961-6. [PubMed Abstract] © Hepatitis C Online PDF created October 15, 2016, 2:15 am The most up to date version of this content may be obtained from: http://www.hepatitisc.uw.edu/page/treatment/drugs/ribavirin-drug 12 / 12 Powered by TCPDF (www.tcpdf.org)