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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
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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.
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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
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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
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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.
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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.
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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.
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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.
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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
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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.
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Figures
Figure 1 Bottle - Ribavirin (Copegus)
Photo: Andrew Karpenko, University of Washington
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Figure 2 Tablets - Ribavirin (Copegus)
Photo: Andrew Karpenko, University of Washington
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Figure 3 Tablets - Ribavirin (Generic from Sandoz)
Photo: Andrew Karpenko, University of Washington
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Figure 4 Capsules - Ribavirin (Generic from Teva)
Photo: Andrew Karpenko, University of Washington
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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]
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The most up to date version of this content may be obtained from:
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