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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA recently approved a "stand-alone package" of ribavirin capsules for the treatment of hepatitis C. Ribavirin is used in combination with interferon—either interferon alfa-2b or peginterferon alfa-2b. In 1998 the FDA approved a combination package of ribavirin and interferon alfa-2b that has been marketed under the trade name Rebetron. With the recent approval of a pegylated interferon alpha (PEG-Intron, Schering) and another on the way (Pegasys-Roche), ribavirin as a stand-alone product allows the flexibility to use these drugs in combination.
Ribavirin is indicated for use in combination with interferon alfa-2b (Intron A) for the treatment of chronic hepatitis C in adult patients with compensated liver disease previously untreated with alpha interferon or who have relapse after interferon therapy.1 It is also indicated in combination with peginterferon alfa-2b (PEG-Intron) for the treatment of chronic hepatitis C in patients with compensated liver disease who are naïve to interferon alpha therapy.2
The recommended dose of ribavirin with interferon alfa-2b is based on body weight. For patients < 75 kg the dose is 400 mg (2×200 mg) in the am and 600 mg (3×200 mg) in the pm. For patients > 75 kg, the dose is 600 mg (3×200 mg) in the am and pm. This is administered with 3 million IU of interferon alfa-2b (Intron A) 3 times weekly. In patients with a history of stable cardiovascular disease, a permanent dose reduction is needed if the hemoglobin decreases by 2 g/dL or greater during any 4-week period. Ribavirin should be discontinued if the hemoglobin remains below 12 g/dL after 4 weeks of a reduced dose. In patients with no cardiac history, the dose should be reduced to 600 mg daily (200 mg am and 400 mg pm) if hemoglobin falls below 10 g/dL and discontinued if it falls below 8.5 mg/dL.1
In combination with peginterferon (1.5 mg/kg/wk), the recommended dose is 800 mg in 2 divided doses (with breakfast and dinner). If hemoglobin drops below 10 mg/dL, but not below 8.5 mg/dL, the dose should be reduced by 200 mg/d.2 In those with a history of stable cardiovascular disease, the dose of peginterferon should be reduced by half and the dose of ribavirin by 200 mg/d if the there is a > 2 g/dL decrease in hemoglobin in any 4-week period, and discontinued if Hgb is < 12 g/dL. Ribavirin should be discontinued if there is significant decrease in WBC, neutrophils, or platelets.2
Treatment is generally 24-48 weeks for treatment-naïve patients and 24 weeks for treatment-relapse patients.
Ribavirin is supplied as 200-mg capsules in packages of 84. The bottles should be stored at 25°C or 77°F.
The approval of the "stand alone" ribavirin provides more dosing flexibility in tailoring individualized therapy for those patients requiring dosage reduction as well as allowing use with peginterferon. In the clinical trials, about 26% of patients required modification in the dose of ribavirin. These included dose reduction or discontinuation. The combination package (Rebetron) contains a week’s supply of ribavirin (35 or 42 capsules) and does not allow for the flexibility of dose reduction in patients with anemia associated with ribavirin therapy.
Ribavirin is not effective as monotherapy for hepatitis C. Hemolytic anemia, which occurs in about 10% of patients, is the primary adverse effect of ribavirin.1 The drug can also potentiate the neutropenia induced by interferon alpha.2 Ribavirin should not be used in pregnant patients or those with a creatinine clearance < 50 mg/min.
The combination of ribavirin and interferon alfa-2b has been approved for the treatment of patients who have relapsed following interferon alfa-2b therapy as well as those naïve to treatment. The combination has been reported to be more effective than interferon alone in both relapsing as well as naïve patients.1,3,4,7 Ribavirin was recently approved for use in combination with peginterferon alfa-2b (PEG-intron) which is a conjugate of monomethoxy polyethylene glycol (PEG) with recombinant interferon alfa-2b. The pegylated interferon permits a more convenient once-weekly dosing. In interferon treatment-naïve patients, the combination of ribavirin (800 mg daily) plus peginterferon (1.5 µg/kg week) produced a better overall response (undetectable virus in the serum in 24 weeks) than ribavirin (1000 or 1200 mg) plus interferon 3 MIU 3 times a week (52% vs 46%, respectively). The difference was seen in genotype 1 hepatitis C compared to genotypes 2-6.2,6 A recent report of a 24-week interim analysis suggests that ribavirin/peginterferon may be effective in patients who have previously failed on other interferon therapy.5
It is estimated that about 4 million Americans are chronically infected with hepatitis C and it is the leading reason for liver transplantation in this country. The combination of ribavirin and interferon is currently considered the standard of care. The approval of "stand alone"ribavirin permits its use with peginterferon and also allows for more flexibility in dosage modification due to adverse effects. As more data are published, peginterferon may become the standard interferon. Schering has agreed to conduct several postmarketing studies including the comparison of weight-adjusted doses of ribavirin with the currently approved fixed dose which is underway. Data suggest that body weight is an important predictor of response to interferon.6 Rebetol is expected to be available in November and a combination PEG-Intron/Rebetol product is also pending.
1. Rebetol Product Information. Schering Corporation. July 2001.
2. PEG-Intron Product Information. Schering Corporation. August 2001.
3. Mereno-Monteagudo, et al. Aliment Pharmacol Ther. 1998;12(8):717-723.
4. Reichard O, et al. Lancet. 1998;351:83-87.
5. Jacobson I, et al. Digestive Disease Week 2001. May 20-23, 2001. Atlanta, GA. Abstract #1964.
6. Manns MP, et al. Lancet. 2001;358:958-965.
7. Poynard T, et al. Lancet. 1998;352:1426-1432.