Rebetron Combination Therapy Now Approved by FDA for Use in Both Previously Untreated and Relapse Hepatitis C Patients


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NEW YORK, Dec. 11 /PRNewswire/

ICN Pharmaceuticals, Inc. (NYSE: ICN) said today that its licensing partner Schering-Plough Corporation (NYSE: SGP) has been informed that the U.S. Food and Drug Administration (FDA) has approved REBETRON(TM) Combination Therapy containing REBETOL(R) (ribavirin, USP) Capsules and INTRON(R) A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon therapy.

The FDA decision was based on clinical data from two pivotal multicenter Phase III studies involving previously untreated patients. Results of these studies showed that REBETRON Combination Therapy resulted in a significant increase in the number of patients showing a sustained loss of detectable* hepatitis C virus as compared to patients receiving standard alpha interferon monotherapy.

Schering-Plough has exclusive rights to market oral ribavirin for hepatitis C in all major world markets through a licensing agreement with ICN. REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad- spectrum antiviral activity. ICN Pharmaceuticals currently markets ribavirin as VIRAZOLE(R) in a variety of dosage forms for at least one of 10 indications in 44 countries, including in the United States and the European Union for aerosol use for the treatment of hospitalized infants and young children with severe lower respiratory infection due to respiratory syncytial virus.

*Defined as HCV RNA below limit of detection using a research-based RT-PCR assay at 24 weeks post-treatment.

The FDA action represents the second indication this year for REBETRON Combination Therapy for the treatment of chronic hepatitis C. On June 3, the FDA approved REBETRON Combination Therapy for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following alpha interferon therapy. Prior to REBETRON Combination Therapy, the only drugs approved in the United States for treating hepatitis C had been alpha interferon monotherapies.

"It is gratifying that ribavirin, a drug discovered and developed by ICN, is playing a major role in the combination treatment for chronic hepatitis C," said Milan Panic, chairman and chief executive officer of ICN Pharmaceuticals. "As part of REBETRON combination therapy, ribavirin should help mitigate a serious health problem and bring new hope to the patients afflicted with this life threatening disease."

"Research into the treatment of many viral diseases has demonstrated that combination therapies rather than monotherapy may offer the best potential for more effective treatment," commented Willis C. Maddrey, M.D., professor of medicine at the University of Texas Southwestern Medical Center in Dallas and a world-renowned hepatologist.

Some 4 million Americans are chronically infected with the hepatitis C virus and approximately 70 percent of infected patients go on to develop chronic liver disease, according to the Centers for Disease Control and Prevention (CDCP). Hepatitis C infection contributes to the deaths of an estimated 8,000 to 10,000 Americans each year. This toll is expected to triple by the year 2010 and exceed the number of annual deaths due to AIDS, according to the CDCP. The American Liver Foundation has reported that liver failure due to hepatitis C infection is the leading cause of liver transplants in the United States.

In Europe, 1 to 2 percent of the general population is chronically infected with the hepatitis C virus. According to a study conducted by the World Health Organization (WHO), as many as 5 million Europeans are chronically infected with the disease.

Clinical Trials with Previously Untreated Patients

The safety and efficacy of REBETRON Combination Therapy were evaluated in two multicenter, double-blind clinical trials involving 1,711 patients with compensated chronic hepatitis C and detectable HCV RNA who were previously untreated with alpha interferon therapy.

Patients were randomized to receive subcutaneous injections of INTRON A 3 million international units (MIU) three times per week and either oral REBETOL 1,000-1,200 mg or a matched placebo daily for 24 or 48 weeks followed by 24 weeks of off-therapy follow up.

Results of these studies showed that patients receiving REBETRON Combination Therapy had a significantly improved virologic and histologic response compared to patients receiving INTRON A alone. Six months after therapy was completed, 198 of 496 patients (40 percent) who were treated with 48 weeks of REBETRON Combination Therapy had undetectable virus levels as compared to 73 of the 491 patients (15 percent) who were treated with 48 weeks of INTRON A alone.

Warnings and Contraindications

Hemolytic anemia associated with REBETRON Combination Therapy may exacerbate symptoms of coronary disease or deteriorate cardiac function. It is advised that complete blood counts (CBC) be obtained at baseline and at week 2 and week 4 of therapy or more frequently if clinically indicated. The most common adverse experiences associated with REBETRON Combination Therapy are "flu- like" symptoms, such as headache, fatigue, myalgia and fever, which appear to decrease in severity as treatment continues. Severe psychiatric adverse events may manifest in patients receiving therapy with interferons, including INTRON A therapy. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS AND COMPLETED SUICIDES, MAY OCCUR.

Combination REBETOL/INTRON A therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and the six months after stopping therapy. Combination REBETOL/INTRON A therapy should not be initiated until a report of a negative pregnancy has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embriocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one-twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling 800-727-7064.


The recommended dosage of REBETRON Combination Therapy is 3 MIU of INTRON A injected subcutaneously three times per week and 1,000-1,200 mg of REBETOL capsules administered orally in a divided daily (morning and evening) dose. Patients weighing 75 kg (165 pounds) or less should receive 1,000 mg of REBETOL daily, while patients weighing more than 75 kg should receive 1,200 mg of REBETOL daily.

The recommended duration of treatment with REBETRON Combination Therapy for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy and tolerability of the regimen. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment with REBETRON Combination Therapy for longer than 48 weeks in the previously untreated patient population.

In patients who relapse following interferon therapy, the recommended duration of treatment with REBETRON Combination Therapy is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

INTRON A is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering-Plough markets INTRON A, the world's largest-selling alpha interferon, for 16 major antiviral and anticancer indications worldwide.

ICN manufactures and markets a broad range of prescription and non- prescription pharmaceuticals and biomedical research products in over 90 countries. The company employs some 17,000 people worldwide. ICN has operations in North and Latin America, Western, Central and Eastern Europe, and the Pacific Rim countries. Additional information is available on the corporate website at

THE 'SAFE HARBOR' STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995. This press release contains forward-looking statements that involve risks and uncertainties including, but not limited to, projections of future sales, operating income, returns on invested assets, regulatory approval processes, financial impact of devaluations, the progress of FDA reviews, and other risks detailed from time to time in the Company's Securities and Exchange Commission filings.

SOURCE ICN Pharmaceuticals, Inc.

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