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FDA Grants Priority Review to Ribavirin for Treating Pediatric Hepatitis C

KENILWORTH, N.J., April 8 /PRNewswire-FirstCall/ -- Schering-Plough Corporation today reported that the U.S. Food and Drug Administration (FDA) has granted six-month priority review status to its New Drug Application (NDA) for REBETOL® (ribavirin, USP) Oral Solution and Capsules. The application seeks FDA approval of REBETOL for use in combination with INTRON® A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease previously untreated with alpha interferon. Schering-Plough submitted the NDA in January 2003.

Priority review status is granted to drugs that, if approved, would address unmet medical needs and represent significant advances over existing treatments. While it is estimated that less than 200,000 children in the United States are infected with the hepatitis C virus (HCV), new infections in children continue to occur.

"FDA approval of REBETOL for use with INTRON A would represent the first and only therapy approved in the United States for treating hepatitis C in the pediatric population," said Robert J. Spiegel, M.D., senior vice president of medical affairs and chief medical officer, Schering-Plough Research Institute. "For more than a decade, Schering-Plough has been the leader in advancing treatment of chronic hepatitis C. We are committed to developing innovative therapies to meet the needs of patients with this serious disease."

REBETOL Oral Solution represents a new formulation of ribavirin, USP. REBETOL Capsules are currently approved in the United States for use in combination therapy with INTRON A for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy. REBETOL Capsules also are indicated in combination with PEG-INTRON® (peginterferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon and are at least 18 years of age.

Commitment to Hepatitis C Patients

Schering-Plough is committed to supporting hepatitis C patients with education and service programs as well as to help locate financial assistance for patients in need. The company's programs for patients in the United States are among the most comprehensive in the industry, providing support and guidance to patients from the time of diagnosis through treatment, and ensuring that all eligible patients have access to the company's hepatitis C products.

Since the introduction of PEG-INTRON and REBETOL combination therapy in 2001, more than 250,000 hepatitis C patients worldwide have received this treatment, including 150,000 patients in the United States. Twenty-five percent of all U.S. patients currently treated with PEG-INTRON and REBETOL are enrolled in the company's Commitment to Care program, which provides medication and/or reimbursement assistance to eligible patients. The market value of assistance and treatment provided to hepatitis C patients through this program exceeded $100 million in 2002.

Schering-Plough's Be In Charge hepatitis C patient-support program has enrolled more than 55,000 U.S. patients to date, with more than 25,000 patients enrolling in 2002 alone. This U.S. program is designed to support patients treated with Schering-Plough hepatitis C products through the use of educational materials and telephone contact with personal nurse counselors skilled in the management of hepatitis C.

In a 2002 survey of patients enrolled in the Be In Charge program, overall patient satisfaction was 91 percent, with 75 percent of patients saying that Be In Charge helped them manage their health condition. Of patients surveyed, 96 percent said they would recommend Be In Charge to others. A survey of physicians also reflects their satisfaction with Be In Charge: 83 percent said they would recommend the program to other physicians, 84 percent said they believe patients have a better understanding of their treatment plan because of Be In Charge, and nearly 75 percent of physicians said Be In Charge has reinforced their treatment suggestions to patients.(1)

REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog. Schering-Plough has worldwide rights to market oral ribavirin for hepatitis C through a licensing agreement with Ribapharm Inc. of Costa Mesa, Calif.

PEG-INTRON is a longer-acting form of INTRON A that uses proprietary PEG technology developed by Enzon, Inc. of Bridgewater, N.J. Schering-Plough holds an exclusive worldwide license to PEG-INTRON.

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 for 16 major antiviral and anticancer indications worldwide.

WARNING -- REBETOL monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication. (See WARNINGS.) -- The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with REBETOL therapy may result in worsening of cardiac disease that has lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. (See WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.) -- Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so it may persist in nonplasma compartments for as long as 6 months. Therefore, REBETOL therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking REBETOL therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period. (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS-Information for Patients and Pregnancy Category X.) -- Alpha interferons, including PEG-INTRON and INTRON A, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping therapy with PEG-INTRON or INTRON A. (See WARNINGS, ADVERSE REACTIONS.) PEG-INTRON

There are no new adverse events specific to PEG-INTRON as compared to INTRON A, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.

Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON. PEG-INTRON is contraindicated in patients with autoimmune hepatitis and decompensated liver disease.

The following serious or clinically significant adverse events have been reported at a frequency

Renal failure patients should be closely monitored for signs and symptoms of interferon toxicity and PEG-INTRON should be used with caution in patients with creatinine clearance


All patients receiving INTRON A therapy experienced mild-to-moderate side effects. Some patients experienced more severe side effects, including neutropenia, fatigue, myalgia, headache, fever, chills and increased SGOT. Other frequently occurring side effects were nausea, vomiting, depression, alopecia, diarrhea and thrombocytopenia. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY.

FORWARD-LOOKING STATEMENT: The information in this press release includes certain "forward-looking" statements concerning the NDA filed for REBETOL Oral Solution in the United States. The reader of this release should understand that approval of new drugs are subject to the risks and uncertainties inherent in the regulatory approval process, and there are no assurances that the FDA will approve the application. In addition, the forward-looking statements may also be adversely affected by general market factors, competitive product development, product availability, current and future branded or generic competition, federal and state regulations and legislation, the regulatory process for new products and indications in the United States, manufacturing issues, trade buying patterns, patent positions, litigation and investigations. For further details on these risks and uncertainties, see the company's SEC filings, including the company's 2002 10-K.

Schering-Plough is a research-based company engaged in the discovery, development, manufacturing and marketing of pharmaceutical products worldwide.

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