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Schering-Plough Announces PEG-Intron and Rebetol Approved in Japan for Expanded Use in Treating Chronic Hepatitis C

Combination Therapy Receives Additional Indication for Treating Patients Other Than Those With Genotype 1 Virus and High Viral Load

KENILWORTH, NJ -- December 22, 2005 -- Schering-Plough Corporation today announced that Schering-Plough K.K., the company's country operations in Japan, has received marketing approval for a new, additional indication for PEG-Intron® (peginterferon alfa-2b) Powder for Injection in combination with Rebetol® (ribavirin) Capsules -- the treatment of chronic hepatitis C in adult patients other than those with genotype 1 virus and high viral load.

This expanded use represents approximately 40% of the patient population in Japan. With this approval, PEG-Intron and Rebetol is indicated for the treatment of the vast majority of Japanese patients diagnosed with chronic hepatitis C virus (HCV) infection.

The approval by the Ministry of Health, Labor and Welfare (MHLW) follows a priority review designation granted May 18, 2005. An estimated 1 to 2 million Japanese are chronically infected with hepatitis C.

PEG-Intron and Rebetol was first approved in Japan in October 2004 for treating patients with genotype 1 virus (genotype 1a or 1b) and high viral load for a recommended duration of 48 weeks. With this new, expanded approval, the recommended duration of therapy for all other HCV indications is 24 weeks. This includes patients with genotype 2 or 3 virus and high viral load, as well as patients with genotype 1, 2 or 3 virus and low viral load who did not respond or who relapsed following treatment with interferon monotherapy. In the Japanese clinical study supporting this approval, a sustained virologic response (SVR)(1) rate of nearly 90% was achieved in these patients with 24 weeks of therapy.

"This expanded indication for PEG-Intron and Rebetol combination therapy represents a significant advance in the treatment of chronic hepatitis C, a major public health problem in Japan," said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute. "This approval, and the supporting clinical data, further underscore the efficacy of individualized, weight-based PEG-Intron used in combination with Rebetol in treating chronic hepatitis C."

PEG-Intron and Rebetol is the only pegylated interferon-based combination therapy for hepatitis C approved in Japan. PEG-Intron is administered once weekly in combination with Rebetol daily. Importantly, PEG-Intron is the only peginterferon product approved in Japan for which a blood test is not required before every injection.

HCV genotype 1 is generally considered to be the most difficult-to-treat form of hepatitis C and is the most common form in Japan, accounting for approximately 70% of all HCV infections there.

Hepatitis C is the leading cause in Japan of liver cancer, with more than 35,000 deaths occurring annually. Hepatitis C is the most common reason for liver transplant in major world markets, including Japan, according to the World Health Organization (WHO).

In the United States, PEG-Intron and Rebetol combination therapy is indicated for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.

Important Safety Information Regarding U.S. Labeling for PEG-Intron and Rebetol

WARNING
Alpha interferons, including PEG-Intron, 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 PEG-Intron therapy.

Ribavirin causes hemolytic anemia. Anemia associated with Rebetol therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with Rebetol. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.

Rebetol and combination Rebetol/PEG-Intron therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. Rebetol and combination Rebetol/PEG-Intron therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embryocidal 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.

PEG-Intron
There are no new adverse events specific to PEG-Intron as compared to Intron® A (interferon alfa-2b, recombinant) for Injection, 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/Rebetol is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).

The following serious or clinically significant adverse events have been reported at a frequency less than or equal to 1% with PEG-Intron or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages, and cotton wool spots.

In the PEG-Intron/Rebetol combination trial the incidence of serious adverse events was 17% in the PEG-Intron/Rebetol groups compared to 14% in the Intron A/Rebetol group. The incidence of severe adverse events in the PEG-Intron/Rebetol combination therapy trial was 23% in the Intron A/Rebetol group and 31-34% in the PEG-Intron/Rebetol groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-Intron (1.5 mcg/kg)/ Rebetol and in 34% of those receiving Intron A/Rebetol.

Rebetol should not be used in patients with creatinine clearance less than 50 mL/min.

(1) SVR is defined as the sustained undetectability of the hepatitis C virus 6 months following therapy.


SOURCE: Schering-Plough Corporation

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