Schering-Plough Announces PEG-INTRON® Approved in Japan for Use in Combination With REBETOL® for Chronic Hepatitis C

KENILWORTH, N.J. -- Schering-Plough Corporation announced that Schering-Plough K.K., the companys subsidiary in Japan, has received marketing approval for PEG-INTRON® (peginterferon alfa-2b) Powder for Injection for use in combination with REBETOL®(ribavirin) capsules for the treatment ofchronic hepatitis C.  PEG-INTRON and REBETOL combination therapy is the first and only pegylated interferon-based combination therapy approved in Japan.  An estimated 1 to 2 million Japanese are chronically infected with hepatitis C.

The approval by the Ministry of Health, Labor and Welfare (MHLW) follows a priority review.  PEG-INTRON will become available in Japan upon National Health Insurance Reimbursement price listing.

The introduction of PEG-INTRON and REBETOL combination therapy represents a significant development in the treatment of hard-to-treat chronic hepatitis C, a major public health problem in Japan, said Robert J. Spiegel, MD, chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute.  This approval, and the supporting clinical data, further underscore the value of individualized, weight-based PEG-INTRON used in combination with REBETOL in treating chronic hepatitis C.

PEG-INTRON, which is administered once weekly in combination with REBETOL daily for 48 weeks, is indicated in patients chronically infected with hepatitis C virus (HCV) genotype 1 (genotype 1a or 1b) and high viral load.  HCV genotype 1 is considered the most difficult-to-treat form of hepatitis C and is the most common form in Japan, accounting for approximately 60 percent of all HCV infections there.

Importantly, PEG-INTRON is the only peginterferon product approved in Japan for which a blood test is not required before every injection.

In the Japanese clinical study supporting the approval, 48 weeks of PEG-INTRON and REBETOL combination therapy achieved a sustained virologic response (SVR)(1) rate of 48 percent in patients with HCV genotype 1 and high viral loads.  An SVR rate of 63 percent was achieved with PEG-INTRON and REBETOL in the portion of these patients who had relapsed following previous interferon treatment.

Hepatitis C is the leading cause in Japan of chronic liver disease, cirrhosis, and hepatocellular carcinoma, which is associated with more than 30,000 deaths there annually.  Hepatitis C is the most common reason for liver transplant in major world markets, including Japan, according to the World Health Organization (WHO).

PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life.  PEG-INTRON is a longer-acting form of INTRON(R) A (interferon alfa-2b, recombinant) injection.

REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.  Schering-Plough K.K. currently markets REBETOL in Japan for use in combination with INTRON A for chronic hepatitis C.

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 are at least 18 years of age.

Important Safety Information from the U.S. PEG-INTRON Label

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 six-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 percent of patients, which may decrease in severity as treatment continues.  Application site disorders were common (47 percent), but all were mild (44 percent) or moderate (4 percent) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation).  Injection site pain was reported in 2 percent 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 percent) with PEG-INTRON, but similar to INTRON A (58 percent).  Depression was most common at 29 percent.  Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1 percent 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 1 percent 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 percent in the PEG-INTRON/REBETOL groups compared to 14 percent in the INTRON A/REBETOL group.  The incidence of severe adverse events in the PEG-INTRON/REBETOL combination therapy trial was 23 percent in the INTRON A/REBETOL group and 31percent tp 34 percent in the PEG-INTRON/REBETOL groups.  Dose reductions due to adverse reactions occurred in 42 percent of patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in 34 percent of those receiving INTRON A/REBETOL.

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

INTRON A

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.
Source: Schering-Plough Corporation