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EU Label Change for Intron A (Interferon Alfa-2b) Incorporates Long-Term Efficacy Data in Patients with Chronic Hepatitis C

Five-Year Follow-Up Data Demonstrate Sustained Viral Response Results in Long-Term Clearance of the Virus and Clinical 'Cure'

KENILWORTH, N.J. -- April 26, 2006 -- Schering-Plough Corporation today reported that the European Commission has adopted changes to the European Union (EU) label for Intron(R) A (interferon alfa-2b) based on long-term efficacy data from a large, 5-year follow-up study to evaluate the durability of sustained virological response (SVR)(1) in patients treated for chronic hepatitis C virus infection (HCV).

This large study confirms that sustained loss of serum HCV RNA six months following the completion of treatment with nonpegylated interferon alfa-2b (with or without ribavirin) is a strong predictor of long-term clearance of the virus, providing resolution of the hepatic infection and clinical "cure" from chronic HCV. However, long-term clearance of the virus does not preclude the occurrence of hepatic events in patients with cirrhosis, including hepatocarcinoma.

"This large study involving more than 1,000 hepatitis C patients demonstrates that, even with close follow-up over a 5-year period, patients who have achieved an SVR have essentially no evidence of clinical or virological disease," said John McHutchison, MD, Duke University, and lead investigator of the study. "Recognition of this durability of response underscores the efficacy of interferon-based antiviral therapy. Furthermore, it may help motivate hepatitis C patients to seek treatment and provides physicians confidence that they are giving their patients a meaningful chance for a cure."

In the study, 1,071 patients were enrolled after completing prior treatment with nonpegylated interferon alfa-2b (with or without ribavirin). Of these, 492 patients achieved an SVR and only 12 relapsed during the follow- up period. In all, 446 patients completed at least five years of long-term follow-up. The Kaplan-Meier estimate for continued sustained response over five years for all patients in the study is 97% with a 95% Confidence Interval of (95 %, 99 %).

A similar long-term follow-up study with pegylated interferon alfa-2b (PEG-Intron(R)) is ongoing.

About Interferon Alfa-2b
Interferon alfa-2b is a recombinant version of naturally occurring alpha interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering-Plough markets interferon alfa-2b (brand name Intron A in most countries) for 16 major antiviral and anticancer indications worldwide. Schering-Plough also markets a longer-acting, once-weekly pegylated version of interferon alfa-2b called PEG-Intron (peginterferon alfa-2b), for use as monotherapy or in combination therapy with Rebetol(R) (ribavirin, USP) for the treatment of chronic hepatitis C in patients with compensated liver disease who are at least 18 years of age.

Chronic hepatitis C is estimated to affect more than 10 million people in major world markets, including 5 million in Europe. It is a leading cause of chronic liver disease and one of the most common reasons for liver transplant in Europe.

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 the accepted criterion for assessing efficacy in HCV therapy and is defined as undetectable virus (HCV RNA) levels 24 weeks after the end of treatment.


SOURCE: Schering-Plough Corporation

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