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FDA Approves Label Revisions Recommending New Robetol (ribavirin) Weight-Based Dosing Regimen:
PEGINTRON PLUS WEIGHT-BASED REBETOL (ribavirin) RESULTED IN HIGHER SVR THAN FLAT DOSING; LOW RELAPSE RATES IN PATIENTS WITH CHRONIC HEPATITIS C. Schering Plough press release
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SCHERING-PLOUGH CORPORATION PRESS RELEASE
THE FOLLOWING PRESS RELEASE WAS ISSUED TODAY BY GLOBAL COMMUNICATIONS:
KENILWORTH, N.J., March 27, 2008 - Schering-Plough Corporation (NYSE: SGP) today reported that the U.S. Food and Drug Administration (FDA) has approved label revisions for PEGINTRONTM (peginterferon alfa-2b) and REBETOL (ribavirin, USP) combination therapy for chronic hepatitis C, recommending weight-based dosing of REBETOL (800-1400 mg daily) based on patient body weight. The revised label also recommends a shorter, 24-week course of the combination therapy for patients with chronic hepatitis C virus (HCV) genotype 2 or 3.
The revisions represent the first FDA approval of a 1400 mg ribavirin dose and the widest ribavirin dosing range approved for use in combination with peginterferon for treating chronic hepatitis C in patients with compensated liver disease.
The label changes are based on the results of the WIN-R trial,1 the largest U.S. hepatitis C study, conducted in more than 4,900 patients. The study showed that PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800-1400 mg daily based on patient body weight) resulted in a significantly higher sustained virologic response (SVR)2 compared to PEGINTRON in combination with a flat 800 mg daily dose of REBETOL, the previously labeled dose. Importantly, the study reported low relapse rates consistent with other PEGINTRON studies.3,4
"PEGINTRON and weight-based ribavirin was significantly more effective than flat-dosed ribavirin, especially in genotype 1 patients, and provided consistent efficacy across all weight groups," said WIN-R principal investigator Ira M. Jacobson, M.D., Vincent Astor Professor of Clinical Medicine at Weill Medical College of Cornell University and chief of the division of gastroenterology and hepatology at New York Presbyterian Hospital/Weill Cornell Medical Center in New York City.
"It is reassuring to now have a validated, FDA-approved regimen that will allow us to use a novel 1400 mg ribavirin dose in our highest-weight hepatitis C patients, who previously were among the most difficult to treat successfully," said Robert S. Brown Jr., M.D., M.P.H., co-principal investigator of the
WIN-R study, and chief of the division of abdominal organ transplantation, New York-Presbyterian Hospital/Columbia University Medical Center.
In WIN-R (Weight-Based Dosing of PEGINTRON and REBETOL), SVR rates remained consistent with increased body weight for patients receiving weight-based REBETOL, but SVR decreased as body weight increased for patients receiving a flat-dose. The study also showed that for patients with HCV genotype 2 or 3, 24 weeks of weight-based dosed combination therapy was as effective as 48 weeks. For patients with genotype 1, 48 weeks of PEGINTRON and REBETOL combination therapy is recommended.
In the WIN-R study, there was a higher rate of anemia among patients in the weight-based dosing group compared to the flat-dosing group. The majority of these cases were mild and responded to dose reductions. There was no difference seen in the rate of serious adverse events between the two groups and there were similar rates of discontinuations for adverse events.
"We are very pleased with the FDA approval of these label revisions. Schering-Plough has long championed an individualized approach to hepatitis C treatment with weight-based PEGINTRON and REBETOL combination therapy to help optimize outcomes for patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "Further underscoring this individualized approach, we recently reported results of another larger study in more than 3,000 U.S. patients, known as the IDEAL study,4 which also confirmed the efficacy and low relapse rate of PEGINTRON in combination with weight-based REBETOL."
WIN-R was an investigator-initiated clinical study supported by Schering-Plough Corporation as part of a post-marketing commitment to the FDA.
About Hepatitis C
Hepatitis C is a serious and potentially life-threatening disease. It is the most common blood-borne infection in America and the most common form of liver disease, affecting nearly 5 million people in the United States and some 170 million people worldwide. It is the leading cause of cirrhosis and liver cancer, and the number one reason for liver transplants in the United States.
About PEGINTRON
In the United States, PEGINTRON is indicated for use alone or with ribavirin 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 PEGINTRON and REBETOL
Alpha interferons, including PEGINTRON 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 PEGINTRON and/or INTRON A therapy.
Use with Ribavirin: Ribavirin may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen
Contraindications
PEGINTRON is contraindicated in patients with hypersensitivity to PEGINTRON or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. INTRON A (Interferon alfa-2b, recombinant) for Injection is contraindicated in patients with hypersensitivity to INTRON A or any component of the product, autoimmune hepatitis, and decompensated liver disease. PEGINTRON or INTRON A in combination with REBETOL therapy is additionally contraindicated in patients with hypersensitivity to ribavirin or any other component of the product, women who are pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL/min.
Avoid Pregnancy
REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during therapy and 6 months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 months after completion of therapy. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
Incidence of Adverse Events
There are no new adverse events specific to PEGINTRON 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 PEGINTRON 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 PEGINTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEGINTRON.
Psychiatric adverse events, which include insomnia, were common (57%) with PEGINTRON 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 PEGINTRON.
The following serious or clinically significant adverse events have been reported at a frequency less than 1% with PEGINTRON 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 PEGINTRON/REBETOL combination trial, the incidence of serious adverse events was 17% in the PEGINTRON/REBETOL groups compared to 14% in the INTRON A/ REBETOL group. The incidence of severe adverse events in the PEGINTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEGINTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL.
Additional Safety Information
Relapse of drug addiction/overdose has occurred in patients on PEGINTRON therapy. Aggressive behavior sometimes directed towards others has occurred in patients with and without a previous psychiatric disorder during PEGINTRON and/or INTRON A treatment and follow-up. If patients develop psychiatric problems, including clinical depression, it is recommended that patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with PEGINTRON and/or INTRON A be discontinued, and the patient be carefully followed with psychiatric intervention, as appropriate. Cases of encephalopathy have been observed in some patients, usually elderly, treated with higher doses of PEGINTRON and/or INTRON A. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha therapies, including PEGINTRON and INTRON A. Dental and periodontal disorders have been reported in patients receiving PEGINTRON or INTRON A in combination with REBETOL therapy.
About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription and consumer products as well as to animal health products. In November 2007, Schering-Plough acquired Organon BioSciences, with its Organon human health and Intervet animal health businesses, marking a pivotal step in the company's ongoing transformation. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is
www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the potential market for PEGINTRON and REBETOL. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part I, Item 1A. "Risk Factors" in Schering-Plough's 2007 10-K/A.
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References:
1 Jacobson IM, et al. Peginterferon alfa-2b and Weight-Based or Flat-Dose Ribavirin in Chronic Hepatitis C Patients: A Randomized Trial. Hepatology 2007; 46:971-981.
2 p=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [weight-based dose or flat dose], genotype and presence/absence of advanced fibrosis, in the model).
3 Manns MP, et al. Peginterferon alfa-2b plus Ribavirin Compared with Interferon alfa-2b plus Ribavirin for Initial Treatment of Chronic Hepatitis C: A Randomized Trial. Lancet 2001;358:958-965.
4 The IDEAL (Individualized Dosing Efficacy vs. Flat Dosing to Assess optimaL pegylated interferon therapy) study. Schering-Plough press release, Jan. 14, 2008.
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