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Biopharmaceuticals FDA

 News Release - March 11, 2009

FDA Approves an Expanded Indication for Peginterferon-Based Combination Therapy for Patients With Chronic Hepatitis C

New use for PEGINTRON(TM) and REBETOL(R) offers certain patients a second chance to achieve treatment success

KENILWORTH, N.J., March 11 (Healthcare Sales & Marketing Network) -- Schering-Plough Corporation (NYSE: SGP ) today announced that the U.S. Food and Drug Administration (FDA) has approved new labeling for PEGINTRON(TM) (peginterferon alfa-2b) and REBETOLĀ® (ribavirin, USP) combination therapy for treating chronic hepatitis C in patients 3 years of age and older with compensated liver disease. With approval of this expanded indication, PEGINTRON and REBETOL is the first and only pegylated interferon combination therapy approved in the United States that is not restricted to treatment-naive patients. Patients less likely to benefit from retreatment after failing a course of therapy include those with previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, or HCV genotype 1 infection. It is estimated that more than 100,000 patients in the United States failed prior treatment of their hepatitis C virus (HCV) infection, representing a large and growing patient population.

"With the FDA approval of PEGINTRON and REBETOL combination therapy for this new indication, U.S. physicians now have a treatment option that offers a second chance for success to certain patients who failed prior therapy," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "This approval further underscores Schering-Plough's leadership and long-term commitment to developing new treatment options and innovative therapies to meet the needs of patients with hepatitis C."

Data from the clinical study supporting the approval helped to define those patient groups most likely to respond to retreatment as well as those unlikely to respond. Overall, previous relapsers, patients with HCV genotype 2 or 3, or those initially treated with nonpegylated interferon therapy achieved higher rates of sustained virologic response (SVR)(1) than patients with previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, or HCV genotype 1 infection.

"Based on a patient's treatment history, physicians can identify which patients may be right for retreatment with PEGINTRON combination therapy and may have the best chance to achieve a sustained response," said Eugene R. Schiff, M.D., director, Center for Liver Diseases, University of Miami Miller School of Medicine, and a lead investigator for the clinical study on which the approval was based. "Conversely, patients with certain treatment characteristics who are unlikely to respond to this regimen can be advised accordingly."

In the clinical study supporting the approval, achievement of undetectable virus (HCV-RNA) at treatment week 12 was a strong predictor of SVR. Patients who still had detectable virus at week 12 of therapy were highly unlikely to achieve SVR.

"Patients with undetectable virus at week 12 have a better chance for success and can be motivated to continue treatment," Schiff added, "and those patients who fail to achieve an early response can have their therapy stopped with confidence, thus avoiding unnecessary treatment and potential adverse events."

The approval of PEGINTRON for the expanded indication is based on the results of one of the clinical studies in the EPIC3 program: a noncomparative trial in which 2,293 adult patients with moderate-to-severe fibrosis or cirrhosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with PEGINTRON (1.5 mcg/kg once weekly) in combination with weight-adjusted REBETOL (800-1,400 mg daily).(2) Eligible patients had received at least 12 weeks of combination therapy and included prior nonresponders (patients who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (patients who were HCV-RNA negative at the end of treatment and subsequently relapsed after post-treatment follow-up). In the study, patients who were HCV-RNA negative at week 12 were treated for a total of 48 weeks and followed for 24 weeks post-treatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.

The overall response rate in the study was 22 percent (497/2,293). Response rates among relapsers overall were 43 percent (130/300) and 35 percent (113/344) for patients previously treated with nonpegylated or pegylated alpha interferon and ribavirin combination therapy, respectively. The response rates in nonresponders overall were 18 percent (158/903) and 6 percent (30/476), respectively.

In the study, 1,470 (64 percent) patients did not achieve undetectable HCV-RNA at treatment week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36 percent) patients who were HCV-RNA undetectable at treatment week 12, those infected with HCV genotype 1 had an SVR rate of 48 percent (245/507), with a range of responses by fibrosis score (F4-F2) of 39-55 percent. Patients infected with HCV genotype 2 or 3 who were HCV-RNA undetectable at treatment week 12 had an overall SVR of 70 percent (196/281), with a range of responses by fibrosis score (F4-F2) of 60-83 percent. For all HCV genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

The recommended treatment duration with PEGINTRON combination therapy for patients who failed prior treatment is 48 weeks, regardless of HCV genotype. Retreated patients who have detectable HCV-RNA at week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Patients receiving PEGINTRON and REBETOL as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naive patients.

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 alone. It is the leading cause of cirrhosis and liver cancer, and the number one reason for liver transplants in the United States.


In the United States, PEGINTRON is indicated for use in combination with ribavirin in patients 3 years of age or older, and as monotherapy in patients 18 years of age and older, for the treatment of chronic hepatitis C in patients with compensated liver disease. Patients with the following characteristics are less likely to benefit from retreatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.

Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL

Alpha interferons, including PEGINTRON, 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 therapy.

Use with Ribavirin: Ribavirin may cause birth defects and 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.


PEGINTRON is contraindicated in patients with known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens Johnson syndrome and toxic epidermal necrolysis to interferon alpha 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. PEGINTRON/REBETOL combination therapy is additionally contraindicated in women who are pregnant or may become pregnant (see Boxed Warning and Pregnancy section), 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 per min.


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. If this drug is used during pregnancy or if a patient becomes pregnant, the patient should be apprised of the potential hazard to a fetus. 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

Most common adverse reactions (more than 40%) in adult patients receiving either PEGINTRON or PEGINTRON/REBETOL are injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and anxiety/emotional lability/irritability. Most common adverse reactions (more than 25%) in pediatric patients receiving PEGINTRON/REBETOL are pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema and vomiting.

In a study with PEGINTRON/REBETOL (weight-based) combination therapy in adult patients, anemia with weight-based dosing was 29%; however, the majority of these cases were mild and responded to dose reductions. The incidence of serious adverse reactions reported for the weight-based REBETOL group was 12%. In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some patients experienced ongoing or new serious adverse reactions during the 6-month follow-up period. Discontinuations for adverse events were 15% and were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. Dose modifications due to adverse reactions occurred in 29% of patients.

Most common adverse reactions with PEGINTRON/REBETOL (weight-based) combination therapy were psychiatric which occurred among 68-69% of patients. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts and suicides) occurred in 2% of all patients during treatment or during follow-up after treatment cessation. PEGINTRON induced fatigue or headache in approximately two-thirds of patients, with fever or rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. There was a 23-24% incidence overall for injection site reactions or inflammation.

Individual serious adverse reactions occurred at a frequency less than or equal to 1% and included suicide attempt, suicidal ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, angina, pericardial effusion, retinal ischemia, retinal artery or vein thrombosis, blindness, decreased visual acuity, optic neuritis, transient ischemic attack, supraventricular arrhythmias, loss of consciousness; neutropenia, infection (sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis obliterans, pleural effusion, gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with or without purpura, rheumatoid arthritis, interstitial nephritis, lupus-like syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection site necrosis, vasculitis and phototoxicity.

Additional serious adverse events included hallucinations. bipolar disorder, mania, encephalopathy (usually elderly treated with higher doses of PEGINTRON), hypotension, tachycardia, retinopathy including macular edema, retinal hemorrhage, cotton wool spots, papilledema, ischemic and hemorrhagic cerebrovascular events, bone marrow toxicity (cytopenia and very rarely aplastic anemia), thyroiditis, dental and periodontal disorders, hemorrhagic/ischemic colitis, dyspnea, pulmonary infiltrates, pneumonia, interstitial pneumonitis, hepatic failure, increases in serum creatinine in patients with renal insufficiency, acute hypersensitivity (angioedema, bronchoconstriction, anaphylaxis and cutaneous eruptions) and hypertriglyceridemia.

During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years receiving PEGINTRON/REBETOL combination therapy, weight loss and growth inhibition were common.

Patients receiving PEGINTRON and REBETOL as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naive patients.

Please see important full U.S. prescribing information and the Medication Guide for PEGINTRON at

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, animal health and consumer health care products. 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

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 uncertainties in the regulatory process, 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 Item 1A "Risk Factors" in Schering-Plough's 2008 10-K, filed Feb. 27, 2009.


(1) SVR is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment.

(2) EPIC3 (Evaluation of PEGINTRON in Control of Hepatitis C Cirrhosis), a large multicenter global clinical study evaluating the benefits of PEGINTRON in fibrotic and cirrhotic patients.

Source: Schering-Plough

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