FDA Advisory Committee Recommends Approval of PEGINTRON(R) for the Adjuvant Treatment of Stage III Malignant Melanoma
10/5/2009 1:28:00 PM
GAITHERSBURG, Md., Oct. 5, /PRNewswire-FirstCall/ -- Schering-Plough Corp. (NYSE: SGP) announced today that the U.S. Food and Drug Administration's (FDA) Oncologic Drugs Advisory Committee (ODAC) recommended approval by a vote of six to four for PEGINTRON® (pegylated interferon alfa-2b) in the adjuvant treatment of patients with Stage III malignant melanoma.
PEGINTRON is a longer-acting form of the protein interferon alfa-2b (INTRON® A). PEGINTRON is administered subcutaneously once-weekly via self-injection.
"Treating malignant melanoma remains a challenge given the limited treatment options that are currently available," said John M. Kirkwood, M.D., Director of the Melanoma Center and Professor and Chief of the Division of Medical Oncology at the University of Pittsburgh School of Medicine, Pittsburgh. "Today's positive recommendation of pegylated interferon alfa-2b by the committee represents an important step toward a potential new option in the treatment of Stage III malignant melanoma, especially as the incidence of the disease continues to increase."
The FDA generally follows the recommendations of its advisory committees, although it is not required to do so. Schering-Plough filed the supplemental Biologics License Application (sBLA) for this indication to the FDA in September 2007.
"The committee's positive recommendation for PEGINTRON is an encouraging development toward the future treatment of melanoma," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "Schering-Plough remains committed to developing new therapies for the treatment of malignant melanoma, as well as for advancing the understanding and prevention of this aggressive form of cancer."
About Malignant Melanoma
Malignant melanoma is the deadliest form of skin cancer. The American Cancer Society estimates that in the United States in 2009 there will be 68,720 new cases of malignant melanoma, and approximately 8,650 people will die from this disease.
About The Melanoma Trial
The efficacy and safety of PEGINTRON was assessed in a trial led by the European Organisation for the Research and Treatment of Cancer (EORTC) and implemented in 101 sites across Europe. In this randomized, controlled trial of 1,256 melanoma patients, pegylated interferon alfa-2b (N=627) vs. observational arm (N=629) had a significant and sustained impact on relapse-free survival (RFS). Median RFS was 34.8 months in the pegylated interferon alfa-2b arm vs. 25.5 months in the observational arm (p-value 0.01).
In this trial, patients receiving PEGINTRON experienced mild-to-moderate or severe side effects. The most common side effects of PEGINTRON are: fatigue, elevations in blood liver function tests, depression, flu-like symptoms (including fever and chills, headache, aches and pains, loss of appetite, nausea); a reaction at the site of injection; changes in hematology tests, including neutropenia (low neutrophil count), anemia (low hemoglobin) and thrombocytopenia.
Pegylated interferon alfa-2b is a longer-acting form of interferon alfa-2b made by attaching an inert molecule called polyethylene glycol, or PEG, to the interferon alfa-2b molecule. This modification increases the size of the interferon molecule and results in slower elimination from the body, allowing for less frequent dosing than required for standard interferon.
Pegylated interferon alfa-2b is not approved for treatment of melanoma in the U.S. and is marketed as PEGINTRON® for other indications in the U.S. Full prescribing information in the U.S. may be found at http://www.spfiles.com/pipeg-intron.pdf.
U.S. Indications for PEGINTRON
PEGINTRON is indicated in the U.S. for use in combination with REBETOL® (ribavirin) for the treatment of chronic hepatitis C in patients 3 years of age and older with compensated liver disease.
The following points should be considered when initiating therapy with PEGINTRON in combination with REBETOL: (1) These indications are based on achieving undetectable HCV RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. (2) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No safety and efficacy data are available for treatment of longer than one year.
PEGINTRON is also indicated in the U.S. for use alone for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha and who are at least 18 years of age.
The following points should be considered when initiating therapy with PegIntron alone: Combination therapy with REBETOL is preferred over PEGINTRON monotherapy unless there are contraindications to, or significant intolerance of, REBETOL. Combination therapy provides substantially better response rates than monotherapy.
Important U.S. Safety Information on PEGINTRON
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS
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 >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 (eg, thalassemia major, sickle-cell anemia); and patients with creatinine clearance < 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 posttreatment. 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 (>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 (>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 (eg, 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 (eg, 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 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 suicide, homicidal ideation, aggressive behavior sometimes directed towards others, hallucinations, bipolar disorders, mania, encephalopathy (usually elderly treated with higher doses of PEGINTRON), hypotension, tachycardia, retinopathy including macular edema, retinal hemorrhage, cotton wool spots, papilledema, serous retinal detachment, 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, pulmonary hypertension, hepatic failure, increases in serum creatinine in patients with renal insufficiency, acute hypersensitivity (angioedema, bronchoconstriction, anaphylaxis and cutaneous eruptions), hypertriglyceridemia, and peripheral neuropathy.
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.
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 www.schering-plough.com.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this media alert includes certain "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including statements relating to clinical development of investigational oncology compounds. 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 II, Item 1A. "Risk Factors" in the Company's second quarter 2009 10-Q, filed July 24, 2009.
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