FDA Approves Sylatron

FDA Approves Merck's Sylatron (peginterferon alfa-2b) for Injection, a New Adjuvant Treatment for Melanoma with Microscopic or Gross Nodal Involvement

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Apr 11, 2011 - Merck (known as MSD outside the United States and Canada) today announced that the U.S. Food and Drug Administration (FDA) has approved Sylatron (peginterferon alfa-2b) for injection, for subcutaneous use. Sylatron is indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, in patients with autoimmune hepatitis, and in patients with hepatic decompensation (Child-Pugh score >6 [class B and C]).

"Merck is pleased to offer patients with node-positive melanoma this new option to treat the disease," said Eric Rubin, M.D., vice president of clinical oncology at Merck. "This is the first such therapy approved for the adjuvant treatment of melanoma by the FDA in more than 15 years. Merck remains committed to further innovative research to help people suffering from cancer."

The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alpha interferons, including Sylatron. Sylatron should be permanently discontinued in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Sylatron.

Sylatron is a once-weekly subcutaneous injection that may be self-injected. The recommended dose is 6 mcg/kg/week subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously for up to 5 years. Patients should be premedicated with acetaminophen 500 to 1000 mg orally 30 minutes prior to the first dose of Sylatron and as needed for subsequent doses.

The Prescribing Information for Sylatron recommends the following dose modifications that are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 2.0):

  • Sylatron should be permanently discontinued for: persistent or worsening severe neuropsychiatric disorders; grade 4 non-hematologic toxicity; inability to tolerate a dose of 1 mcg/kg/week; new or worsening retinopathy.
  • Sylatron should be withheld for any of the following: absolute Neutrophil Count (ANC) <0.5x109/L; platelet Count (PLT) <50x109/L; ECOG PS =2; non-hematologic toxicity = Grade 3.
  • Sylatron should be resumed at a reduced dose (see Table 1 below) when all of the following are present: absolute Neutrophil Count (ANC) =0.5x109/L; platelet Count (PLT) =50x109/L; ECOG PS 0-1; non-hematologic toxicity has completely resolved or improved to Grade 1.

TABLE 1: Sylatron Dose Modifications

Starting Dose Dose Modifications for Doses 1 to 8
6 mcg/kg/week First Dose Modification: 3 mcg/kg/week
Second Dose Modification: 2 mcg/kg/week
Third Dose Modification: 1 mcg/kg/week
Permanently discontinue if unable to tolerate 1 mcg/kg/week
Starting Dose Dose Modifications for Doses 9 to 260
3 mcg/kg/week First Dose Modification: 2 mcg/kg/week
Second Dose Modification: 1 mcg/kg/week
Permanently discontinue if unable to tolerate 1 mcg/kg/week
Preparation and Administration of Sylatron

Sylatron should be reconstituted with 0.7 mL of Sterile Water for Injection USP. Upon reconstitution, the final concentration of Sylatron will be

  • 40 mcg per each 0.1 mL for vials containing 296 mcg of Sylatron
  • 60 mcg per each 0.1 mL for vials containing 444 mcg of Sylatron
  • 120 mcg per each 0.1 mL for vials containing 888 mcg of Sylatron

The Prescribing Information for Sylatron recommends the following when preparing Sylatron for use:

  • Swirl gently to dissolve the lyophilized powder. DO NOT SHAKE.
  • Visually inspect the solution for particulate matter and discoloration prior to administration. Discard if solution is discolored, cloudy, or if particulates are present.
  • Do not withdraw more than 0.5 mL of reconstituted solution from each vial.
  • Administer Sylatron subcutaneously. Rotate injection sites.
  • If reconstituted solution is not used immediately, store at 2°-8°C (36°-46°F) for no more than 24 hours. Discard reconstituted solution after 24 hours. DO NOT FREEZE.
  • For single-use only. DISCARD ANY UNUSED PORTION.

Clinical Trial Results

The approval of Sylatron is based on data from the European Organisation for the Research and Treatment of Cancer (EORTC) clinical trial, a large trial conducted in patients with node-positive melanoma, titled "Adjuvant Therapy with Pegylated Interferon Alfa-2b versus Observation in Resected Stage III Melanoma," which was published in the July 2008 issue of The Lancet.

The clinical trial was an open-label, multi-center, randomized study that evaluated the safety and efficacy of Sylatron in 1,256 patients with surgically resected, AJCC Stage III melanoma within 84 days of regional lymph node dissection. Patients were randomized to observation (no therapy) (n=629) or to Sylatron (n=627) at a dose of 6 mcg/kg by subcutaneous injection once weekly for 8 doses followed by a 3 mcg/kg subcutaneous injection once weekly for a period of up to 5 years total treatment. The dose of Sylatron was adjusted to maintain an ECOG Performance Status of 0 to 1.

In the study, ninety-four patients (16 percent) did not continue on to the 3 mcg/kg/week dosing regimen. Patients who continued on Sylatron after the initial 8 doses received 3 mcg/kg/week for a median duration of treatment of 14.3 months. Approximately half (52 percent) of the patients underwent dose reductions and 70 percent required dose delays (average delay 2.2 weeks).

The study's primary endpoint was Relapse-Free Survival (RFS), defined as the time from randomization to the earliest date of any relapse (local, regional, in-transit, or distant), or death from any cause. Based on 696 RFS events determined by the Independent Review Committee, the estimated hazard ratio (HR) for RFS was 0.82 (95 percent CI: 0.71, 0.96; unstratified log-rank p=0.011) in favor of patients treated with Sylatron. The median RFS was 34.8 months (95 percent CI: 26.1, 47.4) and 25.5 months (95 percent CI: 19.6, 30.8) in the patients treated with Sylatron compared with the patients in the observation group, respectively.

In the study, the most common adverse reactions with Sylatron versus observation were fatigue (94 percent versus 41 percent), increased ALT (77 percent versus 26 percent), increased AST (77 percent versus 26 percent), pyrexia (fever) (75 percent versus 9 percent), headache (70 percent versus 19 percent), anorexia (69 percent versus 13 percent), myalgia (muscle pain) (68 percent versus 23 percent), nausea (64 percent versus 11 percent), chills (63 percent versus 6 percent) and injection site reaction (62 percent versus 0 percent).

The most common serious adverse reactions were fatigue (7 percent), increased ALT (3 percent), increased AST (3 percent), and pyrexia (3 percent) in the group treated with Sylatron versus <1 percent in the observation group for these reactions.

Thirty-three percent of patients receiving Sylatron discontinued treatment due to adverse reactions.

Secondary endpoints of the study included Overall Survival (OS). There was no statistically significant difference in survival between Sylatron and the observation arms. Based on 525 deaths, the estimated hazard ratio of Sylatron versus observation was 0.98 (95 percent CI: 0.82, 1.16).

Select Important Safety Information about Sylatron

WARNING: Depression and other Neuropsychiatric Disorders

The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alpha interferons, including Sylatron. Permanently discontinue Sylatron in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Sylatron.

Sylatron is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b, autoimmune hepatitis, and hepatic decompensation.

Peginterferon alfa-2b can cause life-threatening or fatal neuropsychiatric reactions. These include suicide, suicidal and homicidal ideation, depression, and an increased risk of relapse of recovering drug addicts. Depression occurred in 59 percent of patients treated with Sylatron and 24 percent of patients in the observation group. Depression was severe or life-threatening in 7 percent of patients treated with Sylatron compared with <1 percent of patients in the observation arm.

Cardiac adverse reactions, including myocardial infarction, bundle-branch block, ventricular tachycardia, and supraventricular arrhythmia occurred in 4 percent of patients treated with Sylatron compared with 2 percent of patients in the observation group. Hypotension, cardiomyopathy, and angina pectoris have occurred in patients treated with peginterferon alfa-2b.

Peginterferon alfa-2b can cause decrease in visual acuity or blindness due to retinopathy. Retinal and ocular changes include macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons. The overall incidence of serious retinal disorders, visual disturbances, blurred vision, and reduction in visual acuity was <1 percent in both patients treated with Sylatron and those in the observation group.

Peginterferon alfa-2b increases the risk of hepatic decompensation and death in patients with cirrhosis.

Peginterferon alfa-2b can cause new onset or worsening of hypothyroidism, hyperthyroidism, and diabetes mellitus. Hypothyroidism developed in 1 percent of patients treated with Sylatron. The overall incidence of endocrine disorders was 2 percent in patients treated with Sylatron compared to <1 percent for patients in the observation group.

The most common adverse reactions in patients treated with Sylatron versus observation were fatigue (94 percent versus 41 percent), increased ALT (77 percent versus 26 percent), increased AST (77 percent versus 26 percent), pyrexia (75 percent versus 9 percent), headache (70 percent versus 19 percent), anorexia (69 percent versus 13 percent), myalgia (68 percent versus 23 percent), nausea (64 percent versus 11 percent), chills (63 percent versus 6 percent), and injection site reaction (62 percent versus 0 percent).

The most common serious adverse reactions in patients treated with Sylatron versus observation were fatigue (7 percent versus <1 percent), increased ALT (3 percent versus <1 percent), increased AST (3 percent versus <1 percent), and pyrexia (3 percent versus <1 percent).

When administering Sylatron with medications metabolized by CYP2C9 or CYP2D6, the therapeutic effect of these drugs may be altered.

There are no adequate and well-controlled studies of Sylatron in pregnant women. Use Sylatron during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether the components of Sylatron are excreted in human milk. Because of the potential for adverse reactions from the drug in nursing infants, a decision must be made whether to discontinue nursing or discontinue the Sylatron treatment.

Safety and effectiveness in patients below the age of 18 years have not been established.

About Merck Oncology

Merck is committed to advancing all aspects of cancer care – prevention, treatment and supportive care. Through strong internal research capabilities, selective alliances and acquisitions, and enabling technologies, Merck is looking to lead in the discovery, development and delivery of anticancer therapies. With respect to Sylatron specifically, Sylatron is a pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Please see Prescribing Information, including Boxed Warning about depression and other neuropsychiatric disorders, and Medication Guide for Sylatron. The Prescribing Information and Medication Guide are also available at http://www.merck.com/product/usa/pi_circulars/s/sylatron/sylatron_pi.pd and http://www.merck.com/product/usa/pi_circulars/s/sylatron/sylatron_mg.pdf.

Posted: April 2011

Sylatron (peginterferon alfa-2b) FDA Approval History

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