FDA Approves Merck's SYLATRON™ (peginterferon alfa-2b) for Injection, a New Adjuvant Treatment for Melanoma with Mic

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-- Merck (NYSE:MRK) (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 attached 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.

ONCO-1003684-0000

SYLATRON is a trademark of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SYLATRON safely and effectively. See full prescribing information for SYLATRON.

 

SYLATRON (peginterferon alfa-2b)

for injection, for subcutaneous use

Initial U.S. Approval: 2011

 
 

WARNING: DEPRESSION AND OTHER NEUROPSYCHIATRIC DISORDERS

See full prescribing information for complete boxed warning.

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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

 

INDICATIONS AND USAGE

SYLATRON is an alpha interferon indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. (1)

DOSAGE AND ADMINISTRATION

  • 6 mcg/kg/week subcutaneously for 8 doses followed by;
  • 3 mcg/kg/week subcutaneously for up to 5 years. (2.1)

DOSAGE FORMS AND STRENGTHS

  • 296 mcg lyophilized powder per single-use vial
  • 444 mcg lyophilized powder per single-use vial
  • 888 mcg lyophilized powder per single-use vial

CONTRAINDICATIONS

  • Known serious hypersensitivity reactions to peginterferon alfa-2b or interferon alfa-2b. (4)
  • Autoimmune hepatitis. (4)
  • Hepatic decompensation (Child-Pugh score >6 [class B and C]). (4)

WARNINGS AND PRECAUTIONS

  • Depression and other serious neuropsychiatric adverse reactions. (5.1)
  • History of significant or unstable cardiac disease. (5.2)
  • Retinal disorders. (5.3)
  • Child-Pugh score >6 (class B and C). (4, 5.4)
  • Hypothyroidism, hyperthyroidism, hyperglycemia, diabetes mellitus that cannot be effectively treated by medication. (4, 5.5)

ADVERSE REACTIONS

Most common adverse reactions (>60%) are: fatigue, increased ALT, increased AST, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reaction. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Drug metabolized by cytochrome P-450 (CYP) enzymes: Monitor closely when used in combination with drugs metabolized by CYP2C9 or CYP2D6. (7)

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data, may cause fetal harm. (8.1)
  • Pediatrics: Safety and efficacy in patients <18 years old have not been established. (8.4)
  • Renal Impairment: Increase frequency of monitoring for SYLATRON toxicity in patients with moderate and severe renal impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 03/2011

_________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION: CONTENTS*

 

WARNING: RISK OF SERIOUS DISORDERS

1

 

INDICATIONS AND USAGE

2

DOSAGE AND ADMINISTRATION

2.1

  Recommended Dose

2.2

Dose Modification

2.3

Preparation and Administration

3

DOSAGE FORMS AND STRENGTHS

4

CONTRAINDICATIONS

5

WARNINGS AND PRECAUTIONS

5.1

Depression and Other Serious Neuropsychiatric Adverse Reactions

5.2

Cardiovascular Adverse Reactions

5.3

Retinopathy and Other Serious Ocular Adverse Reactions

5.4

Hepatic Failure

5.5

Endocrinopathies

6

ADVERSE REACTIONS

6.1

Clinical Trials Experience

6.2

Immunogenicity

6.3

Postmarketing Experience

7

DRUG INTERACTIONS

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

8.3

Nursing Mothers

8.4

Pediatric Use

8.5

Geriatric Use

8.6

Hepatic Impairment

8.7

Renal Impairment

10

OVERDOSAGE

11

DESCRIPTION

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

12.3

Pharmacokinetics

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

14

CLINICAL STUDIES

16

HOW SUPPLIED/STORAGE AND HANDLING

17

PATIENT COUNSELING INFORMATION

 

*Sections or subsections omitted from the full prescribing information are not listed.

 

_________________________________________________________________________________________________________________________

FULL PRESCRIBING INFORMATION

 

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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

1 INDICATIONS AND USAGE

SYLATRON is an alpha interferon indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

  • 6 mcg/kg/week subcutaneously for 8 doses, followed by 3 mcg/kg/week subcutaneously for up to 5 years.
  • Premedicate with acetaminophen 500 to 1000 mg orally 30 minutes prior to the first dose of SYLATRON and as needed for subsequent doses.

2.2 Dose Modification

Guidelines for Dose Modification provided below are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 2.0).

  • Permanently discontinue SYLATRON for:
    • Persistent or worsening severe neuropsychiatric disorders
    • Grade 4 non-hematologic toxicity
    • Inability to tolerate a dose of 1 mcg/kg/wk
    • New or worsening retinopathy
  • Withhold SYLATRON dose 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
  • Resume dosing at a reduced dose (see Table 1) 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

2.3 Preparation and Administration

Reconstitute SYLATRON 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
  • 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.

3 DOSAGE FORMS AND STRENGTHS

  • 296 mcg lyophilized powder per single-use vial
  • 444 mcg lyophilized powder per single-use vial
  • 888 mcg lyophilized powder per single-use vial

4 CONTRAINDICATIONS

SYLATRON is contraindicated in patients with:

  • A history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b
  • autoimmune hepatitis
  • hepatic decompensation (Child-Pugh score >6 [class B and C])

5 WARNINGS AND PRECAUTIONS

5.1 Depression and Other Serious Neuropsychiatric Adverse Reactions

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. In the clinical trial, depression occurred in 59% of SYLATRON-treated patients and 24% of patients in the observation group. Depression was severe or life threatening in 7% of SYLATRON-treated patients compared with <1% of patients in the observation arm.

In post-marketing experience, neuropsychiatric adverse reactions have been reported up to 6 months after discontinuation of peginterferon alfa-2b. Based on post-marketing experience with peginterferon alfa-2b and interferon alfa-2b, treatment may also result in aggressive behavior, psychoses, hallucinations, bipolar disorders, mania, and encephalopathy.

Advise patients and their caregivers to immediately report any symptoms of depression or suicidal ideation to their healthcare provider. Monitor and evaluate patients for signs and symptoms of depression and other psychiatric symptoms every 3 weeks during the first 8 weeks of treatment and every 6 months thereafter. Monitor patients during treatment and for at least 6 months after the last dose of SYLATRON. Permanently discontinue SYLATRON for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation.

5.2 Cardiovascular Adverse Reactions

In the clinical trial, cardiac adverse reactions, including myocardial infarction, bundle-branch block, ventricular tachycardia, and supraventricular arrhythmia occurred in 4% of SYLATRON-treated patients compared with 2% of patients in the observation group. In post-marketing experience, hypotension, cardiomyopathy, and angina pectoris have occurred in patients treated with peginterferon alfa-2b.

Permanently discontinue SYLATRON for new onset of ventricular arrhythmia or cardiovascular decompensation.

5.3 Retinopathy and Other Serious Ocular Adverse Reactions

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. In the clinical study, two SYLATRON-treated patients developed partial loss of vision due to retinal thrombosis (n=1) or retinopathy (n=1). The overall incidence of serious retinal disorders, visual disturbances, blurred vision, and reduction in visual acuity was <1% in both SYLATRON-treated patients and the observation group.

Perform an eye examination that includes assessment of visual acuity and indirect ophthalmoscopy or fundus photography at baseline in patients with preexisting retinopathy and at any time during SYLATRON treatment in patients who experience changes in vision. Permanently discontinue SYLATRON in patients who develop new or worsening retinopathy.

5.4 Hepatic Failure

Peginterferon alfa-2b, increases the risk of hepatic decompensation and death in patients with cirrhosis. Monitor hepatic function with serum bilirubin, ALT, AST, alkaline phosphatase, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation of SYLATRON, then every 6 months while receiving SYLATRON. Permanently discontinue SYLATRON for evidence of severe (Grade 3) hepatic injury or hepatic decompensation (Child-Pugh score >6 [class B and C]) [see Contraindications (4)].

5.5 Endocrinopathies

Peginterferon alfa-2b can cause new onset or worsening of hypothyroidism, hyperthyroidism, and diabetes mellitus. In the clinical study, 1% of patients developed hypothyroidism; the overall incidence of endocrine disorders was 2% in SYLATRON-treated patients compared to <1% for patients in the observation group.

Obtain TSH levels within 4 weeks prior to initiation of SYLATRON, at 3 and 6 months following initiation, then every 6 months thereafter while receiving SYLATRON. Permanently discontinue SYLATRON in patients who develop hypothyroidism, hyperthyroidism or diabetes mellitus that cannot be effectively managed.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Depression and Other Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.1)]
  • Cardiovascular Adverse Reactions [see Warnings and Precautions (5.2)]
  • Retinopathy and Other Serious Ocular Adverse Reactions [see Warnings and Precautions (5.3)]
  • Hepatic Failure [see Warnings and Precautions (5.4)]
  • Endocrinopathies [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

The data described below reflect exposure to SYLATRON in 608 patients with surgically resected, AJCC Stage III melanoma. SYLATRON was studied in an open label, multicenter, randomized, observation controlled trial. The median age of the population was 50 years with 10% of patients 65 years or older, and 42% were female. Fourteen percent of patients completed the 5 year treatment schedule.

Patients randomized to SYLATRON were to receive total doses of 48 mcg/kg (6 mcg/kg subcutaneous once weekly for 8 doses), and 780 mcg/kg (3 mcg/kg subcutaneous once weekly until disease recurrence or for up to 5 years), as tolerated. The median total dose received was 42 mcg/kg (range: 6 to 78 mcg/kg) for the first 8 doses, and 136 mcg/kg (range: 1 to 774 mcg/kg) for doses 9 to 260.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious adverse events were reported in 199 (33%) patients who received SYLATRON and 94 (15%) patients in the observation group.

The most common adverse reactions experienced by SYLATRON-treated patients were fatigue (94%), increased ALT (77%), increased AST (77%), pyrexia (75%), headache (70%), anorexia (69%), myalgia (68%), nausea (64%), chills (63%), and injection site reaction (62%). The most common serious adverse reactions were fatigue (7%), increased ALT (3%), increased AST (3%), and pyrexia (3%) in the SYLATRON-treated group vs. <1% in the observation group for these reactions.

Thirty three percent of patients receiving SYLATRON discontinued treatment due to adverse reactions. The most common adverse reactions present at the time of treatment discontinuation were fatigue (27%), depression (17%), anorexia (15%), increased ALT (14%), increased AST (14%), myalgia (13%), nausea (13%), headache (13%), and pyrexia (11%). Adverse events that occurred in the clinical study at ≥ 5% incidence in the SYLATRON-treated group and with a greater incidence in patients receiving SYLATRON as compared to the observation group are presented in Table 2.

TABLE 2: Incidence of Adverse Reactions(1) Occurring in ≥ 5% of Melanoma Patients Treated with SYLATRON and with a
Greater Incidence as Compared to Observation

 
Adverse Reaction       SYLATRON

N=608

  Observation

N=628

        All Grades

(%)

  Grade 3 and 4

(%)

  All Grades

(%)

  Grade 3 and 4

(%)

Any Adverse Reaction       100   51   82   18
                     
General Disorders and Administrative Site Conditions                    
Fatigue       94   16   41   1
Pyrexia       75   4   9   0
Chills       63   1   6   0
Injection Site Reaction       62   1.8   0   0
                     
Metabolic/Laboratory                    
ALT or AST Increased       77   11   26   1
Blood Alkaline Phosphatase Increased       23   0   11   <1
Weight Decreased       11   <1   1   <1
GGT Increased       8   4   1   <1
Proteinuria       7   0   3   0
Anemia       6   <1   2   <1
                     
Nervous System Disorders                    
Headache       70   4   19   1
Dysgeusia       38   0   1   0
Dizziness       35   2   11   <1
Olfactory Nerve Disorder       23   0   1   0
Paraesthesia       21   <1   14   <1
                     
Metabolism and Nutrition Disorders                    
Anorexia       69   3   13   0
                     
Musculoskeletal and Connective Tissue Disorders                    
Myalgia       68   4   23   <1
Arthralgia       51   3   22   1
                     
Gastrointestinal Disorders                    
Nausea       64   3   11   <1
Diarrhea       37   1   8   <1
Vomiting       26   1   4   0
                     
Psychiatric Disorders                    
Depression       59   7   24   <1
                     
Skin and Subcutaneous Tissue Disorders                    
Exfoliative Rash       36   1   4   0
Alopecia       34   0   1   0
                     
Respiratory, Thoracic and Mediastinal Disorders                    
Dyspnea       6   1   2   1
Cough       5   <1   2   0
   

1.

 

Adverse reactions were graded using NCI CTCAE, V.2.0.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The incidence of antibodies to peginterferon alfa-2b has not been studied in patients with melanoma. In clinical studies conducted in patients with chronic hepatitis C, the incidence of binding antibodies to peg-interferon alfa-2b was approximately 10% (174/1759). Among the patients tested positive for binding antibodies, 18% (32/174) developed neutralizing antibodies.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SYLATRON with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of peginterferon alfa-2b as monotherapy and in combination with ribavirin in chronic hepatitis C (CHC) patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

 

Blood and Lymphatic System Disorders

pure red cell aplasia, thrombotic thrombocytopenic purpura

Ear and Labyrinth Disorders

hearing loss, vertigo, hearing impairment

Endocrine Disorders

diabetic ketoacidosis

Eye Disorders

Vogt-Koyanagi-Harada syndrome

Gastrointestinal Disorders

aphthous stomatitis, pancreatitis, colitis

Infusion reactions

angioedema, urticaria, bronchoconstriction

Immune System Disorders

systemic lupus erythematosus, erythema multiforme, thyroiditis, thrombotic thrombocytopenic purpura, idiopathic
thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, and systemic lupus erythematosus

Infections

sepsis

Metabolism and Nutrition Disorders

hypertriglyceridemia

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, myositis

Nervous System Disorders

seizures, memory loss, peripheral neuropathy, paraesthesia, migraine headache

Respiratory, Thoracic and Mediastinal Disorders

dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, sarcoidosis and pulmonary hypertension

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis

Vascular Disorders

hypertension, hypotension, stroke
 

7 DRUG INTERACTIONS

In healthy subjects who were administered peginterferon alfa-2b subcutaneously at 1 mcg/kg once weekly for four weeks with probe drugs of metabolic enzymes administered before the first dose and after the fourth dose, a measure of CYP2C9 activity increased to 125% of baseline, whereas a measure of CYP2D6 activity decreased to 51% of baseline [see Clinical Pharmacology (12.3)].

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

The effects of pegylated interferon alfa-2b on the pharmacokinetics of drugs metabolized by cytochrome P-450 enzymes have not been studied at the higher clinical doses for patients with melanoma (3 mcg/kg/week and 6 mcg/kg/week).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of SYLATRON in pregnant women. Nonpegylated interferon alfa-2b was an abortifacient in Macaca mulatta (rhesus monkeys) at 15 and 30 million international units (IU)/kg (estimated human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60-kg adult). The estimated Intron A human equivalent dose of 5 to 10 million IU/kg daily is approximately equal to a human equivalent dose of 79 to 158 mcg/kg/week of SYLATRON. Use SYLATRON during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether the components of SYLATRON are excreted in human milk. Studies in mice have shown that mouse interferons are excreted in breast 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, taking into account the importance of the therapy to the mother.

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of SYLATRON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

SYLATRON has not been studied in patients with severe hepatic impairment. Peginterferon alfa-2b treatment is contraindicated in patients with viral hepatitis who have moderate or severe hepatic impairment (Child-Pugh scores >6). Discontinue SYLATRON if hepatic decompensation (Child-Pugh scores >6) occurs during treatment. [See Contraindications (4) and Warnings and Precautions (5.4).]

8.7 Renal Impairment

The mean area under the concentration-time curve (AUClast) following a single dose of peginterferon alfa-2b at 1 mcg/kg increased by 1.3-, 1.7- and 1.9-fold in subjects with mild (creatinine clearance 50-79 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 10-29 mL/min) renal impairment, respectively. After multiple doses, the mean AUCtau increased by 1.3-fold in moderate and 2.1-fold in severe renal impairment. No clinical meaningful amounts of peginterferon alfa-2b were removed during hemodialysis. Dose reductions of 25% and 50% are recommended in patients with moderate and severe renal impairment, respectively, receiving alpha interferons for chronic hepatitis C.

The effect of varying degrees of renal impairment on the pharmacokinetics of peginterferon alfa-2b at the recommended doses of 3 mcg/kg or 6 mcg/kg for patients with melanoma has not been studied. [See Dosage and Administration (2.2).]

10 OVERDOSAGE

The experience with overdose of SYLATRON is limited. Patients who were over dosed experienced the following adverse reactions: severe fatigue, headache, mylagia, neutropenia, and thrombocytopenia. The highest single dose administered was 14 mcg/kg.

11 DESCRIPTION

SYLATRON, peginterferon alfa-2b, is a covalent conjugate of recombinant alfa-2b interferon with monomethoxy polyethylene glycol (PEG). The average molecular weight of the PEG portion of the molecule is 12,000 daltons. The average molecular weight of the SYLATRON molecule is approximately 31,000 daltons. The specific activity of pegylated interferon alfa-2b is approximately 0.7 x 108 international units/mg protein.

Interferon alfa-2b is a protein with a molecular weight of 19,271 daltons produced by recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes.

Each vial contains either 296 mcg, 444 mcg or 888 mcg of peginterferon alfa-2b as a sterile, white to off-white lyophilized powder, and dibasic sodium phosphate anhydrous (1.11 mg), monobasic sodium phosphate dihydrate (1.11 mg), polysorbate 80 (0.074 mg), and sucrose (59.2 mg). Following reconstitution with 0.7 mL of Sterile Water for Injection USP, each vial contains SYLATRON at 40 mcg per 0.1 mL, 60 mcg per 0.1 mL, or 120 mcg per 0.1 mL.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Peginterferon alfa-2b is a pleiotropic cytokine; the mechanism by which it exerts its effects in patients with melanoma is unknown.

12.3 Pharmacokinetics

The pharmacokinetics were studied in 32 patients receiving adjuvant therapy for melanoma with SYLATRON according to the recommended dose and schedule (6 mcg/kg/week for 8 doses, followed by 3 mcg/kg/week thereafter). At a dose of 6 mcg/kg/week once weekly, the geometric mean Cmax was 4.4 ng/mL (CV 51%) and the geometric mean AUC(tau) was 430 ng•hr/mL (CV 35%) at week 8. The mean terminal half-life was approximately 51 hours (CV 18%). The mean accumulation from week 1 to week 8 was 1.7. After administration of 3 mcg/kg/week once weekly, the mean geometric Cmax was 2.5 ng/mL (CV 33%) and the geometric mean AUC(tau) was 228 ng•hr/mL (CV 24%) at week 4. The mean terminal half-life was approximately 43 hours (CV 19%).

Renal Dysfunction:

The disposition of peginterferon alfa-2b was studied in 26 subjects with varying degrees of renal function after administration of a single subcutaneous dose of peginterferon alfa-2b at 1 mcg/kg. Renal clearance accounts for approximately 30% of total peginterferon alfa-2b clearance. The AUClast increased by 1.3-, 1.7- and 1.9-fold in mild, moderate and severe renal impairment, respectively. The mean elimination half-life and maximal plasma concentration (Cmax) increased in subjects with renal impairment. The mean AUClast was similar in subjects with severe renal impairment on and not on hemodialysis, suggesting that no clinical meaningful amounts of peginterferon alfa-2b were removed during hemodialysis.

After subcutaneous administration of 1 mcg/kg of peginterferon alfa-2b once weekly for four weeks in 21 subjects with varying degrees of renal function, AUCtau at week 4 increased 1.3-fold in moderate and 2.1-fold in severe renal impairment. The Cmax at week 4 increased 1.8-fold in severe renal impairment, but no difference was observed in moderate renal impairment [see Use in Specific Populations (8.7)].

The effect of varying degrees of renal impairment on pharmacokinetics of peginterferon alfa-2b at 3 mcg/kg and 6 mcg/kg recommended for patients with melanoma has not been studied.

Drug Interactions:

In a two-way crossover trial, 12 healthy subjects were administered probe drugs of metabolic enzymes: caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), midazolam (CYP3A4), and dapsone (N-acetyltransferase, NAT), with or without a single subcutaneous (SC) dose of peginterferon alfa-2b at 1 mcg/kg. The results suggest that single doses of peginterferon alfa-2b do not affect activities of CYP1A2, CYP2C9, CYP2D6, CYP3A4 and NAT enzymes.

In 24 healthy subjects, the effect of subcutaneous doses of peginterferon alfa-2b at 1 mcg/kg/week for 4 weeks on the pharmacokinetics of caffeine, tolbutamide, dextromethorphan and midazolam were studied. A measure of CYP2C9 activity increased to 125% (90% CI: 116% to 135%) of baseline, whereas a measure of CYP2D6 activity decreased to 51% (90% CI: 38% to 67%) of baseline when coadministered with peginterferon alfa-2b at week 4, indicating that peginterferon alfa-2b may affect the metabolism of CYP2C9 and CYP2D6 drugs. A measure of CYP1A2 and CYP3A4 activity did not show clinically meaningful changes.

When patients are administered SYLATRON with medications metabolized by CYP2C9 or CYP2D6, the therapeutic effect of these drugs may be altered.

The effects of peginterferon alfa-2b at the clinical doses for melanoma (3 mcg/kg/week and 6 mcg/kg/week) on the systemic exposure of drugs metabolized by cytochrome P-450 enzymes have not been studied [see Drug Interactions (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis:

SYLATRON has not been tested for its carcinogenic potential. Neither peginterferon alfa-2b nor its components, interferon or methoxypolyethylene glycol, caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.

Impairment of Fertility:

SYLATRON may impair human fertility. Irregular menstrual cycles were observed in female cynomolgus monkeys given subcutaneous injections of 4239 mcg/m2 peginterferon alfa-2b alone every other day for 1 month (approximately 72 to 144 times the recommended weekly human dose based upon body surface area). These effects included transiently decreased serum levels of estradiol and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels resumed in these animals 2 to 3 months following cessation of peginterferon alfa-2b treatment. Every other day dosing with 262 mcg/m2 (approximately 3.5 to 7 times the recommended weekly human dose) had no effects on cycle duration or reproductive hormone status. The effects of SYLATRON on male fertility have not been studied.

14 CLINICAL STUDIES

The safety and effectiveness of SYLATRON were evaluated in an open-label, multicenter, randomized (1:1) study conducted in 1256 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.

The median age of the population was 50 years with 11% of patients 65 years or older, and 42% were female. Forty percent of the study population had microscopic, nonpalpable nodal involvement and 59% had clinically palpable nodes prior to lymphadenectomy. A total of 54% of subjects had one pathologically positive lymph node, 34% had 2 to 4 positive nodes, and 12% had 5 or more. Most subjects had no second primary lesion (98%). Ulceration of the primary lesion was present in 30% of subjects (52% had no ulceration of the primary lesion, and the status was missing/unknown for 18% of subjects). The most common sites were the trunk (43%) or the leg (32%). Eighty-four percent had an International Prognostic Index (IPI) score of 0 and 16% had an IPI score of 1. The main outcome measure 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. Secondary outcome measures included overall survival.

Patients in the SYLATRON arm received 6 mcg/kg/week for a median of 8.0 weeks. Less than 1% of patients took longer than 9 weeks to complete the 6 mcg/kg/week dosing regimen. Approximately one-third (36%) of patients required dose reductions and 29% of patients required a dose delay, with an average delay of 1.2 weeks, during the initial 8 weeks of SYLATRON. Ninety-four patients (16%) 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%) of the patients underwent dose reductions and 70% required dose delays (average delay 2.2 weeks).

Based on 696 RFS events, determined by the Independent Review Committee, median RFS was 34.8 months (95% CI: 26.1, 47.4) and 25.5 months (95% CI: 19.6, 30.8) in the SYLATRON and observation arms, respectively. The estimated hazard ratio for RFS was 0.82 (95% CI: 0.71, 0.96; unstratified log-rank p =0.011) in favor of SYLATRON. Figure 1 shows the Kaplan-Meier curves of RFS.

FIGURE 1: Kaplan-Meier Curves for Relapse-Free Survival

(Graphic Omitted)

There was no statistically significant difference in survival between the SYLATRON and the observation arms. Based on 525 deaths, the estimated hazard ratio of SYLATRON versus observation was 0.98 (95% CI: 0.82,1.16).

16 HOW SUPPLIED/STORAGE AND HANDLING

             
Each SYLATRON Package Contains:    

A box containing one 296 mcg vial of SYLATRON powder and one
1.25 mL vial of Sterile Water for Injection, USP, 2 B-D Safety Lok syringes
with a safety sleeve and 2 alcohol swabs.

  (NDC 0085-1388-01)

A box containing one 444 mcg vial of SYLATRON powder and one
1.25 mL vial of Sterile Water for Injection, USP, 2 B-D Safety Lok syringes
with a safety sleeve and 2 alcohol swabs.

  (NDC 0085-1287-02)

A box containing one 888 mcg vial of SYLATRON powder and one
1.25 mL vial of Sterile Water for Injection, USP, 2 B-D Safety Lok syringes
with a safety sleeve and 2 alcohol swabs.

  (NDC 0085-1312-01)
 
             
Each SYLATRON PACK 4 Contains:    

A box containing four 296 mcg vials of SYLATRON powder and four
1.25 mL vials of Sterile Water for Injection, USP, 8 B-D Safety Lok syringes
with a safety sleeve and 8 alcohol swabs.

  (NDC 0085-1388-02)

A box containing four 444 mcg vials of SYLATRON powder and four
1.25 mL vials of Sterile Water for Injection, USP, 8 B-D Safety Lok syringes
with a safety sleeve and 8 alcohol swabs.

  (NDC 0085-1287-03)

A box containing four 888 mcg vials of SYLATRON powder and four
1.25 mL vials of Sterile Water for Injection, USP, 8 B-D Safety Lok syringes
with a safety sleeve and 8 alcohol swabs.

  (NDC 0085-1312-02)
 

Storage:

SYLATRON should be stored at 25°C (77°F); excursions permitted to 15°-30°C (59-86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE.

17 PATIENT COUNSELING INFORMATION

  • See FDA-approved patient labeling (Instructions for Use and Medication Guide).
  • Advise patients that SYLATRON may be administered with antipyretics at bedtime to minimize common “flu-like” symptoms (including chills, fever, muscle aches, joint pain, headaches, tiredness).
  • Advise patients to maintain hydration if experiencing “flu-like” symptoms.
  • Advise patients and their caregivers to immediately report any symptoms of depression or suicidal ideation to their healthcare provider during treatment and up to 6 months after the last dose.
  • Use SYLATRON during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].
  • Instruct patients to not re-use or share syringes and needles.
  • Instruct patients on proper disposal of vials, syringes and needles.

_________________________________________________________________________________________________________________________

Manufactured by Schering Corporation
Kenilworth, NJ 07033 USA
 
U.S. Patent Nos. 5,951,974; 6,180,096; and 6,610,830.
 
BD and Safety-Lok are registered trademarks of Becton, Dickinson and Company.
 
Issued: March 2011
 
35039104T
B-35068309

MEDICATION GUIDE

SYLATRON™ (SY-LA-TRON)

(Peginterferon alfa-2b)

Read this Medication Guide before you start taking SYLATRON, and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about SYLATRON?

SYLATRON can cause serious mental health problems which can lead to suicide. Signs and symptoms can include:

  • depression (feeling so sad or hopeless that it interferes with your life or you have thoughts of hurting yourself)
  • aggressive behavior towards others, or thoughts of hurting others
  • memory changes and confusion

Call your healthcare provider if you have any of these signs or symptoms or if they get worse.

See “What are the possible side effects of SYLATRON?” for more information about side effects.

What is SYLATRON?

SYLATRON is a prescription medicine that is used to prevent malignant melanoma (a kind of skin cancer) from coming back after it has been removed by surgery. SYLATRON should be started within 84 days of surgery to remove lymph nodes containing cancer.

It is not known if SYLATRON is safe and effective in children less than 18 years of age.

Who should not take SYLATRON?

Do not take SYLATRON:

  • if you have had a serious allergic reaction to peginterferon alfa-2b or to interferon alfa-2b
  • if you have certain types of hepatitis
  • if you have severe liver damage

What should I tell my healthcare provider before taking SYLATRON?

Before you take SYLATRON, tell your healthcare provider about all of your health problems, including if you:

  • are being treated for a mental illness or had treatment in the past for mental illness, including depression or thoughts of suicide or suicide attempts. See “What is the most important information I should know about SYLATRON?
  • have severe liver damage from drugs or disease
  • have or had an overactive or underactive thyroid gland
  • have diabetes
  • have any other medical problem(s)
  • are pregnant or plan to become pregnant. It is not known if SYLATRON will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you should use SYLATRON or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

SYLATRON and certain other medicines may affect each other and cause side effects.

Know the medicines you take. Keep a list of them to show your doctors and pharmacists each time you get a new medicine.

You should not start a new medicine before your talk with the healthcare provider who prescribes you SYLATRON.

How should I take SYLATRON?

  • Take SYLATRON exactly as your healthcare provider tells you to.
  • SYLATRON is given as an injection under your skin (subcutaneous injection). Your healthcare provider should show you how to prepare and measure your dose of SYLATRON, and how to inject yourself before you use SYLATRON for the first time.
  • Do not take more than your prescribed dose. Call your healthcare provider right away if you take too much SYLATRON.
  • Inject SYLATRON one time each week unless instructed differently by your healthcare provider. Call your healthcare provider for instructions if you miss a dose.
  • Expect to get “flu-like” symptoms when taking SYLATRON. To help reduce flu-like symptoms:
    • You should take 500 mg to 1,000 mg of acetaminophen 30 minutes before your first dose of SYLATRON.
    • Follow your healthcare provider’s instructions about taking acetaminophen before future doses of SYLATRON.
    • Inject SYLATRON at bedtime to help reduce flu-like symptoms.

Your healthcare provider should do blood tests before starting and during treatment with SYLATRON.

It is important for you to keep all appointments with your healthcare provider. Call your healthcare provider if you miss an appointment. There may be special instructions for you.

What are the possible side effects of SYLATRON?

SYLATRON can cause serious side effects or worsen existing problems, including:

See “What is the most important information I should know about SYLATRON? ”.

  • Heart problems. Signs and symptoms can include:
    • fast heart rate or abnormal heart beat
    • trouble breathing or chest pain
  • Serious eye problems. Symptoms can include:
    • decrease in vision
    • blurred vision
  • Severe or worsening liver problems. Symptoms can include:
    • yellowing of your skin or the white part of your eyes
    • swelling of your stomach area (abdomen)
  • Thyroid problems. Signs and symptoms can include:
    • problems concentrating
    • feeling cold or hot all of the time
    • weight changes
  • High blood sugar (diabetes). Signs and symptoms can include:
    • increased thirst
    • urinating more often than normal
    • weight loss
    • your breath smells like fruit

Call your healthcare provider right away if you have any of these serious side effects.

The most common side effects of SYLATRON include:

  • flu-like symptoms, which may include fever, headache, tiredness, muscle or joint aches, chills, nausea, or loss of appetite
  • feeling sad or depressed
  • redness, swelling, or itching around the injection site
  • changes in blood tests measuring how your liver works

These are not all of the possible side effects of SYLATRON. For more information, ask your healthcare provider.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1–800–FDA–1088.

You may also report side effects to Schering Corporation at 1-800-526-4099.

How should I store SYLATRON?

  • Store SYLATRON vials in the carton at 59°F to 86°F (15°C to 30°C).
  • After mixing, use SYLATRON right away or store it in the refrigerator for no longer than 24 hours at 36°F to 46°F (2°C to 8°C).
  • Do not freeze SYLATRON.

Keep SYLATRON and all medicines out of the reach of children.

General information about the safe and effective use of SYLATRON

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SYLATRON for a condition for which it was not prescribed. Do not give to other people; it may harm them.

This Medication Guide summarizes the most important information about SYLATRON. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about SYLATRON that is written for healthcare professionals.

For more information, go to www.SYLATRON.com or call 1-800-526-4099.

What are the ingredients in SYLATRON?

Active ingredient: peginterferon alfa-2b

Inactive ingredients: dibasic sodium phosphate anhydrous, monobasic sodium phosphate dihydrate, polysorbate 80, sucrose, sterile water for injection is supplied as a diluent.

_________________________________________________________________________________________________________________________

The Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by Schering Corporation
Kenilworth, NJ 07033 USA
 
U.S. Patent Nos. 5,951,974; 6,180,096; and 6,610,830.
 
Issued: March 2011
31858704T

SYLATRON IFU Powder for Injection

Instructions for Use

 
SYLATRON (SY-LA-TRON)
(Peginterferon alfa-2b)
For Injection

Be sure that you read, understand and follow these instructions before injecting SYLATRON solution. Your healthcare provider should show you how to prepare, measure, and inject SYLATRON properly before you use it for the first time. Ask your healthcare provider if you have any questions.

Before starting, collect all of the supplies that you will need to use for preparing and injecting SYLATRON. For each injection you will need a SYLATRON vial package that contains:

  • 1 vial of SYLATRON powder
  • 1 vial of sterile water for injection (diluent)
  • 2 single-use disposable syringes (BD Safety Lok syringes with a safety sleeve)
  • 2 alcohol swabs

You will also need:

  • 1 cotton ball or gauze
  • a puncture-proof disposable container to throw away used syringes, needles, and vials.

Important:

  • Do not re-use or share syringes and needles.
  • The vial of mixed SYLATRON should be used right away. Do not mix more than 1 vial of SYLATRON at a time. If you do not use the vial of the prepared solution right away, store it in a refrigerator and use within 24 hours. See the end of these Instructions for Use for information about “How should I store SYLATRON?”
  • Make sure you have the right syringe and needle to use with SYLATRON. Your healthcare provider should tell you what syringes and needles to use to inject SYLATRON.

How should I prepare a dose of SYLATRON?

Before you inject SYLATRON, the powder must be mixed with 0.7 mL of the sterile water for injection (diluent) that comes in the SYLATRON vial package.

1. Find a clean, well-lit, flat work surface.

2. Get 1 of your SYLATRON vial packages. Check the date printed on the SYLATRON carton. Make sure that the expiration date has not passed. Do not use your SYLATRON vial packages if the expiration date has passed. The medicine in the SYLATRON vial should look like a white to off-white tablet that is whole, or in pieces, or powdered.

If you have already mixed the SYLATRON solution and stored it in the refrigerator, take it out of the refrigerator before use and allow the solution to come to room temperature.

3. Wash your hands well with soap and water, rinse and towel dry (see Figure 1). Keep your work area, your hands, and injection site clean to decrease the risk of infection.

(Graphic Omitted)

Figure 1

The disposable syringes have needles that are already attached and cannot be removed. Each syringe has a clear plastic safety sleeve that is pulled over the needle for disposal after use. The safety sleeve should remain tight against the flange while using the syringe and moved over the needle only when ready for disposal. (See Figure 2.)

(Graphic Omitted)

Figure 2

4. Remove the protective wrapper from one of the syringes provided. Use the syringe for steps 4 through 15. Make sure that the syringe safety sleeve is sitting against the flange. (See Figure 2.)

5. Remove the protective plastic cap from the tops of both the sterile water for injection (diluent) and the SYLATRON vials (see Figure 3). Clean the rubber stopper on the top of both vials with an alcohol swab.

(Graphic Omitted)

Figure 3

6. Carefully remove the protective cap straight off of the needle to avoid damaging the needle point.

7. Fill the syringe with air by pulling back on the plunger to 0.7 mL. (See Figure 4.)

(Graphic Omitted)

Figure 4

8. Hold the diluent vial upright. Do not touch the cleaned top of the vial with your hands.

  • Push the needle through the center of the rubber stopper of the diluent vial. (See Figure 5.)
  • Slowly inject all the air from the syringe into the air space above the diluent in the vial. (See Figure 6.)

(Graphic Omitted)

Figure 5

 

Figure 6

9. Turn the vial upside down and make sure the tip of the needle is in the liquid.

10. Withdraw only 0.7 mL of diluent by pulling the plunger back to the 0.7 mL mark on the side of the syringe. (See Figure 7.)

(Graphic Omitted)

Figure 7

11. With the needle still inserted in the vial, check the syringe for air bubbles.

  • If there are any air bubbles, gently tap the syringe with your finger until the air bubbles rise to the top of the syringe.
  • Slowly push the plunger up to remove the air bubbles.
  • If you push diluent back into the vial, slowly pull back on the plunger to draw the correct amount of diluent back into the syringe.

12. Remove the needle from the vial. (See Figure 8.) Do not let the syringe touch anything.

(Graphic Omitted)

Figure 8

13. Throw away the diluent vial.

14. Insert the needle through the center of the rubber stopper of the SYLATRON powder vial. Do not touch the cleaned rubber stopper.

  • Place the needle tip, at an angle, against the side of the vial. (See Figure 9.)
  • Slowly push the plunger down to inject the 0.7 mL diluent. The stream of diluent should run down the side of the vial.
  • To prevent bubbles from forming, do not aim the stream of diluent directly on the medicine in the bottom of the vial.
(Graphic Omitted)

Figure 9

15. Remove the needle from the vial.

  • Firmly grasp the safety sleeve and pull it over the exposed needle until you hear a click (see Figure 10). The green stripe on the safety sleeve will completely cover the red stripe on the needle. Discard the syringe, needle, and vial in the puncture-proof container.
(Graphic Omitted)

Figure 10

16. Gently swirl the vial in a gentle circular motion, until the SYLATRON is completely dissolved (mixed together). (See Figure 11.)

  • Do not shake the vial. If any powder remains undissolved in the vial, gently turn the vial upside down until all of the powder is dissolved.
  • The solution may look cloudy or bubbly for a few minutes. If air bubbles form, wait until the solution settles and all bubbles rise to the top.
(Graphic Omitted)

Figure 11

17. After the SYLATRON completely dissolves, the solution should be clear, colorless and without particles. It is normal to see a ring of foam or bubbles on the surface.

  • Do not use the mixed solution if you see particles in it, or it is not clear and colorless. Throw away the syringe and needle in the puncture-proof container. (See the section "How should I dispose of the used syringes, needles, and vials?".) Then, repeat steps 1 through 17 with a new vial of SYLATRON and diluent to prepare a new syringe.

18. After the SYLATRON powder completely dissolves, clean the rubber stopper again with an alcohol swab before you withdraw your dose.19. Unwrap the second syringe provided. You will use it to give yourself the injection.

19. Unwrap the second syringe provided. You will use it to give yourself the injection.

  • Carefully remove the protective cap from the needle. Fill the syringe with air by pulling the plunger to the number on the side of the syringe (mL) that matches your prescribed dose. (See Figure 12.)
(Graphic Omitted)

Figure 12

  • Hold the SYLATRON vial upright. Do not touch the cleaned top of the vial with your hands. (See Figure 13.)
(Graphic Omitted)

Figure 13

  • Insert the needle into the vial containing the SYLATRON solution. Inject the air into the center of the vial. (See Figure 14.)
(Graphic Omitted)

Figure 14

20. Turn the SYLATRON vial upside down. Be sure the tip of the needle is in the SYLATRON solution.

  • Hold the vial and syringe with one hand. Be sure the tip of the needle is in the SYLATRON solution. With the other hand, slowly pull the plunger back to fill the syringe with the exact amount of SYLATRON into the syringe your healthcare provider told you to use. (See Figure 15.)
(Graphic Omitted)

Figure 15

21. Check for air bubbles in the syringe. If you see any air bubbles, hold the syringe with the needle pointing up. Gently tap the syringe until the air bubbles rise. Then, slowly push the plunger up to remove any air bubbles. If you push solution into the vial, slowly pull back on the plunger again to draw the correct amount of SYLATRON back into the syringe. When you are ready to inject the medicine, remove the needle from the vial. (See Figure 16.)

(Graphic Omitted)

Figure 16

How should I choose a site for injection?

The best sites for giving yourself an injection are those areas with a layer of fat between the skin and muscle, like your thigh, the outer surface of your upper arm, and abdomen (see Figure 17). Do not inject yourself in the area near your navel or waistline. If you are very thin, you should only use the thigh or outer surface of the arm for injection.

(Graphic Omitted)

Figure 17

You should use a different site each time you inject SYLATRON to help avoid soreness at any one site. Do not inject SYLATRON solution into an area where the skin is irritated, red, bruised, infected or has scars, stretch marks, or lumps.

How should I inject a dose of SYLATRON?

22. Clean the skin where the injection is to be given with an alcohol swab. Wait for the area to dry.

  • Make sure the safety sleeve of the syringe is pushed firmly against the syringe flange so that the needle is fully exposed. (See Figure 2.)

23. With one hand, pinch a fold of skin. With your other hand, pick up the syringe and hold it like a pencil.

  • Insert the needle into the pinched skin at a 45- to 90-degree angle with a quick dart-like motion (see Figure 18).
(Graphic Omitted)

Figure 18

  • After the needle is inserted, remove the hand that you used to pinch your skin. Use it to hold the syringe barrel.
  • Pull the plunger of the syringe back very slightly.
  • If no blood is present in the syringe, inject the medicine by gently pressing the plunger all the way down the syringe barrel, until the syringe is empty.
  • If blood comes into the syringe, the needle has entered a blood vessel. Do not inject.
    • Withdraw the needle and throw away the syringe and needle in the puncture-proof container. (See step 24 and the disposal steps below.)
    • Then, repeat steps 1 through 23 with a new vial of SYLATRON and diluent to prepare a new syringe, and inject the medicine at a new site.

24. When the syringe is empty, pull the needle out of the skin.

  • Place a cotton ball or gauze over the injection site and press for several seconds. Do not massage the injection site.
  • If there is bleeding, cover it with a bandage.

25. After injecting your dose:

  • Firmly grasp the safety sleeve and pull it over the exposed needle until you hear a click, and the green stripe on the safety sleeve covers the red stripe on the needle (see Figure 19).
(Graphic Omitted)

Figure 19

26. Throw away the used syringe, needle, and SYLATRON vial(s) in the puncture-proof disposable container. (See “How should I dispose of the used syringes, needles, and vials?”.)

How should I dispose of the used syringes, needles, and vials?

  • Throw away used syringes, needles, and vials in a puncture-proof container, sharps container, or a hard container like a metal can with a lid. Always place needles facing down. Do not use glass or clear plastic containers. Always keep the puncture-proof container out of the reach of children.
  • Do not throw away used needles, syringes, or the puncture-proof container in household trash and do not recycle them.
  • Check with your healthcare provider for instructions about the right way to throw away used needles and syringes. There may be local or state laws about how to throw away used needles and syringes. Always follow the instructions of your healthcare provider.

How should I store SYLATRON?

  • Before mixing, store SYLATRON vials at 59°F to 86°F (15°C to 30°C).
  • After mixing, use SYLATRON right away or store it in the refrigerator for up to 24 hours between 36°F to 46°F (2°C to 8°C). Throw away any mixed SYLATRON that is not used within 24 hours.
  • Do not freeze SYLATRON.
  • Keep SYLATRON away from heat.
  • Keep SYLATRON and all medicines out of the reach of children.

_________________________________________________________________________________________________________________________

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Manufactured by Schering Corporation
Kenilworth, NJ 07033 USA
 
U.S. Patent Nos. 5,951,974; 6,180,096; and 6,610,830.
 
Issued: March 2011
35045104T



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