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Active ingredient: Peginterferon Alfa-2b

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Peginterferon Alfa-2b uses


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 Peginterferon Alfa-2b. Permanently discontinue Peginterferon Alfa-2b in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Peginterferon Alfa-2b .

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 Peginterferon Alfa-2b. Permanently discontinue Peginterferon Alfa-2b in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy. These disorders may not resolve after stopping Peginterferon Alfa-2b .

Warnings and Precautions
Depression and Other Serious Neuropsychiatric Adverse Reactions (5.1) 5/2015
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1 INDICATIONS AND USAGE

Peginterferon Alfa-2b 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.

Peginterferon Alfa-2b 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)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

Degree of Renal Impairment Creatinine Clearance (mL/min/1.73m2) Initial doses for 8 weeks Follow-up doses for 5 years
Moderate 30 – 50 4.5 mcg/kg/week 2.25 mcg/kg/week
Severe <30 3 mcg/kg/week 1.5 mcg/kg/week
End-Stage Renal Disease On dialysis 3 mcg/kg/week 1.5 mcg/kg/week

2.2 Dose Modification Guidelines

Guidelines for Dose Modification provided below are based on the National Cancer Institute Common Terminology Criteria for Adverse Events.

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 Peginterferon Alfa-2b with 0.7 mL of Sterile Water for Injection, USP.

Peginterferon Alfa-2b

Single-Use Vial

 Diluent (Sterile Water for Injection, USP) Deliverable Product and Volume Final Concentration
200 mcgTotal vial content of Peginterferon Alfa-2b is 296 mcg. add 0.7 mL = 200 mcg in 0.5 mL 40 mcg/0.1 mL
300 mcgTotal vial content of Peginterferon Alfa-2b is 444 mcg. add 0.7 mL = 300 mcg in 0.5 mL 60 mcg/0.1 mL
600 mcgTotal vial content of Peginterferon Alfa-2b is 888 mcg. add 0.7 mL = 600 mcg in 0.5 mL 120 mcg/0.1 mL
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3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

Peginterferon Alfa-2b is contraindicated in patients with:

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 Peginterferon Alfa-2b. Permanently discontinue Peginterferon Alfa-2b for suicidal or homicidal ideation, aggressive behavior towards others, or other severe or persistent psychiatric symptoms; institute psychiatric intervention and follow-up as appropriate.

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 Peginterferon Alfa-2b 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 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 Peginterferon Alfa-2b treatment in patients who experience changes in vision. Permanently discontinue Peginterferon Alfa-2b 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 Peginterferon Alfa-2b, then every 6 months while receiving Peginterferon Alfa-2b. Permanently discontinue Peginterferon Alfa-2b for evidence of severe (Grade 3) hepatic injury or hepatic decompensation (Child-Pugh score >6 [class B and C]) .

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 Peginterferon Alfa-2b, at 3 and 6 months following initiation, then every 6 months thereafter while receiving Peginterferon Alfa-2b. Permanently discontinue Peginterferon Alfa-2b in patients who develop hypothyroidism, hyperthyroidism or diabetes mellitus that cannot be effectively managed.

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6 ADVERSE REACTIONS

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


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.

6.1 Clinical Trials Experience

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.

The data described below reflect exposure to Peginterferon Alfa-2b in 608 patients with surgically resected, AJCC Stage III melanoma. Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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.

Serious adverse events were reported in 199 (33%) patients who received Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b as compared to the observation group are presented in Table 4.

Adverse Reaction Peginterferon Alfa-2b

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

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In a clinical study conducted in patients with melanoma, the incidence of binding antibodies to peg-interferon alfa-2b was approximately 35%. Among the patients who tested positive for binding antibodies, one patient developed neutralizing antibodies. The impact of antibody formation on pharmacokinetics, safety and efficacy of peg-interferon alfa-2b could not be assessed based on limited available data.

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 Peginterferon Alfa-2b 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, pulmonary hypertension, and pulmonary fibrosis

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome, toxic epidermal necrolysis, psoriasis

Vascular Disorders

hypertension, hypotension, stroke

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7 DRUG INTERACTIONS

Peginterferon Alfa-2b inhibits CYP1A2 and CYP2D6 activity. When caffeine (CYP1A2 substrate) or desipramine (CYP2D6 substrate) was coadministered with Peginterferon Alfa-2b (3 mcg/kg once weekly for two weeks), the exposure to caffeine increased 36% and the exposure to desipramine increased 30% as compared to when caffeine or desipramine was administered alone. Monitor for potential increased toxicities of drugs with a narrow therapeutic range metabolized by CYP1A2 or CYP2D6 when coadministered with Peginterferon Alfa-2b.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of Peginterferon Alfa-2b 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 Peginterferon Alfa-2b. Use Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

Peginterferon Alfa-2b has not been studied in patients with melanoma who have hepatic impairment. In patients treated for viral hepatitis, Peginterferon Alfa-2b treatment is contraindicated in those with moderate or severe hepatic impairment. Discontinue Peginterferon Alfa-2b if hepatic decompensation (Child-Pugh scores >6) occurs during treatment.

8.7 Renal Impairment

Reduce the dose of Peginterferon Alfa-2b by 25% in patients with moderate renal impairment (CLcr 30 to 50 mL/min/1.73m2) and 50% in patients with severe renal impairment (CLcr < 30 mL/min/1.73m2) or ESRD requiring dialysis . A study in subjects with varying degrees of renal impairment showed that the mean exposure (AUC) to Peginterferon Alfa-2b increased in subjects with moderate and severe renal impairment or ESRD requiring dialysis, as compared to subjects with normal renal function (CLcr > 80 mL/min/1.73m2) following a single 4.5 mcg/kg dose of Peginterferon Alfa-2b .

10 OVERDOSAGE

The experience with overdose of Peginterferon Alfa-2b is limited. Patients who were over dosed experienced the following adverse reactions: severe fatigue, headache, myalgia, neutropenia, and thrombocytopenia. The highest single dose administered was 14 mcg/kg.

11 DESCRIPTION

Peginterferon Alfa-2b, 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 Peginterferon Alfa-2b molecule is approximately 31,000 daltons. The specific activity of pegylated interferon alfa-2b is approximately 0.7 × 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).

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 was studied in 32 patients receiving adjuvant therapy for melanoma with Peginterferon Alfa-2b 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 AUCtau 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 AUCtau was 228 ng∙hr/mL (CV 24%) at week 4. The mean terminal half-life was approximately 43 hours (CV 19%).

Renal Impairment:

Renal clearance accounts for approximately 30% of total Peginterferon Alfa-2b clearance. The effect of renal impairment on the pharmacokinetics of Peginterferon Alfa-2b was studied in 24 subjects with normal or impaired renal function after a single 4.5 mcg/kg dose. Compared to subjects with normal renal function (CLcr > 80 mL/min/1.73 m2), the geometric mean AUClast to Peginterferon Alfa-2b increased by 1.4-fold in subjects with moderate renal impairment (CLcr 30 to 50 mL/min/1.73m2) and 2.1-fold in subjects with severe renal impairment (CLcr < 30 mL/min/1.73m2) or ESRD requiring dialysis .

No clinically meaningful amounts of Peginterferon Alfa-2b were removed during hemodialysis following a single 1 mcg/kg dose in subjects with renal impairment.

Drug Interactions:

Peginterferon Alfa-2b inhibits CYP1A2 and CYP2D6 activity. In a drug interaction study, healthy subjects received a dose of 200 mg of caffeine (CYP1A2 substrate), 2 mg of midazolam (CYP3A4 substrate), 500 mg of tolbutamide (CYP2C9 substrate), or 50 mg of desipramine (CYP2D6 substrate) before and after two doses of Peginterferon Alfa-2b administered subcutaneously at a dose of 3 mcg/kg. The geometric mean AUClast was increased by 36% for caffeine and 30% for desipramine when coadministered with Peginterferon Alfa-2b compared to caffeine or desipramine administered alone. No clinically meaningful changes in CYP2C9 activity and CYP3A4 activity were observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis:

Peginterferon Alfa-2b 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:

Peginterferon Alfa-2b 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 Peginterferon Alfa-2b on male fertility have not been studied.

14 CLINICAL STUDIES

The safety and effectiveness of Peginterferon Alfa-2b 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 Peginterferon Alfa-2b (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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b. Ninety-four patients (16%) did not continue on to the 3 mcg/kg/week dosing regimen.

Patients who continued on Peginterferon Alfa-2b 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b. Figure 1 shows the Kaplan-Meier curves of RFS.

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

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.

  • 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.
  • Remove the protective plastic cap from the tops of both the sterile water for injection (diluent) and the Peginterferon Alfa-2b vials. Clean the rubber stopper on the top of both vials with an alcohol swab.

  • Carefully remove the protective cap straight off of the needle to avoid damaging the needle point.
  • Fill the syringe with air by pulling back on the plunger to 0.7 mL.

  • 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.
    • Slowly inject all the air from the syringe into the air space above the diluent in the vial.
  • 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.
  • Remove the needle from the vial. Do not let the syringe touch anything.

  • Throw away the diluent vial.
  • Insert the needle through the center of the rubber stopper of the Peginterferon Alfa-2b powder vial. Do not touch the cleaned rubber stopper.
    • Place the needle tip, at an angle, against the side of the vial.
    • 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.
  • Remove the needle from the vial.
    • Firmly grasp the safety sleeve and pull it over the exposed needle until you hear a click. The green stripe on the safety sleeve will completely cover the red stripe on the needle. Dispose of the syringe, needle, and vial in the sharps disposal container. See "How should I dispose of used syringes, needles, and vials?" at the end of this Instructions for Use.
  • Gently swirl the vial in a gentle circular motion, until the Peginterferon Alfa-2b is completely dissolved (mixed together).
    • 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.
  • After the Peginterferon Alfa-2b 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. Dispose of the syringe and needle in the sharps disposal container. See the section "How should I dispose of used syringes, needles, and vials?" at the end of this Instructions for Use. Then, repeat steps 1 through 17 with a new vial of Peginterferon Alfa-2b and diluent to prepare a new syringe.
  • After the Peginterferon Alfa-2b powder completely dissolves, clean the rubber stopper again with an alcohol swab before you withdraw your dose.
  • 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.

    • Hold the Peginterferon Alfa-2b vial upright. Do not touch the cleaned top of the vial with your hands.

    • Insert the needle into the vial containing the Peginterferon Alfa-2b solution. Inject the air into the center of the vial.

  • Turn the Peginterferon Alfa-2b vial upside down. Be sure the tip of the needle is in the Peginterferon Alfa-2b solution.
    • Hold the vial and syringe with one hand. Be sure the tip of the needle is in the Peginterferon Alfa-2b solution. With the other hand, slowly pull the plunger back to fill the syringe with the exact amount of Peginterferon Alfa-2b into the syringe your healthcare provider told you to use.

  • 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 Peginterferon Alfa-2b back into the syringe. When you are ready to inject the medicine, remove the needle from the vial.


    • 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. 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.

    You should use a different site each time you inject Peginterferon Alfa-2b to help avoid soreness at any one site. Do not inject Peginterferon Alfa-2b 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 Peginterferon Alfa-2b?

    • 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.
    • 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.

      • 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 dispose of the syringe and needle in the sharps disposal container.
        • If there is bleeding, cover the injection site with a bandage.
        • Then, repeat steps 1 through 23 with a new vial of Peginterferon Alfa-2b and diluent to prepare a new syringe, and inject the medicine at a new site.
    • 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.
    • 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.

    • Dispose of the used syringes, needles, and vials in the sharps disposal container.
    How should I dispose of used syringes, needles, and vials?

    • Put your used syringes and needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes and needles in your household trash.
    • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
      • made of a heavy-duty plastic,
      • can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
      • upright and stable during use,
      • leak resistant, and
      • properly labeled to warn of hazardous waste inside the container.
    • When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to FDA's website at: http://www.fda.gov/safesharpsdisposal.

    • Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

      Always keep the sharps disposal container out of the reach of children.


    How should I store Peginterferon Alfa-2b?

    • Before mixing, store Peginterferon Alfa-2b vials at 59°F to 86°F (15°C to 30°C).
    • After mixing, use Peginterferon Alfa-2b 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 Peginterferon Alfa-2b that is not used within 24 hours.
    • Do not freeze Peginterferon Alfa-2b.

    • Keep Peginterferon Alfa-2b away from heat.

      Keep Peginterferon Alfa-2b and all medicines out of the reach of children.


    This Instructions for Use has been approved by the U.S. Food and Drug Administration.

    Manufactured by: Schering Corporation, a subsidiary of

    MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

    Revised: August 2014

    For patent information: www.merck.com/product/patent/home.html

    Copyright © 2011 Merck Sharp & Dohme Corp.,

    a subsidiary of Merck & Co., Inc.

    All rights reserved.

    usifu-mk4031-pwi-1408r009

    Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P Figure Q Figure R Figure S

    MEDICATION GUIDE

    Peginterferon Alfa-2b (SY-LA-TRON)

    (Peginterferon alfa-2b)

    Read this Medication Guide before you start taking Peginterferon Alfa-2b, 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 Peginterferon Alfa-2b?

    Peginterferon Alfa-2b can cause serious mental health problems which can lead to suicide.

    Peginterferon Alfa-2b may cause you to develop mood or behavior problems that may get worse during treatment with Peginterferon Alfa-2b or after your last dose. Call your healthcare provider right away if you, your family, or caregiver notice any of the following:

    • irritability (getting upset easily)
    • depression (feeling low, feeling bad about yourself, or feeling hopeless)
    • aggressive behavior, being angry or violent
    • thoughts of hurting yourself or others, or suicide

    Former drug addicts may fall back into drug addiction or overdose.

    If you have these symptoms, your healthcare provider should carefully monitor you during treatment with Peginterferon Alfa-2b and for 6 months after your last dose.

    If symptoms get worse or become severe and continue, your healthcare provider may tell you to stop taking Peginterferon Alfa-2b permanently. These signs or symptoms may not go away after you stop taking Peginterferon Alfa-2b.

    See " What are the possible side effects of Peginterferon Alfa-2b? " for more information about side effects.

    What is Peginterferon Alfa-2b?

    Peginterferon Alfa-2b 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. Peginterferon Alfa-2b should be started within 84 days of surgery to remove lymph nodes containing cancer.

    It is not known if Peginterferon Alfa-2b is safe and effective in children less than 18 years of age.

    Who should not take Peginterferon Alfa-2b?

    Do not take Peginterferon Alfa-2b:

    • 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 Peginterferon Alfa-2b?

    Before you take Peginterferon Alfa-2b, 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 hurting yourself or others or suicide attempts. See " What is the most important information I should know about Peginterferon Alfa-2b? "
    • have liver damage from drugs or cirrhosis or other liver disease
    • have kidney problems or are receiving kidney dialysis treatment
    • have ever been addicted to drugs or alcohol
    • 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 Peginterferon Alfa-2b will harm your unborn baby.
    • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you should use Peginterferon Alfa-2b 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.

    Peginterferon Alfa-2b 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 healthcare provider and pharmacist each time you get a new medicine.

    You should not start a new medicine before your talk with the healthcare provider who prescribes you Peginterferon Alfa-2b.

    How should I take Peginterferon Alfa-2b?

    • Take Peginterferon Alfa-2b exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much Peginterferon Alfa-2b to take and when to take it.
    • Do not take more than your prescribed dose. Call your healthcare provider right away if you take too much Peginterferon Alfa-2b.
    • Inject Peginterferon Alfa-2b one time each week unless instructed differently by your healthcare provider. Call your healthcare provider for instructions if you miss a dose.
    • Peginterferon Alfa-2b is given as an injection under your skin (subcutaneous injection). Your healthcare provider should show you how to prepare and measure your dose of Peginterferon Alfa-2b, and how to inject yourself before you use Peginterferon Alfa-2b for the first time.
    • Expect to get "flu-like" symptoms when taking Peginterferon Alfa-2b. To help reduce flu-like symptoms:
      • You should take 500 mg to 1,000 mg of acetaminophen 30 minutes before your first dose of Peginterferon Alfa-2b.
      • Follow your healthcare provider's instructions about taking acetaminophen before future doses of Peginterferon Alfa-2b.
      • Inject Peginterferon Alfa-2b at bedtime to help reduce flu-like symptoms.
      • Drink plenty of fluids.

    Your healthcare provider should do blood tests before you start and regularly during treatment with Peginterferon Alfa-2b.

    Your healthcare provider will monitor you while taking Peginterferon Alfa-2b. Based on this monitoring, your healthcare provider may:

    • Keep your prescribed dose the same;
    • Reduce your prescribed dose;
    • Tell you to skip a dose or doses; or
    • Tell you to stop taking Peginterferon Alfa-2b permanently.
    What are the possible side effects of Peginterferon Alfa-2b?

    Peginterferon Alfa-2b can cause serious side effects or worsen existing problems, including:

    See " What is the most important information I should know about Peginterferon Alfa-2b? ".

    • 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 Peginterferon Alfa-2b 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 Peginterferon Alfa-2b. 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 Peginterferon Alfa-2b?

    • Store Peginterferon Alfa-2b vials in the carton at 59°F to 86°F (15°C to 30°C).
    • After mixing, use Peginterferon Alfa-2b 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 Peginterferon Alfa-2b.

    Keep Peginterferon Alfa-2b and all medicines out of the reach of children.

    General information about the safe and effective use of Peginterferon Alfa-2b

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Peginterferon Alfa-2b for a condition for which it was not prescribed. Do not give Peginterferon Alfa-2b to other people, even if they have the same symptoms that you have. It may harm them.

    This Medication Guide summarizes the most important information about Peginterferon Alfa-2b. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Peginterferon Alfa-2b 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 Peginterferon Alfa-2b?

    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.

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

    Manufactured by: Schering Corporation, a subsidiary of

    MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

    Revised: May 2015

    For patent information: www.merck.com/product/patent/home.html

    Copyright © 2011 Merck Sharp & Dohme Corp.,

    a subsidiary of Merck & Co., Inc.

    All rights reserved.

    usmg-mk4031-pwi-1505r011

    Peginterferon Alfa-2b available forms, composition, doses:

    • N/A

    Indications and Usages:

    ATC codes:


    ICD-10 codes:

    • N/A

    Peginterferon Alfa-2b destination | category:

    • Human:
    • Interferons
    • Nucleosides and nucleotides

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    Drugs with same active ingredients (Pharmaceutical companies):


    References

    1. Dailymed."SYLATRON (PEGINTERFERON ALFA-2B) KIT [MERCK SHARP & DOHME CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
    2. "Peginterferon alfa-2b". https://pubchem.ncbi.nlm.nih.gov/su... (accessed August 28, 2018).
    3. "Peginterferon alfa-2b - DrugBank". http://www.drugbank.ca/drugs/DB0002... (accessed August 28, 2018).

    Frequently asked Questions

    Can i drive or operate heavy machine after consuming Peginterferon Alfa-2b?

    Depending on the reaction of the Peginterferon Alfa-2b after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Peginterferon Alfa-2b not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

    Is Peginterferon Alfa-2b addictive or habit forming?

    Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

    Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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    Review

    sdrugs.com conducted a study on Peginterferon Alfa-2b, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Peginterferon Alfa-2b consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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    The information was verified by Dr. Rachana Salvi, MD Pharmacology


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