AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Peginterferon Alfa-2b

• Peginterferon Alfa

Peginterferon alfa contains interferon alfa (recombinant DNA origin) covalently bound to monomethoxy polyethylene glycol (PEG).2 Peginterferon alfa-2b is used as an antineoplastic agent.2 Peginterferon alfa-2a and peginterferon alfa-2b are used as antiviral agents (see Peginterferon Alfa 8:18.20).1,20 For information on nonconjugated interferon alfa, see Interferon Alfa 8:18.20 and Interferon Alfa 10:00.

Melanoma

Peginterferon alfa-2b (Sylatron^®) is used as an adjuvant to surgery for the treatment of melanoma in adults with microscopic or gross nodal involvement who have undergone definitive surgical resection including complete lymphadenectomy.2 Adjuvant treatment with peginterferon alfa-2b should be initiated in such patients within 84 days of surgery.2

Efficacy and safety of peginterferon alfa-2b for the adjuvant treatment of melanoma were evaluated in a phase 3, open-label, randomized controlled study (EORTC 18991).2,430,431 Adults with surgically resected stage 3 melanoma were randomized (within 84 days of regional lymph node dissection) to observation alone or treatment with peginterferon alfa-2b (Sylatron^®; 6 mcg/kg subcutaneously once weekly for 8 weeks [induction], then 3 mcg/kg subcutaneously once weekly for up to 5 years [maintenance]).2,430,431 Demographics and baseline characteristics were similar between groups (median age 50 years, 42% female, 54% with 1 pathologically positive lymph node, 34% with 2-4 positive nodes, 12% with 5 or more positive nodes).2,430,431 Patients randomized to the peginterferon alfa-2b group received the induction dosage of 6 mcg/kg once weekly for a median of 8 weeks; during this time, 36% of patients required dosage reductions, 29% required dosage delays (average delay 1.2 weeks), and 16% did not continue on to the maintenance dosage.2 Of the patients who continued to the maintenance dosage of 3 mcg/kg once weekly, the median duration of treatment was 14.3 months; during this time, 52% of patients required dosage reductions and 70% required dosage delays (average delay 2.2 weeks).2 The median relapse-free survival was 34.8 months in the peginterferon alfa-2b group and 25.5 months in the observation group.2 There was no statistically significant difference in survival between the peginterferon alfa-2b group and the observation group.2

General

Several peginterferon alfa subtypes (alfa-2a, alfa-2b), dosage forms, and strengths are commercially available, and care should be taken to ensure that the correct preparation is used.1,2,20

Of the commercially available peginterferon alfa preparations, only peginterferon alfa-2b (Sylatron^®) should be used for adjuvant treatment of melanoma.2 Patients should be cautioned not to change brands of peginterferon alfa without consulting their clinician.20

Reconstitution and Administration

Peginterferon alfa-2b is administered by subcutaneous injection once weekly.2

Subcutaneous injections of peginterferon alfa-2b should be made into the thigh, outer surface of the upper arm, or abdomen (avoiding areas of the navel and waistline).2 Injection sites should be rotated.2

Peginterferon alfa-2b may be self-administered if the clinician determines that the patient and/or their caregiver are competent to safely administer the drug after appropriate training and with medical follow-up as necessary.2 Patients and/or their caregivers who administer peginterferon alfa-2b in a home setting should be carefully instructed in the proper administration of the drug, including aseptic technique.2 They should be cautioned against reuse of syringes and needles and should be given instruction regarding the proper, safe disposal of such equipment after use.2

Administration of peginterferon alfa-2b (Sylatron^®) with an antipyretic at bedtime may minimize adverse flu-like effects.2 The manufacturer recommends administration of acetaminophen 0.5-1 g orally 30 minutes prior to the first dose of peginterferon alfa-2b and as needed for subsequent doses.2

Single-dose vials containing lyophilized peginterferon alfa-2b should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C; the drug should not be frozen or exposed to heat.2

Peginterferon alfa-2b lyophilized powder for injection must be reconstituted prior to administration using only sterile water for injection.2 Prior to reconstitution, peginterferon alfa-2b should appear as a white to off-white powder.2 Single-dose vials labeled as containing 200, 300, or 600 mcg of peginterferon alfa-2b per 0.5 mL contain 296, 444, or 888 mcg of lyophilized drug, respectively.2

Peginterferon alfa-2b in single-dose vials should be reconstituted by adding 0.7 mL of the sterile water diluent provided by the manufacturer and gently swirling the vial; the vial should not be shaken.2

Reconstituted peginterferon alfa-2b should be inspected visually for particulate matter and discoloration prior to administration; the solution should be clear and colorless and should not be used if discolored or cloudy or if particulates are present.2

If the reconstituted solution is not used immediately, it may be stored for up to 24 hours at 2-8°C; the solution should not be frozen.2

No more than 0.5 mL of reconstituted solution should be withdrawn from each vial.2 Peginterferon alfa-2b vials are for single-use only; any unused portions should be discarded.2

Dosage

Dosage modification may be necessary if adverse effects occur.2 (See Dosage and Administration: Dosage Modification for Toxicity.)

Melanoma

When peginterferon alfa-2b (Sylatron^®) is used as an adjuvant to surgery for treatment of melanoma in adults with microscopic or gross nodal involvement who have undergone definitive surgical resection including lymphadenectomy, the recommended dosage is 6 mcg/kg subcutaneously once weekly for 8 doses (induction), followed by 3 mcg/kg subcutaneously once weekly for up to 5 years (maintenance).2 Peginterferon alfa-2b should be initiated within 84 days of surgery.2

Dosage Modification for Toxicity

Peginterferon alfa-2b (Sylatron^®) should be permanently discontinued if the patient experiences persistent or worsening severe neuropsychiatric disorders, develops grade 4 nonhematologic toxicity, is unable to tolerate a dosage of 1 mcg/kg once weekly, or develops new or worsening retinopathy.2

Peginterferon alfa-2b should be withheld if the patient has an absolute neutrophil count (ANC) less than 500/mm³, platelet count less than 50,000/mm³, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, or grade 3 or higher nonhematologic toxicity.2,432 Peginterferon alfa-2b may be resumed using a reduced dosage when the patient exhibits all of the following: ANC 500/mm³ or greater, platelet count 50,000/mm³ or greater, ECOG performance status 0 or 1, and nonhematologic toxicity that has completely resolved or improved to grade 1.2,432

If dosage modification of peginterferon alfa-2b is required during weeks 1-8 of treatment (induction) because of adverse reactions, a 3-step decrease from the original dosage of 6 mcg/kg once weekly is recommended (i.e., dosage should be decreased to 3 mcg/kg once weekly; if needed, decrease to 2 mcg/kg once weekly; then, if needed, further decrease to 1 mcg/kg once weekly).2 If the patient is unable to tolerate peginterferon alfa-2b at a dosage of 1 mcg/kg once weekly, the drug should be permanently discontinued.2

If dosage modification of peginterferon alfa-2b is required during weeks 9-260 of treatment (maintenance) because of adverse reactions, a 2-step decrease from the original dosage of 3 mcg/kg once weekly is recommended (i.e., dosage should be decreased to 2 mcg/kg once weekly; if needed, decrease to 1 mcg/kg once weekly).2 If the patient is unable to tolerate peginterferon alfa-2b at a dosage of 1 mcg/kg once weekly, the drug should be permanently discontinued.2

Special Populations

Hepatic Impairment

Peginterferon alfa-2b (Sylatron^®) has not been studied in patients with melanoma who have hepatic impairment.2 The drug is contraindicated in those with hepatic decompensation (Child-Pugh score greater than 6, class B and C).2

Renal Impairment

When peginterferon alfa-2b (Sylatron^®) is used as an adjuvant to surgery for treatment of melanoma in adults with moderate renal impairment (creatinine clearance 30-50 mL/minute per 1.73 m²), dosage should be reduced to 4.5 mcg/kg subcutaneously once weekly for 8 doses (induction), followed by 2.25 mcg/kg subcutaneously once weekly for up to 5 years (maintenance).2 In adults with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m²) and adults with end-stage renal disease requiring dialysis, dosage of peginterferon alfa-2b should be reduced to 3 mcg/kg subcutaneously once weekly for 8 doses (induction), followed by 1.5 mcg/kg subcutaneously once weekly for up to 5 years (maintenance).2 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustments of peginterferon alfa-2b (Sylatron^®) are not needed in adults with creatinine clearance exceeding 50 mL/minute per 1.73 m².2

Contraindications

Peginterferon alfa-2b (Sylatron^®) is contraindicated in patients with a history of anaphylaxis to peginterferon alfa-2b or interferon alfa-2b and in those with autoimmune hepatitis or hepatic decompensation (Child-Pugh score greater than 6, class B and C).2

Warnings/Precautions

Warnings

Neuropsychiatric Effects

Peginterferon alfa-2b (Sylatron^®) can cause life-threatening or fatal neuropsychiatric reactions.2 The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders (e.g., homicidal ideation, increased risk of relapse in recovering drug addicts) are increased with alpha interferons, including peginterferon alfa-2b.2

In a clinical study of peginterferon alfa-2b in patients with melanoma, depression occurred in 59 or 24% of patients in the peginterferon alfa-2b or observation group, respectively; severe or life-threatening depression occurred in 7 or less than 1% of patients, respectively.2 In postmarketing experience, adverse neuropsychiatric reactions have been reported up to 6 months after discontinuance of peginterferon alfa-2b.2 Aggressive behavior, psychoses, hallucinations, bipolar disorders, mania, and encephalopathy also have been reported with peginterferon alfa-2b and interferon alfa-2b.2

Patients and their caregivers should be advised to immediately contact a clinician if the patient experiences symptoms of depression or suicidal ideation.2 Patients should be monitored and evaluated 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; monitoring should be continued for at least 6 months after the last dose of peginterferon alfa-2b.2

Peginterferon alfa-2b should be permanently discontinued if the patient develops persistent severe or worsening psychiatric symptoms or behaviors, and the patient should be referred for psychiatric evaluation.2 These disorders may not resolve after peginterferon alfa-2b is discontinued.2

Other Warnings/Precautions

Cardiovascular Effects

Adverse cardiac effects (e.g., myocardial infarction, bundle-branch block, ventricular tachycardia, supraventricular arrhythmia) occurred in 4% of patients receiving peginterferon alfa-2b in a clinical study compared with 2% of patients in the observation group.2 In postmarketing experience, hypotension, cardiomyopathy, and angina pectoris have occurred in patients receiving peginterferon alfa-2b.2

Peginterferon alfa-2b should be permanently discontinued if new onset of ventricular arrhythmia or cardiovascular decompensation occurs.2

Ocular Effects

Peginterferon alfa-2b can cause decreased visual acuity or blindness due to retinopathy.2 Certain retinal or ocular changes may be induced or aggravated by treatment with peginterferon alfa-2b or other alpha interferons (e.g., macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, serous retinal detachment).2 In a clinical study in patients with melanoma, 2 patients receiving peginterferon alfa-2b developed partial loss of vision due to retinal thrombosis or retinopathy.2 The overall incidence of serious retinal disorders, visual disturbances, blurred vision, and reduction in visual acuity was less than 1% in both the peginterferon alfa-2b and observation groups.2

An eye examination, including assessment of visual acuity and indirect ophthalmoscopy or fundus photography, should be performed at baseline in patients with preexisting retinopathy and at any time vision changes occur during peginterferon alfa-2b treatment.2

Peginterferon alfa-2b should be permanently discontinued in patients who develop new or worsening retinopathy.2

Hepatic Effects

Peginterferon alfa-2b increases the risk of hepatic decompensation and death in patients with cirrhosis.2 Hepatic function (i.e., serum bilirubin, ALT, AST, alkaline phosphatase, LDH) should be assessed at 2 weeks, 8 weeks, 2 months, and 3 months following initiation of peginterferon alfa-2b and every 6 months thereafter during treatment.2

Peginterferon alfa-2b should be permanently discontinued if the patient exhibits evidence of severe (grade 3) hepatic injury or hepatic decompensation (Child-Pugh score greater than 6, class B and C).2

Endocrine Effects

Peginterferon alfa-2b can cause new onset or worsening hypothyroidism, hyperthyroidism, or diabetes mellitus.2 In a clinical study in patients with melanoma, 1% of patients developed hypothyroidism.2 The overall incidence of endocrine disorders was 2% in patients receiving peginterferon alfa-2b compared with less than 1% for patients in the observation group.2

Thyroid-stimulating hormone (TSH) levels should be assessed within the 4 weeks preceding initiation of peginterferon alfa-2b, at 3 and 6 months following initiation of the drug, and every 6 months thereafter during treatment.2

Peginterferon alfa-2b should be permanently discontinued in patients who develop hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed.2

Antibody Formation

In a clinical study evaluating peginterferon alfa in patients with melanoma, the overall incidence of binding antibodies to peginterferon alfa-2b was approximately 35% (50/144);2,434 one patient developed neutralizing antibodies.2 Antibody development occurred in more patients receiving peginterferon alfa-2b than the observation group (52 and 18%, respectively).434 The effects of antibody formation on pharmacokinetics, safety, and efficacy of peginterferon alfa-2b have not been fully elucidated.2

The percentage of individuals who test positive for antibody formation is highly dependent on the sensitivity and specificity of the assay used.2 The observed incidence of antibody positivity in an assay may be influenced by several factors (e.g., assay methodology, sample handling, timing of sample collection, concomitant medications, underlying disease).2 Therefore, comparison of the incidence of antibodies to peginterferon alfa-2b (Sylatron^®) with the incidence of antibodies to other peginterferon or interferon preparations may be misleading.2

Specific Populations

Pregnancy

Category C.2 (See Users Guide.)

Lactation

It is not known whether peginterferon alfa-2b is distributed into human milk.2 Studies in mice indicate that mouse interferons are distributed into milk.2 Because of the potential for adverse reactions to peginterferon alfa-2b in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.2

Pediatric Use

Safety and efficacy of peginterferon alfa-2b (Sylatron^®) have not been established in children younger than 18 years of age.2

Geriatric Use

There are insufficient data to determine whether patients older than 65 years of age respond differently to peginterferon alfa-2b than younger adults.2

Hepatic Impairment

Safety and efficacy of peginterferon alfa-2b have not been studied in patients with melanoma who have hepatic impairment.2 The drug is contraindicated in patients with hepatic decompensation (Child-Pugh score greater than 6, class B and C) and should be discontinued if hepatic decompensation occurs during treatment.2

Renal Impairment

Because the mean exposure (area under the concentration-time curve [AUC]) of peginterferon alfa-2b is increased 1.4-fold in individuals with moderate renal impairment and increased 2.1-fold in individuals with severe renal impairment and in those with end-stage renal disease requiring dialysis when compared with the AUC in individuals with normal renal function, dosage of the drug should be decreased 25% in adults with moderate renal impairment and decreased 50% in adults with severe renal impairment and in those with end-stage renal impairment requiring dialysis.2 (See Renal Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

In a clinical trial evaluating peginterferon alfa-2b for adjuvant treatment of melanoma, essentially all patients receiving the drug experienced adverse effects at some time during the course of treatment; the drug was discontinued in 33% because of adverse effects.2 The most common adverse effects (occurring in greater than 50% of patients) are flu-like symptoms (fatigue, headache, myalgia, pyrexia, chills), anorexia, arthralgia, injection site reaction, depression, nausea, and elevated AST and ALT concentrations.2

Drugs Metabolized by Hepatic Microsomal Enzymes

The following information on possible interactions with drugs metabolized by cytochrome P-450 (CYP) enzymes is based on studies using peginterferon alfa-2b in a dosage of 1 mcg/kg once weekly.2 The effects of peginterferon alfa-2b given in dosages recommended for adjuvant treatment of melanoma (6 mcg/kg once weekly and 3 mcg/kg once weekly) on the pharmacokinetics of drugs metabolized by CYP enzymes have not been studied.2

In healthy individuals who received multiple doses of peginterferon alfa-2b (1 mcg/kg subcutaneously once weekly for 4 weeks) and received probe drugs of metabolic enzymes (e.g., caffeine, tolbutamide, dextromethorphan, midazolam) before the first and after the fourth dose of peginterferon alfa-2b, CYP2C9 activity increased to 125% of baseline and CYP2D6 activity decreased to 51% of baseline; there was no clinically important effect on activity of CYP1A2 or CYP3A4.2

In a 2-way crossover trial in healthy individuals who received probe drugs of metabolic enzymes (e.g., caffeine, tolbutamide, dextromethorphan, midazolam, dapsone) with or without a single dose of peginterferon alfa-2b (1 mcg/kg subcutaneously), there was no effect on the activity of CYP1A2, CYP2C9, CYP2D6, CYP3A4, or N -acetyltransferase (NAT) enzymes.2

If peginterferon alfa-2b dosages used for adjuvant treatment of melanoma are used concomitantly with drugs metabolized by CYP2C9 or CYP2D6, the therapeutic effects of these drugs may be altered.2

Description

Peginterferon alfa-2b is used as an antineoplastic agent.2 The mechanism by which peginterferon alfa-2b exerts therapeutic effects in the adjuvant treatment of melanoma is unknown; the drug is a pleiotropic cytokine.2 Peginterferon alfa-2b contains interferon alfa-2b (recombinant DNA origin) covalently bound to monomethoxy polyethylene glycol (PEG).2 As a result of conjugation with PEG, the apparent clearance of peginterferon alfa-2b is lower and mean half-life of the drug is greater than that reported for nonconjugated interferon alfa-2b.1,433 Consequently, peginterferon alfa-2b can be administered less frequently than nonconjugated preparations.1,433

Pharmacokinetics of peginterferon alfa-2b were studied in adults receiving the drug for adjuvant treatment of melanoma.2,435 Initial treatment in these patients using a dosage of 6 mcg/kg subcutaneously once weekly for 8 doses (induction) resulted in mean peak serum concentrations of 4.4 ng/mL at week 8; the mean terminal half-life was approximately 51 hours and the mean accumulation from week 1 to week 8 was 1.7.2,435 After dosage was decreased to 3 mcg/kg subcutaneously once weekly (maintenance), peak serum concentrations at week 4 of the lower dosage were 2.5 ng/mL and the mean terminal half-life was 43 hours.2,435 Renal clearance accounts for approximately 30% of total peginterferon alfa-2b clearance.2 Following a single 4.5-mg subcutaneous dose of peginterferon alfa-2b, the mean exposure (area under the concentration-time curve [AUC]) of the drug was increased 1.4-fold in individuals with moderate renal impairment (creatinine clearance 30-50 mL/minute per 1.73 m²) and was increased 2.1-fold in those with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m²) or end-stage renal disease requiring dialysis when compared with the AUC in individuals with normal renal function (creatinine clearance exceeding 80 mL/minute per 1.73 m²).2

Advice to Patients

Advise patients of the importance of reading the manufacturer's patient information and medication guide.2

Advise patients receiving peginterferon alfa-2b (Sylatron^®) that administration with an antipyretic at bedtime may minimize common flu-like symptoms (e.g., chills, fever, muscle aches, joint pain, headaches, tiredness).2

Advise patients to maintain hydration if they experience flu-like symptoms.2

Importance of not reusing or sharing syringes or needles.2 Importance of proper disposal of vials, syringes, and needles.2

Importance of informing clinicians of existing or previous treatment for mental illness, including depression, suicidal thoughts, or suicide attempts.2 Importance of reporting any sign or symptom of depression or suicidal ideation to clinician during treatment and up to 6 months after the last dose.2 Advise patients that immediate discontinuance of the drug may be necessary in severe cases.2

Importance of informing clinicians of existing or contemplated concomitant therapy, including herbal supplements, prescription and OTC drugs, as well as concomitant illnesses.2

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.2 Importance of using peginterferon alfa-2b during pregnancy only if potential benefits justify potential risks to the fetus.2

Importance of advising patients of other important precautionary information.2 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Schering Corporation. PegIntron^® (peginterferon alfa-2b) injection, powder for solution for subcutaneous use prescribing information. Whitehouse Station, NJ; 2014 Jul.

2. Schering Corporation. Sylatron^® (peginterferon alfa-2b) injection, powder for solution for subcutaneous use prescribing information. Whitehouse Station, NJ; 2014 Aug.

20. Genentech. Pegasys^® (peginterferon alfa-2a) injection for subcutaneous use prescribing information. South San Francisco, CA; 2013 Jul.

430. Eggermont AM, Suciu S, Santinami M et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet . 2008; 372:117-26. [PubMed 18620949]

431. Eggermont AM, Suciu S, Testori A et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol . 2012; 30:3810-8. [PubMed 23008300]

432. Eastern Cooperative Oncology Group. ECOG performance status. From the ECOG website. [Web]

433. Glue P, Fang JW, Rouzier-Panis R et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther . 2000; 68:556-67. [PubMed 11103758]

434. Bouwhuis MG, Suciu S, Testori A et al. Phase III trial comparing adjuvant treatment with pegylated interferon Alfa-2b versus observation: prognostic significance of autoantibodies--EORTC 18991. J Clin Oncol . 2010; 28:2460-6. [PubMed 20385998]

435. Daud AI, Xu C, Hwu WJ et al. Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma. Cancer Chemother Pharmacol . 2011; 67:657-66. [PubMed 20509027]