peginterferon alfa 2b (PEG Intron, PegIntron Redipen, Sylatron)

Dosing and uses of PEG Intron, Sylatron (peginterferon-alfa-2b)

• Adult
• Pediatric

 

Adult dosage forms and strengths

prefilled pen/vial (PegIntron Redipen, PEG Intron)

• 50mcg
• 80mcg
• 120mcg
• 150mcg

injectable powder with diluent (Sylatron)

• 296mcg/vial
• 444mcg/vial
• 888mcg/vial

 

Chronic Hepatitis C

Patients who are initiating therapy for HCV infection or who experienced relapse after prior PEG/RBV therapy, by HCV genotype (AASLD and IAS guidelines, April 2014)

Peginterferon is not recommended as monotherapy for any patient group

Genotypes 1, 4, 5, or 6

• Peginterferon alfa 2b + ribavirin + sofosbuvir (preferred regimen)
• 1.5 mcg/kg/Week SC; not to exceed 150 mcg/week, PLUS
• Ribavirin PO 1000-1200 mg/day (based on body weight) plus sofosbuvir 400 mg PO qDay
• Treat for 12 weeks (treatment-naive or relapsed); for nonresponders, may extend treatment of PEG/RBV to 24 weeks
• Reduce ribavirin dose if CrCl ≤50 mL/min

Alternative regimens

• Genotype 1: Simeprevir 150 mg/day x 12 weeks + PEG/RBV x 24 weeks
• Genotype 3: Sofosbuvir + PEG/RBV x 12 weeks
• Genotype 4: Simeprevir 150 mg/day x 12 weeks + PEG/RBV x 24-48 weeks
• Genotypes 5 and 6: PEG/RBV x 48 weeks

 

Melanoma (Sylatron)

Indicated for melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy

6 mcg/kg/week SC for 8 doses, THEn

3 mcg/kg/week SC for up to 5 years

 

Renal Impairment

Dose reductions of 25% and 50% are recommended in patients with moderate and severe renal impairment, respectively, receiving alpha interferons for chronic hepatitis C

CrCl 30-50 mL/min: Reduce 25%

CrCl 10-29 mL/min (including HD): 50%

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

 

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 (Child-Pugh scores >6)

Discontinue Sylatron if hepatic decompensation (Child-Pugh scores >6) occurs during treatment

 

Orphan Designations

Thrombocythemia

Myelofibrosis

 

Pediatric dosage forms and strengths

prefilled pen/vial (PegIntron Redipen, PEG Intron)

• 50mcg
• 80mcg
• 120mcg
• 150mcg

 

Chronic Hepatitis C

<3 years: Safety and efficacy not established

3-17 years: 60 mcg/m² SC qWeek (+ ribavirin 15 mg/kg/day PO divided q12hr); administer on same day each week

 

PEG Intron, Sylatron (peginterferon-alfa-2b) adverse (side) effects

>10% (Hepatitis C Trials)

Headache (56%)

Fatigue (52%)

Injection site inflammation/reaction (47%)

Depression (16-29%)

Anxiety/emotional lability/irritability (28%)

Nausea (26%)

Insomnia (23%)

Alopecia (22%)

Fever (22%)

Anorexia (20%)

Diarrhea (18%)

Abdominal pain (15%)

Dizziness (12%)

Impaired concentration (5-12%)

Pain (12%)

Pruritus (12%)

Dry skin (11%)

Weight loss (11%)

 

>10% (Melanoma Trials)

Fatigue (94%)

ALT or AST increased (77%)

Pyrexia (75%)

Headache (70%)

Anorexia (69%)

Myalgia (68%)

Nausea (64%)

Arthralgia (51%)

Chills (63%)

Injection site reactions (62%)

Depression (59%)

Dysgeusia (38%)

Diarrhea (37%)

Exfoliative rash (36%)

Dizziness (35%)

Alopecia (34%)

Vomiting (26%)

Olfactory nerve disorder (23%)

Blood alkaline phosphatase increased (23%)

Paraesthesia (21%)

Weight loss (11%)

 

1-10% (Hepatitis C Trials)

Pharyngitis (10%)

Transient increase in transaminases (10%)

Malaise (8%)

Dermatitis (7%)

Sinusitis (7%)

Vomiting (7%)

Dyspepsia (6%)

Flushing (6%)

Hepatomegaly (6%)

Rash (6%)

Hypertonia (5%)

Hypothyroidism (5%)

Injection site pain (2%)

Taste perversion

Neutropenia

Thrombocytopenia

 

1-10% (Melanoma Trials)

GGT increased (8%)

Proteinuria (7%)

Anemia (6%)

Dyspnea (6%)

Cough (5%)

 

<1% (Hepatitis C Trials)

Colitis

Pancreatitis

Autoimmune thrombocytopenia

Blindess, thrombosis of retinal vein

Aggressive behavior

Depression

Homicidal thoughts, suicidal thoughts, suicide

 

Frequency not defined

As with all proteins, there is a potential for immunogenicity

 

Postmarketing reports

Pulmonary fibrosis

 

Warnings

Black box warnings

Alfa interferons cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders

The risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders are increased with alpha interferons

Discontinue drug if persistently severe or worsening signs or symptoms of the above conditions are present; disorders typically resolve after stopping therapy

These disorders may not resolve after the drug is discontinued

Monitored closely with periodic clinical and laboratory evaluations

Combination therapy with ribavirin

• Ribavirin may cause birth defects and/or fetal death
• Extreme care must be taken to avoid pregnancy in women taking peginterferon alfa-2a and in female partners of men taking peginterferon alfa-2a
• Ribavirin causes hemolytic anemia; associated anemia may result in worsening of cardiac disease
• Because ribavirin is genotoxic and mutagenic, consider it a potential carcinogen

 

Contraindications

Hypersensitivity

Autoimmune hepatitis

Decompensated liver disease (Child-Pugh >6 [class B and C])

Contraindications for combination therapy with ribavirin:

• Pregnant women and men whose female partners are pregnant
• Hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
• Creatinine clearance less than 50 mL/min

 

Cautions

May cause/aggravate fatal or life threatening autoimmune, ischemic, and infectious disorders

Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior sometimes directed towards others reported in patients with and without a previous psychiatric disorder during therapy and follow-up; psychoses, hallucinations, bipolar disorders, and mania have been observed in patients receiving this therapy and should be used with caution in patients with a history of psychiatric disorders; report any symptoms of depression or suicidal ideation to healthcare provider

Monitor and evaluate patients for signs and symptoms of depression and other psychiatric symptoms every 3 weeks during first 8 weeks of treatment and every 6 months thereafter; monitor patients during treatment and for at least 6 months after last dose; permanently discontinue therapy for suicidal or homicidal ideation, aggressive behavior towards others, or other severe or persistent psychiatric symptoms (see Black box warnings)

Caution with hypothyroidism, hyperthyroidism, hyperglycemia, and diabetes mellitus that cannot be effectively treated by medication

Cardiac adverse reactions occurred in 4% of patients during clinical trials; permanently discontinue with new onset ventricular arrhythmia or cardiovascular decompensation

Risk of visual impairment and retinal disorders; discontinue if ophthalmologic problems develop

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by therapy; recurrence of respiratory failure has been observed with interferon rechallenge; monitor

Ischemic and hemorrhagic cerebrovascular events observed

Development or exacerbation of autoimmune disorders (e.g., thyroiditis, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis) observed; use with caution in patients with autoimmune disorders

Pancreatitis and ulcerative or hemorrhagic/iscemic colitis may occur

Severe decreases in neutrophil or platelet counts reported

May cause birth defects and fetal death: use extreme care to avoid pregnancy in female patients and female partners of male patients

When administered in combination with ibavirin causes hemolytic anemia; associated anemia may result in worsening of cardiac disease

Hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alpha 2b; cirrhotic CHC patients co-infected with HIV receiving highly active antiretroviral therapy (HAART) and alpha interferons with or without ribavirin appear to be at increased risk for development of hepatic decompensation compared to patients not receiving HAART; monitor clinical status and hepatic function during treatment and discontinue immediately if decompensation (Child-Pugh score greater than 6) observed

Monitor closely patients with impaired renal function, for signs and symptoms of interferon toxicity, including increases in serum creatinine; adjust dose or discontinue therapy accordingly

Serious, acute hypersensitivity reactions and cutaneous eruptions reported 

Dental/periodontal disorders reported with combination therapy

Hypertriglyceridemia may result in pancreatitis (e.g., triglycerides greater than 1000 mg/dL)

Weight loss and growth inhibition reported during combination therapy in pediatric patients

Long-term growth inhibition (height) reported in some patients

Peripheral neuropathy observed when used in combination with telbivudine

 

Pregnancy and lactation

Pregnancy category: C

Lactation: Unknown if excreted in human milk; decide whether to discontinue drug or breastfeeding

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of PEG Intron, Sylatron (peginterferon-alfa-2b)

Mechanism of action

Immunomodulatory cytokine that enhances phagocytic activity of macrophages and cytotoxic activity of lymphocytes for target cells

 

Absorption

Half-life: 4.6 hr

Peak plasma time: 15-44 hr

 

Metabolism

Conjugation with polyethylene glycol slows metabolism

 

Elimination

Half-life: 40 hr

Excretion: Urine (30%)

 

Pharmacogenomics

A genetic variant near the gene encoding interferon-lambda-3 (IL28B rs12979860, a C to T change) is a strong predictor of response to peginterferon and ribavirin

Sustained virologic response rates tended to be lower with the C/T and T/T genotypes compared to those with the C/C genotype, particularly among previously untreated subjects receiving 48 weeks of peginterferon and ribavirin

 

Administration

SC Preparation (Sylatron)

Reconstitute with 0.7 mL sterile water for injection

Do not withdraw more than 0.5 mL of reconstituted solution from viaL

Resulting concentration following reconstitution

• 296 mg/vial = 40 mcg/0.1 mL
• 444 mg/vial = 60 mcg/0.1 mL
• 888 mg/vial = 120 mcg/0.1 mL

 

SC Administration

Once weekly dosing: Administer on same day each week

Rotate injection site