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Peginterferon Alfa-2b

Pronunciation

(peg in ter FEER on AL fa too bee)

Index Terms

  • Interferon Alfa-2b (PEG Conjugate)
  • PEG-IFN Alfa-2b
  • Pegylated Interferon Alfa-2b
  • Polyethylene Glycol Interferon Alfa-2b

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Kit, Subcutaneous:

Sylatron: 4 x 200 mcg, 4 x 300 mcg, 4 x 600 mcg [DSC] [contains polysorbate 80]

Kit, Subcutaneous [preservative free]:

Peg-Intron: 50 mcg/0.5 mL [DSC], 80 mcg/0.5 mL [DSC], 120 mcg/0.5 mL [DSC], 150 mcg/0.5 mL [DSC]

Peg-Intron Redipen: 50 mcg/0.5 mL, 80 mcg/0.5 mL, 120 mcg/0.5 mL, 150 mcg/0.5 mL

Peg-Intron Redipen Pak 4: 50 mcg/0.5 mL [DSC], 80 mcg/0.5 mL [DSC], 120 mcg/0.5 mL, 150 mcg/0.5 mL [DSC]

PegIntron: 50 mcg/0.5 mL, 80 mcg/0.5 mL, 120 mcg/0.5 mL, 150 mcg/0.5 mL [contains polysorbate 80]

Sylatron: 200 mcg, 300 mcg, 600 mcg [contains polysorbate 80]

Brand Names: U.S.

  • Peg-Intron Redipen
  • Peg-Intron Redipen Pak 4
  • Peg-Intron [DSC]
  • PegIntron
  • Sylatron

Pharmacologic Category

  • Antineoplastic Agent, Biological Response Modulator
  • Biological Response Modulator
  • Immunomodulator, Systemic
  • Interferon

Pharmacology

Alpha interferons are a family of proteins, produced by nucleated cells, that have antiviral, antiproliferative, and immune-regulating activity. There are 16 known subtypes of alpha interferons. Interferons interact with cells through high affinity cell surface receptors. Following activation, multiple effects can be detected including induction of gene transcription. Inhibits cellular growth, alters the state of cellular differentiation, interferes with oncogene expression, alters cell surface antigen expression, increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells.

Excretion

Urine (~30%); clearance reduced in renal impairment by 17% in moderate dysfunction, 44% in severe dysfunction

Time to Peak

CHC: 15 to 44 hours

Half-Life Elimination

CHC: ~40 hours (range: 22 to 60 hours); Melanoma: ~43 to 51 hours

Special Populations: Renal Function Impairment

Mean exposure is increased 1.4 fold in patients with moderate impairment and by 2.1-fold in patients with severe renal impairment (including ESRD on dialysis) following a single 4.5 mcg/kg dose. Reduce dose in patients with moderate or severe renal impairment.

Special Populations: Children

In children receiving PegIntron 60 mcg/m2/week, exposure may be ~50% higher than that observed in adults receiving 1.5 mcg/kg/week.

Use: Labeled Indications

Chronic hepatitis C (CHC): Peg-Intron: Treatment of chronic hepatitis C (CHC) in compensated liver disease:

Combination therapy with ribavirin and an approved hepatitis C virus [HCV] NS3/4A protease inhibitor in adult patients with HCV genotype 1 infection.

Combination therapy with ribavirin in adult patients with HCV genotypes other than 1, in pediatric patients (3 to 17 years), or in patients with HCV genotype 1 with contraindications or intolerance to HCV NS3/4A protease inhibitor use.

Monotherapy in adult patients with contraindications or significant intolerance to ribavirin if previously untreated.

Limitations of use: Combination therapy with ribavirin provides substantially better response rates than monotherapy

Melanoma: Sylatron: Adjuvant treatment of melanoma (with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy)

Use: Unlabeled

Chronic hepatitis C: Treatment of chronic hepatitis C (CHC) genotypes 1,4, 5 or 6 in combination with ribavirin and an HCV NS5B polymerase inhibitor. Note: Current AASLD/IDSA recommendations do not specify a particular peginterferon (eg, 2a or 2b); however, guideline recommendations are based on clinical trials that used peginterferon alfa-2a.

Contraindications

Hypersensitivity (including urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) to peginterferon alfa-2b, interferon alfa-2b, other alfa interferons, or any component of the formulation; autoimmune hepatitis; decompensated liver disease (Child-Pugh score >6, classes B and C)

Documentation of allergenic cross-reactivity for interferons is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty

Combination therapy with peginterferon alfa-2b and ribavirin is also contraindicated in pregnancy, women who may become pregnant, males with pregnant partners; hemoglobinopathies (eg, thalassemia major, sickle-cell anemia); renal dysfunction (CrCl <50 mL/minute)

Dosing: Adult

Melanoma: SubQ: Initial: 6 mcg/kg/week for 8 doses; Maintenance: 3 mcg/kg/week for up to 5 years. Note: Premedicate with acetaminophen (500-1000 mg orally) 30 minutes prior to the first dose and as needed for subsequent doses thereafter.

Chronic hepatitis C (CHC): SubQ:

Manufacturer's labeling: Note: Discontinue after 12 weeks in patients with HCV (genotype 1) if HCV RNA does not decrease by at least 2 log (compared to pretreatment) or if detectable HCV RNA present at 24. Discontinuation is also recommended in patients who previously failed therapy (regardless of genotype) if detectable HCV RNA present at 12 or 24 weeks.

Combination therapy with ribavirin (treatment duration is 48 weeks for genotype 1, 24 weeks for genotypes 2 and 3, or 48 weeks for patients who previously failed therapy [regardless of genotype]): Initial dose (based on an average weekly dose of 1.5 mcg/kg):

<40 kg: 50 mcg once weekly (with ribavirin 800 mg/day)

40 to 50 kg: 64 mcg once weekly (with ribavirin 800 mg/day)

51 to 60 kg: 80 mcg once weekly (with ribavirin 800 mg/day)

61 to 65 kg: 96 mcg once weekly (with ribavirin 800 mg/day)

66 to 75 kg: 96 mcg once weekly (with ribavirin 1000 mg/day)

76 to 80 kg: 120 mcg once weekly (with ribavirin 1000 mg/day)

81 to 85 kg: 120 mcg once weekly (with ribavirin 1200 mg/day)

86 to 105 kg: 150 mcg once weekly (with ribavirin 1200 mg/day)

>105 kg: 1.5 mcg/kg once weekly (with ribavirin 1400 mg/day)

Monotherapy (duration of treatment is 1 year): Initial dose (based on average weekly dose of 1 mcg/kg):

≤45 kg: 40 mcg once weekly

46 to 56 kg: 50 mcg once weekly

57 to 72 kg: 64 mcg once weekly

73 to 88 kg: 80 mcg once weekly

89 to 106 kg: 96 mcg once weekly

107 to 136 kg: 120 mcg once weekly

137 to 160 kg: 150 mcg once weekly

Alternative dosing: Note: Current AASLD/IDSA recommendations do not specify a particular peginterferon (eg, 2a or 2b); however, guideline recommendations are based on clinical trials that used peginterferon alfa-2a. It is not known whether peginterferon alfa 2b could be used interchangeably. Please refer to http://www.hcvguidelines.org for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis C (CHC):

Manufacturer labeling: Children 3 to 17 years: SubQ: Combination therapy with ribavirin: 60 mcg/m2 once weekly; Note: Children who reach their 18th birthday during treatment should remain on the pediatric regimen. Treatment duration is 48 weeks for genotype 1, 24 weeks for genotypes 2 and 3. Discontinue combination therapy in patients with HCV (genotype 1) at 12 weeks if HCV-RNA does not decrease by at least 2 log (compared to pretreatment) or if detectable HCV-RNA present at 24 weeks.

American Association for the Study of Liver Diseases (AASLD) guideline recommendations (Ghany, 2009): Children 2-17 years: SubQ: Treatment of choice: Peginterferon alfa-2b 60 mcg/m2 once weekly in combination with oral ribavirin 15 mg/kg/day for 48 weeks

Dosing: Renal Impairment

Chronic hepatitis C:

Peginterferon alfa-2b combination with ribavirin:

Adults: CrCl <50 mL/minute: Combination therapy with ribavirin is not recommended.

Children: Serum creatinine >2 mg/dL: Discontinue treatment.

Peginterferon alfa-2b monotherapy:

CrCl 30 to 50 mL/minute: Reduce dose by 25%

CrCl 10 to 29 mL/minute: Reduce dose by 50%

Hemodialysis: Reduce dose by 50%

Discontinue use if renal function declines during treatment.

Melanoma:

CrCl >50 mL/minute/1.73 m2: No dosage adjustment is necessary.

CrCl 30 to 50 mL/minute/1.73 m2: Reduce initial dose to 4.5 mcg/kg/week; reduce maintenance dose to 2.25 mcg/kg/week

CrCl <30 mL/minute/1.73 m2 and ESRD on dialysis: Reduce initial dose to 3 mcg/kg/week; reduce maintenance dose to 1.5 mcg/kg/week

Hemodialysis: Following a single 1 mcg/kg/ dose, no clinically meaningful amount of peginterferon alfa-2b was removed during hemodialysis.

Dosing: Hepatic Impairment

Decompensated liver disease or autoimmune hepatitis: Use is contraindicated.

Hepatic decompensation or severe hepatic injury during treatment (Child-Pugh score >6 [class B or C]): Discontinue immediately.

Dosing: Adjustment for Toxicity

Melanoma:

Discontinue for any of the following: Persistent or worsening severe neuropsychiatric disorders (depression, psychosis, encephalopathy), grade 4 nonhematologic toxicity, new or worsening retinopathy, new-onset ventricular arrhythmia or cardiovascular decompensation, evidence of hepatic injury (severe) or hepatic decompensation (Child-Pugh score >6 [Class B or C]), development of hyper- or hypothyroidism or diabetes that cannot be effectively managed with medication, or inability to tolerate a dose of 1 mcg/kg/week

Temporarily withhold for any of the following: ANC <500/mm3, platelets <50,000/mm3, ECOG performance status (PS) ≥2, nonhematologic toxicity ≥ grade 3

May reinitiate at a reduced dose once ANC ≥500/mm3, platelets ≥50,000/mm3, ECOG PS at 0 to 1, and nonhematologic toxicity completely resolved or improved to grade 1.

Reduced dose schedule, Weeks 1 to 8:

First dose reduction (if prior dose 6 mcg/kg/week): 3 mcg/kg/week

Second dose reduction (if prior dose 3 mcg/kg/week): 2 mcg/kg/week

Third dose reduction (if prior dose 2 mcg/kg/week): 1 mcg/kg/week

Discontinue permanently if unable to tolerate 1 mcg/kg/week

Reduced dose schedule, Weeks 9 to 260:

First dose reduction (if prior dose 3 mcg/kg/week): 2 mcg/kg/week

Second dose reduction (if prior dose 2 mcg/kg/week): 1 mcg/kg/week

Discontinue permanently if unable to tolerate 1 mcg/kg/week

Chronic hepatitis C: Dosage adjustment for depression (severity based upon DSM-IV criteria):

Mild depression: No dosage adjustment required; evaluate once weekly by visit/phone call. If depression remains stable, continue weekly visits. If depression improves, resume normal visit schedule. For worsening depression, see “Moderate depression” or “Severe depression” below.

Moderate depression: Note: Evaluate once weekly (visit or phone) with an office visit at least every other week. If depression remains stable, consider psychiatric evaluation and continue with reduced dosing. If symptoms improve and remain stable for 4 weeks, resume normal visit schedule; continue reduced dosing or return to normal dose. For worsening depression, see “Severe depression” below.

Children: Decrease peginterferon alfa-2b dose to 40 mcg/m2/week, may further decrease to 20 mcg/m2/week if needed

Adults:

Peginterferon alfa-2b combination therapy: Refer to adult weight-based dosage reduction with combination therapy for depression below

Peginterferon alfa-2b monotherapy: Refer to adult weight-based dosage reduction with monotherapy for depression below

Severe depression: Discontinue peginterferon alfa-2b and ribavirin permanently. Obtain immediate psychiatric consultation. Utilize followup psychiatric therapy as needed.

Chronic hepatitis C: Dosage adjustment in hematologic toxicity:

Children:

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose by 50%; decrease ribavirin dose by 200 mg daily (regardless of the patient’s initial dose); monitor and evaluate weekly. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue both peginterferon alfa-2b and ribavirin.

Hemoglobin 8.5 to <10 g/dL and no history of cardiac disease: Decrease ribavirin dose to 12 mg/kg/day; may further reduce to 8 mg/kg/day; no dosage adjustment necessary for peginterferon alfa-2b.

WBC 1000 to <1500/mm3, neutrophils 500 to <750/mm3, or platelets 50,000 to <70,000/mm3: Reduce peginterferon alfa-2b dose to 40 mcg/m2/week; may further reduce to 20 mcg/m2/week

Hemoglobin <8.5 g/dL, WBC <1000/mm3, neutrophils <500/mm3, or platelets <50,000/mm3: Permanently discontinue peginterferon alfa-2b and ribavirin

Adults:

Hemoglobin decrease ≥2 g/dL in any 4-week period and stable cardiac disease: Decrease peginterferon alfa-2b dose by 50%; decrease ribavirin dose by 200 mg daily. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue both peginterferon alfa-2b and ribavirin.

Hemoglobin 8.5 to <10 g/dL and no history of cardiac disease: Decrease ribavirin dose by 200 mg daily (patients receiving 1400 mg daily should decrease dose by 400 mg daily [ie, first dose reduction to 1000 mg daily]); may further reduce ribavirin dose by additional 200 mg daily if needed. No dosage adjustment necessary for peginterferon alfa-2b.

WBC 1000 to <1500/mm3, neutrophils 500 to <750/mm3, or platelets 25,000 to <50,000/mm3:

Peginterferon alfa-2b combination therapy: Refer to adult weight-based dosage reduction with combination therapy for hematologic toxicity below.

Peginterferon alfa-2b monotherapy: Refer to adult weight-based dosage reduction monotherapy for hematologic toxicity below.

Hemoglobin <8.5 g/dL, WBC <1000/mm3, neutrophils <500/mm3, or platelets <25,000/mm3: Permanently discontinue peginterferon alfa-2b and ribavirin.

Chronic hepatitis C: Adult weight-based dosage reduction for depression or hematologic toxicity:

Peginterferon alfa-2b combination therapy: Initially reduce to average weekly dose of 1 mcg/kg; may further reduce to average weekly dose of 0.5 mcg/kg if needed as follows:

<40 kg: 35 mcg once weekly; may further reduce to 20 mcg once weekly if needed

40 to 50 kg: 45 mcg once weekly; may further reduce to 25 mcg once weekly if needed

51 to 60 kg: 50 mcg once weekly; may further reduce to 30 mcg once weekly if needed

61 to 75 kg: 64 mcg once weekly; may further reduce to 35 mcg once weekly if needed

76 to 85 kg: 80 mcg once weekly; may further reduce to 45 mcg once weekly if needed

86 to 104 kg: 96 mcg once weekly; may further reduce to 50 mcg once weekly if needed

105 to 125 kg: 108 mcg once weekly; may further reduce to 64 mcg once weekly if needed

>125 kg: 135 mcg once weekly; may further reduce to 72 mcg once weekly if needed

Peginterferon alfa-2b monotherapy: Reduce to average weekly dose of 0.5 mcg/kg as follows:

≤45 kg: 20 mcg once weekly

46 to 56 kg: 25 mcg once weekly

57 to 72 kg: 30 mcg once weekly

73 to 88 kg: 40 mcg once weekly

89 to 106 kg: 50 mcg once weekly

107 to 136 kg: 64 mcg once weekly

≥137 kg: 80 mcg once weekly

Reconstitution

Redipen: Hold cartridge upright and press the two halves together until there is a “click”. Gently invert to mix; do not shake; do not reuse (single use).

Peg-Intron (vial): Add 0.7 mL sterile water for injection, USP (supplied single-use diluent; discard unused portion) to the vial. Gently swirl. Do not re-enter vial after dose removed.

Sylatron (vial): Add 0.7 mL sterile water for injection and swirl gently (do not shake), resulting in the following concentrations (do not withdraw more than 0.5 mL from each vial):

296 mcg vial: 40 mcg/0.1 mL

444 mcg vial: 60 mcg/0.1 mL

888 mcg vial: 120 mcg/0.1 mL

Administration

For SubQ administration; rotate injection site; thigh, outer surface of upper arm, and abdomen are preferred injection sites; do not inject near navel or waistline; patients who are thin should only use thigh or upper arm. Do not inject into bruised, infected, irritated, red, or scarred skin. The weekly dose may be administered at bedtime to reduce flu-like symptoms. For the treatment of CHC, the administration volume depends on the patient’s weight and the peginterferon concentration used.

Compatibility

Do not mix with any other medicines.

Storage

Prior to reconstitution, store Redipen at 2°C to 8°C (36°F to 46°F). Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Once reconstituted each product should be used immediately or may be stored for ≤24 hours at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Keep away from heat. Products do not contain preservative (single use; do not reuse).

Drug Interactions

Aldesleukin: Interferons (Alfa) may enhance the adverse/toxic effect of Aldesleukin. In particular, risks of myocardial and renal toxicity may be increased by this combination. Consider therapy modification

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CYP1A2 Substrates: Peginterferon Alfa-2b may increase the serum concentration of CYP1A2 Substrates. Monitor therapy

CYP2D6 Substrates: Peginterferon Alfa-2b may decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

FLUoxetine: Peginterferon Alfa-2b may decrease the serum concentration of FLUoxetine. Monitor therapy

Methadone: Interferons (Alfa) may increase the serum concentration of Methadone. Monitor therapy

Pegloticase: May diminish the therapeutic effect of Peginterferon Alfa-2b. Monitor therapy

Ribavirin (Oral Inhalation): Interferons (Alfa) may enhance the adverse/toxic effect of Ribavirin (Oral Inhalation). Hemolytic anemia has been observed. Monitor therapy

Ribavirin (Systemic): Interferons (Alfa) may enhance the adverse/toxic effect of Ribavirin (Systemic). Hemolytic anemia has been observed. Monitor therapy

Telbivudine: Peginterferon Alfa-2b may enhance the adverse/toxic effect of Telbivudine. Specifically, the risk for peripheral neuropathy may be increased. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Monitor therapy

Adverse Reactions

Antiviral:

>10%:

Central nervous system: Headache (56%), fatigue (including asthenia; ≤52%), depression (29%), anxiety (≤28%), emotional lability (≤28%), irritability (≤28%), insomnia (23%), rigors (23%), dizziness (12%)

Dermatologic: Alopecia (22%), pruritus (12%)

Endocrine & metabolic: Weight Loss (11%)

Gastrointestinal: Nausea (26%), anorexia (20%), diarrhea (18%), abdominal pain (15%)

Infection: Viral infection (11%)

Local: Inflammation at injection site (47%), injection site reaction (47%)

Neuromuscular & skeletal: Myalgia (54%), weakness (52%), musculoskeletal pain (28%), arthralgia (23%)

Miscellaneous: Fever (22%)

1 to 10%:

Cardiovascular: Chest pain (6%), flushing (6%)

Central nervous system: Lack of concentration (10%), right upper quadrant pain (8%), malaise (7%), nervousness (4%), agitation (2%), suicidal ideation (≤2%)

Dermatologic: Diaphoresis (6%), skin rash (6%)

Endocrine & metabolic: Hypothyroidism (5%), menstrual disease (4%), hyperthyroidism (3%)

Gastrointestinal: Vomiting (7%), dyspepsia (6%), xerostomia (6%), constipation (1%)

Hematologic & oncologic: Thrombocytopenia (7%), neutropenia (6%)

Hepatic: Increased serum ALT (10%), hepatomegaly (6%)

Local: Pain at injection site (2% to 3%)

Ophthalmic: Conjunctivitis (4%), blurred vision (2%)

Respiratory: Pharyngitis (10%), cough (8%), sinusitis (7%), dyspnea (4%), rhinitis (2%)

Antineoplastic:

>10%:

Central nervous system: Fatigue (94%), headache (70%), chills (63%), depression (59%, grades 3/4: 7%), dizziness (35%), neuropathy (olfactory) (23%), paresthesia 21%)

Dermatologic: Exfoliative rash (36%), alopecia (34%)

Endocrine & metabolic: Weight loss (11%)

Gastrointestinal: Anorexia (69%), nausea (64%), dysgeusia (38%), diarrhea (37%), vomiting (26%)

Hepatic: Increased serum ALT (≤77%, grades 3/4: ≤11%), increased serum AST (≤77%, grades 3/4: ≤11%), increased serum alkaline phosphatase (23%)

Local: Injection site reaction (62%)

Neuromuscular & skeletal: Myalgia (68%), arthralgia (51%)

Miscellaneous: Fever (75%)

1 to 10%:

Cardiovascular: Bundle branch block (≤4%), myocardial infarction (≤4%), supraventricular cardiac arrhythmia (≤4%), ventricular tachycardia (≤4%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (8%, grades 3/4: 4%)

Genitourinary: Proteinuria (7%)

Hematologic & oncologic: Anemia (6%)

Respiratory: Dyspnea (6%), cough (5%)

<1% (Limited to important or life-threatening): Aggressive behavior, amnesia, anaphylaxis, angina pectoris, angioedema, aphthous stomatitis, aplastic anemia, auditory impairment, bacterial infection, bipolar mood disorder, brain disease (including exacerbations), bronchiolitis obliterans, bronchoconstriction, cardiac arrest, cardiac arrhythmia, cardiomyopathy, cerebrovascular accident, colitis, cytopenia, dehydration, diabetes mellitus, diabetic ketoacidosis, drug dependence (including relapse), drug overdose, dysgeusia, erythema multiforme, exacerbation of autoimmune disease, exacerbation of renal failure (increases in serum creatinine), fungal infection, hallucination, hearing loss, hemorrhagic colitis, homicidal ideation, hyperglycemia, hypersensitivity reaction, hypertension, hypertriglyceridemia, hypotension, immune thrombocytopenia, interstitial nephritis, interstitial pneumonitis, ischemic colitis, leukopenia, lupus-like syndrome, macular edema, mania, migraine, myositis, optic neuritis, palpitations, pancreatitis, papilledema, paresthesia, peripheral neuropathy, pneumonia, psoriasis, pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, pure red cell aplasia, renal failure, renal insufficiency, retinal cotton-wool spot, retinal detachment, retinal hemorrhage, retinal thrombosis, retinopathy, rhabdomyolysis, rheumatoid arthritis, sarcoidosis, seizure, sepsis, Stevens-Johnson syndrome, systemic lupus erythematosus, tachycardia, thrombotic thrombocytopenic purpura, thyroiditis, toxic epidermal necrolysis, ulcerative colitis, urticaria, vertigo, vision loss, visual disturbance, Vogt-Koyanagi-Harada syndrome

ALERT: U.S. Boxed Warning

Neuropsychiatric disorders (PegIntron):

Alpha interferons, including PegIntron, may cause or aggravate fatal or life-threatening neuropsychiatric disorders. Closely monitor patients with periodic clinical and laboratory evaluations. Withdraw patients with persistently severe or worsening signs or symptoms of these conditions from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy.

Autoimmune disorders (PegIntron):

Alpha interferons, including PegIntron, may cause or aggravate fatal or life-threatening autoimmune disorders. Closely monitor patients with periodic clinical and laboratory evaluations. Withdraw patients with persistently severe or worsening signs or symptoms of these conditions from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy.

Ischemic disorders (PegIntron):

Alpha interferons, including PegIntron, may cause or aggravate fatal or life-threatening ischemic disorders. Closely monitor patients with periodic clinical and laboratory evaluations. Withdraw patients with persistently severe or worsening signs or symptoms of these conditions from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy.

Infectious disorders (PegIntron):

Alpha interferons, including PegIntron, may cause or aggravate fatal or life-threatening infectious disorders. Closely monitor patients with periodic clinical and laboratory evaluations. Withdraw patients with persistently severe or worsening signs or symptoms of these conditions from therapy. In many, but not all cases, these disorders resolve after stopping PegIntron therapy.

Ribavirin use (PegIntron):

Ribavirin may cause birth defects and/or death of the fetus. Take extreme care to avoid pregnancy in women and in female partners of men. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease.

Depression and other neuropsychiatric disorders (Sylatron):

The risk of serious depression with suicidal ideation, 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.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Causes bone marrow suppression, including potentially severe cytopenias; alfa interferons may (rarely) cause aplastic anemia. Use with caution in patients who are chronically immunosuppressed, with low peripheral blood counts or myelosuppression, including concurrent use of myelosuppressive therapy. Dosage modification may be necessary for hematologic toxicity. Combination therapy with ribavirin may potentiate the neutropenic effects of alfa interferons. When used in combination with ribavirin, an increased incidence of anemia was observed when using ribavirin weight-based dosing, as compared to flat-dose ribavirin.

• Colitis: Ulcerative or hemorrhagic/ischemic colitis has been observed with alfa interferons (within 12 weeks of initiation); discontinue therapy if signs of colitis (abdominal pain, bloody diarrhea, fever) develop; symptoms typically resolve within 1-3 weeks.

• Dental/periodontal disorders: Have been reported with combination therapy; dry mouth may affect teeth and mucous membranes. Instruct patients to brush teeth twice daily; encourage regular dental exams. Rinse mouth thoroughly after vomiting.

• Flu-like symptoms: Interferons are commonly associated with flu-like symptoms. Use with caution in patients with debilitating conditions.

• Hypersensitivity: Acute hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) and cutaneous reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported (rarely) with alfa interferons; prompt discontinuation and management is recommended. Transient rashes do not require interruption of therapy.

• Hypertriglyceridemia: Has been reported (may result in pancreatitis); periodically monitor and manage with appropriate treatment; consider discontinuing peginterferon if persistent and severe (triglycerides >1000 mg/dL), particularly if combined with symptoms of pancreatitis.

• Neuropsychiatric disorders: [U.S. Boxed Warning]: May cause or aggravate severe depression or other neuropsychiatric adverse events (including suicide and suicidal ideation) in patients with and without a history of psychiatric disorder; monitor closely with clinical evaluations (periodic). Discontinue treatment with worsening or persistently severe signs/symptoms of neuropsychiatric disorders (eg, depression, encephalopathy, psychosis). Many cases resolve upon discontinuation, although some cases may persist. Addiction relapse, aggression, depression, homicidal ideation and suicidal behavior/ideation have been observed with peginterferon alfa-2b; bipolar disorder, encephalopathy, hallucinations, mania, and psychosis have been observed with other alfa interferons. Onset may be delayed (up to 6 months after discontinuation). Higher doses may be associated with the development of encephalopathy (higher risk in elderly patients). Use with caution in patients with a history of psychiatric disorders, including depression or substance abuse history. New or exacerbated neuropsychiatric or substance abuse disorders are best managed with early intervention. Drug screening and periodic health evaluation (including monitoring of psychiatric symptoms) is recommended if initiating treatment in patients with coexisting psychiatric condition or substance abuse disorders. Monitor all patients for evidence of depression and other psychiatric symptoms; patients being treated for melanoma should be monitored for depression and psychiatric symptoms every 3 weeks during the first 8 weeks of treatment and every 6 months thereafter and permanently discontinue treatment if psychiatric symptoms persist, worsen or if suicidal behavior develops. Patients should continue to be monitored for 6 months after completion of therapy.

• Ophthalmic effects: Ophthalmologic disorders (including decreased visual acuity, blindness, macular edema, retinal hemorrhages, optic neuritis, papilledema, cotton wool spots, retinal detachment [serous], and retinal artery or vein thrombosis) have occurred with peginterferon alfa-2b and/or with other alfa interferons. Prior to start of therapy, ophthalmic exams are recommended for all patients; patients with diabetic or hypertensive retinopathy should have periodic ophthalmic exams during treatment; a complete eye exam should be done promptly in patients who develop ocular symptoms. Permanently discontinue treatment with new or worsening ophthalmic disorder.

• Pancreatitis: Pancreatitis, including fatal cases, has been observed with alfa interferon therapy; withhold treatment for suspected pancreatitis; discontinue therapy for known pancreatitis.

• Pulmonary effects: May cause or aggravate dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis which may result in respiratory failure; may recur upon rechallenge with treatment; monitor closely. Use with caution in patients with existing pulmonary disease (eg, chronic obstructive pulmonary disease). Withhold combination therapy with ribavirin for development of pulmonary infiltrate or pulmonary function impairment.

Disease-related concerns:

• Autoimmune disease: [U.S. Boxed Warning]: May cause or exacerbate autoimmune disorders; monitor closely with clinical and lab evaluations (periodic); discontinue treatment in patients with worsening or persistently severe signs/symptoms of autoimmune disease; may resolve with discontinuation. Thyroiditis, thrombotic thrombocytopenic purpura, immune thrombocytopenia (ITP), rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, and psoriasis have been reported with therapy; use with caution in patients with autoimmune disorders.

• Cardiovascular disease: Use with caution in patients with cardiovascular disease or a history of cardiovascular disease; hypotension, arrhythmia, bundle branch block, tachycardia, cardiomyopathy, angina pectoris and MI have been observed with treatment. Patients with pre-existing cardiac abnormalities should have baseline ECGs prior to combination treatment with ribavirin; closely monitor patients with a history of MI or arrhythmia. Patients with a history of significant or unstable cardiac disease should not receive combination treatment with ribavirin. Discontinue treatment (permanently) for new-onset ventricular arrhythmia or cardiovascular decompensation.

• Diabetes: Diabetes mellitus (including new-onset type I diabetes) and hyperglycemia have been reported; discontinue if diabetes cannot be effectively managed with medication. Use with caution in patients with a history of diabetes mellitus, particularly if prone to DKA.

• Hepatic impairment: Use is contraindicated in patients with hepatic decompensation or autoimmune hepatitis. Discontinue treatment immediately with hepatic decompensation (Child Pugh score >6) or evidence of severe hepatic injury. Patients with chronic hepatitis C (CHC) with cirrhosis and patients coinfected with human immunodeficiency virus (HIV) receiving highly-active antiretroviral therapy (HAART) are at increased risk for hepatic decompensation; monitor closely. A transient increase in ALT (2-5 times above baseline) which is not associated with liver dysfunction may occur with peginterferon alfa-2b use (for the treatment of chronic hepatitis C); may continue treatment with close monitoring. Instruct patients to avoid alcohol; may increase hepatic effects.

• Infectious disorders: [U.S. Boxed Warning]: May cause or aggravate infectious disorders; monitor closely with clinical and lab evaluations (periodic); discontinue treatment in patients with worsening or persistently severe signs/symptoms of infectious disorders; may resolve with discontinuation. Interferon therapy is commonly associated with flu-like symptoms, including fever; rule out other causes/infection with persistent or high fever.

• Ischemic disorders: [U.S. Boxed Warning]: May cause or aggravate ischemic and hemorrhagic cerebrovascular events; monitor closely with clinical and lab evaluations (periodic); discontinue treatment in patients with worsening or persistent ischemia; may resolve with discontinuation. Have been reported in patients without risk factors for stroke.

• Renal impairment: Use with caution in patients with renal impairment (CrCl <50 mL/minute); monitor closely for signs of interferon toxicity. For the treatment of chronic hepatitis C, dosage adjustments are recommended with monotherapy in patients with moderate to severe impairment; do not use combination therapy with ribavirin in adults with renal dysfunction (CrCl <50 mL/minute); discontinue if serum creatinine >2 mg/dL in children. Dosage adjustment is also recommended when used for the treatment of melanoma. Serum creatinine increases have been reported in patients with renal insufficiency.

• Thyroid disorders: Use with caution in patients with thyroid disorders; may cause or aggravate hyper- or hypothyroidism. Discontinue use in patients with thyroid disease who cannot be controlled with medication.

Concurrent drug therapy issues:

• Combination therapy with ribavirin: [U.S. Boxed Warning]: Combination treatment with ribavirin may cause birth defects and/or fetal mortality, hemolytic anemia (which may worsen cardiac disease), genotoxicity, mutagenicity, and may possibly be carcinogenic.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Telbivudine: Peripheral neuropathy has been reported with alpha interferons when used in combination with telbivudine.

Special populations:

• Elderly: Use with caution in the elderly; the potential adverse effects (eg, neuropsychiatric events, cardiac events, systemic effects) may be more pronounced. Encephalopathy has also been observed in primarily elderly patients treated with higher doses of peginterferon alfa-2b. For the treatment of hepatitis, elderly patients generally do not respond to interferon treatment as well as younger patients. When used in combination with ribavirin, closely monitor adults >50 years of age for the development of anemia.

• Pediatric: Growth velocity (height and weight) was decreased in children on combination treatment with ribavirin, during the length of treatment. In clinical studies, decreases were noted in weight and height for age z-scores and normative growth curve percentiles. Severely inhibited growth velocity has been noted. Following treatment, rebound growth and weight gain occurred in most patients; however, a small percentage did not. Long-term follow-up data indicate that combination therapy may inhibit growth, resulting in reduced adult height in some patients. Growth should be closely monitored in pediatric patients during therapy and posttreatment until growth catch-up has occurred.

• Pregnancy: [U.S. Boxed Warning]: Combination therapy with ribavirin may cause birth defects and/or fetal mortality; avoid pregnancy in females and female partners of male patients. Combination therapy with ribavirin is contraindicated in pregnancy.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

• Product variability: Due to differences in dosage, patients should not change brands of interferon.

Other warnings/precautions:

• Appropriate use: Combination therapy with ribavirin is preferred over monotherapy for the treatment of chronic hepatitis C. Safety and efficacy have not been established in patients who have received organ transplants or are coinfected with HIV or hepatitis B. Patients with significant bridging fibrosis or cirrhosis, genotype 1 infection or who have not responded to prior therapy, including previous pegylated interferon treatment are less likely to benefit from combination therapy with peginterferon alfa-2b and ribavirin.

Monitoring Parameters

Baseline and periodic TSH (for patients being treated for melanoma, obtain baseline within 4 weeks prior to treatment initiation, and then at 3 and 6 months, and every 6 months thereafter during treatment); CBC with differential and platelets; serum chemistries, liver function tests (for patients with melanoma, monitor serum bilirubin, ALT, AST, alkaline phosphatase, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months during therapy), renal function, triglycerides; serum glucose or HbA1c (for patients with diabetes mellitus). Clinical studies (for combination therapy) tested as follows: CBC (including hemoglobin, WBC, and platelets) and chemistries (including liver function tests and uric acid) measured at weeks 2, 4, 8, and 12, and then every 6 weeks; TSH measured every 12 weeks during treatment. ECG at baseline for patients with pre-existing cardiac abnormalities (for combination therapy with ribavirin).

Hepatitic C: Serum HCV RNA levels (pretreatment, 12 and 24 weeks after therapy initiation, 24 weeks after completion of therapy). Note: Discontinuation of therapy may be considered after 12 weeks in patients with HCV (genotype 1) who fail to achieve an early virologic response (EVR) (defined as ≥2-log decrease in HCV RNA compared to pretreatment) or after 24 weeks with detectable HCV RNA. Treat patients with HCV (genotypes 2,3) for 24 weeks (if tolerated) and then evaluate HCV RNA levels (Ghany, 2009).

Evaluate for depression and other psychiatric symptoms before and after initiation of therapy; patients being treated for melanoma should be monitored for depression and psychiatric symptoms every 3 weeks during the first eight weeks of treatment and every 6 months thereafter, and continued monitoring for 6 months after the last dose; baseline ophthalmic eye examination; periodic ophthalmic exam in patients with diabetic or hypertensive retinopathy; baseline ECG in patients with cardiac disease; serum glucose or HbA1c (for patients with diabetes mellitus). In combination therapy with ribavirin, pregnancy tests (for women of childbearing age who are receiving treatment or who have male partners who are receiving treatment), continue monthly up to 6 months after discontinuation of therapy. In pediatric patients, growth velocity and weight should also be monitored during and periodically after treatment discontinuation.

Pregnancy Risk Factor

C / X in combination with ribavirin

Pregnancy Considerations

[US Boxed Warning]: Combination therapy with ribavirin may cause birth defects and/or fetal mortality; avoid pregnancy in females and female partners of male patients; combination therapy with ribavirin is contraindicated in pregnancy. Two forms of contraception should be used along with monthly pregnancy tests during combination therapy and for 6 months after therapy has been discontinued.

Reproduction studies with pegylated interferon alfa have not been conducted. Animal reproduction studies with nonpegylated interferon alfa-2b have demonstrated abortifacient effects. Disruption of the normal menstrual cycle was also observed in animal studies; therefore, the manufacturer recommends that reliable contraception is used in women of childbearing potential. Alfa interferon is endogenous to normal amniotic fluid (Lebon 1982). In vitro administration studies have reported that when administered to the mother, it does not cross the placenta (Waysbort 1993). Case reports of use in pregnant women are limited. The HHS Perinatal HIV Guidelines do not recommend that peginterferon alfa be used during pregnancy (HHS [perinatal] 2016).

A pregnancy registry has been established for women inadvertently exposed to ribavirin while pregnant (800-593-2214).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience flu-like symptoms, nausea, vomiting, diarrhea, lack of appetite, hair loss, insomnia, loss of strength and energy, weight loss, headache, muscle pain, joint pain, change in taste, dry mouth, or injection site irritation. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), hallucinations, psychosis, signs of infection, signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, tachycardia, arrhythmia, severe dizziness, passing out, shortness of breath, excessive weight gain or loss, swelling of arms or legs, bruising, bleeding, vision changes, eye pain, severe eye irritation, blindness, difficulty focusing, temperature sensitivity, teeth or gingival changes, burning or numbness feeling, signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; diarrhea), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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