Peginterferon Alfa-2a

Dosage Forms

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

Solution, Subcutaneous:

Pegasys: 180 mcg/mL (1 mL) [contains benzyl alcohol, polysorbate 80]

Solution, Subcutaneous [preservative free]:

Pegasys: 180 mcg/0.5 mL (0.5 mL) [contains benzyl alcohol, polysorbate 80]

Pegasys ProClick: 135 mcg/0.5 mL (0.5 mL [DSC]); 180 mcg/0.5 mL (0.5 mL) [contains benzyl alcohol, polysorbate 80]

Pharmacology

Mechanism of Action

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. Interferons inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells.

Pharmacokinetics/Pharmacodynamics

Time to Peak

Serum: 72 to 96 hours

Half-Life Elimination

Terminal: 50-160 hours; increased with renal dysfunction

Use in Specific Populations

Special Populations: Renal Function Impairment

Clearance is decreased 43% in patients with severe renal impairment (CrCl <30 mL/minute).

Special Populations: Elderly

AUC is increased in patients >62 years of age.

Special Populations: Children

Clearance was nearly 4-fold lower in children 2 to 8 years of age.

Use: Labeled Indications

Chronic hepatitis B: Treatment of adults with hepatitis B e antigen (HBeAg)-positive and HBeAg-negative chronic hepatitis B virus (HBV) infection who have compensated liver disease and evidence of viral replication and liver inflammation; treatment of pediatric patients ≥3 years of age with HBeAg-positive chronic HBV infection who are non-cirrhotic and have evidence of viral replication and elevations of serum alanine aminotransferase.

Contraindications

Hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome) to peginterferon alfa-2a, other alfa interferons, or any component of the formulation; autoimmune hepatitis; hepatic decompensation in cirrhotic patients (Child-Pugh score >6, class B and C) before treatment; hepatic decompensation with Child-Pugh score ≥6 in cirrhotic CHC coinfected with HIV before treatment; neonates and infants (due to benzyl alcohol component)

Combination therapy with peginterferon alfa-2a and ribavirin is also contraindicated in pregnancy; men whose female partners are pregnant; patients with hemoglobinopathies (ie, thalassemia major, sickle cell disease); coadministration with didanosine

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to E. coli-derived products; history of autoimmune disease; severe psychiatric disorder or history of severe psychiatric disorder; uncontrolled thyroid disorder; breastfeeding

Dosage and Administration

Dosing: Adult

Chronic hepatitis B: SubQ: 180 mcg once weekly for 48 weeks.

Missed dose: If within 2 days of the usual day of administration, administer dose as soon as possible then resume prior schedule; if >2 days after the usual day of administration then contact health care provider.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis B (CHB) infection (hepatitis B e antigen [HBeAg] positive): Children ≥3 years and Adolescents: SubQ: 104 mcg/m² once weekly; maximum dose: 180 mcg/dose; duration of therapy: 48 weeks. Note: Dosing presented is mathematically equivalent to weekly dosing presented in manufacturer's labeling: 180 mcg/1.73 m² x Body Surface Area (BSA); adolescents who reach their 18th birthday during treatment should remain on the pediatric regimen.

Chronic hepatitis C (CHC) infection: Note: Although FDA approved in pediatric patients ≥5 years of age, AASLD/IDSA guidelines do not recommend the use of interferon products for the treatment of hepatitis C in children 3 to 11 years (AASLD/IDSA 2018).

Children ≥5 years and Adolescents: SubQ: 104 mcg/m² once weekly; maximum dose: 180 mcg/dose; in combination with ribavirin (Schwarz 2011); Note: Dosing presented is mathematically equivalent to weekly dosing presented in manufacturer's labeling: 180 mcg/1.73 m² x BSA; adolescents who reach their 18th birthday during treatment should remain on the pediatric regimen.

Duration of therapy (based on genotype):

HCV genotype 1, 4, 5, 6: 48 weeks

HCV genotype 2, 3: 24 weeks

Note: Pharmacokinetic simulation and modeling (including 14 pediatric and 402 adult patients [accounting for 143 pediatric and 4,020 adult pharmacokinetic observations] from multiple clinical trials) has developed a simplified weight-band dosing for BSA ranges (see the following) to provide similar exposure to the 104 mcg/m² (180 mcg/1.73 m²) weekly regimen; direct patient experience is lacking (Brennan 2016)

BSA 0.71 to 0.74 m²: 65 mcg/dose

BSA 0.75 to 1.08 m²: 90 mcg/dose

BSA 1.09 to 1.51 m²: 135 mcg/dose

BSA >1.51 m²: 180 mcg/dose

Dosing adjustment for toxicity: Note: Pediatric dosing adjustments shown below correspond to the following doses in manufacturer's labeling: 78 mcg/m² = 135 mcg/1.73 m²; 52 mcg/m² = 90 mcg/1.73 m²; and 26 mcg/m² = 45 mcg/1.73 m² (Schwarz 2011).

Depression: CHB, CHC: Children ≥3 years and Adolescents:

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. If depression worsens after 8 weeks, consider psychiatric consultation; discontinue therapy or decrease dose to 78 mcg/m² once weekly or a further dose reduction to 52 mcg/m² once weekly.

Moderate depression: Decrease dose to 78 mcg/m² once weekly or a further dose reduction to 52 mcg/m² once weekly. Evaluate once weekly with an office visit at least every other week. After 8 weeks, if symptoms improve and remain stable for 4 weeks, resume normal visit schedule; may continue reduced dosing or return to normal dose. If depression remains stable, consider psychiatric evaluation and continue reduced dosing. If symptoms worsen, obtain immediate psychiatric consultation and discontinue therapy permanently.

Severe depression: Discontinue interferon treatment permanently. Obtain immediate psychiatric consultation and therapy necessary.

Hematologic toxicity: Note: For CHC, management dependent upon weeks of therapy

Neutropenia:

ANC 750 to 999/mm³:

CHB: Children ≥3 years and Adolescents: No dosage modification.

CHC: Children ≥5 years and Adolescents:

Week 1 to 2: Decrease dose to 78 mcg/m² once weekly

Weeks 3 to 48: No modification

ANC 500 to 749/mm³:

CHB: Children ≥3 years and Adolescents: Decrease dose to 78 mcg/m² once weekly

CHC: Children ≥5 years and Adolescents:

Week 1 to 2: Hold dose until ANC >750/mm³ then resume therapy at 78 mcg/m² once weekly. Assess WBC 3 times weekly to verify ANC >750/mm³.

Weeks 3 to 48: Decrease dose to 78 mcg/m² once weekly

ANC 250 to 499/mm³:

CHB: Children ≥3 years and Adolescents: Hold dose until ANC ≥1,000/mm³, then resume dose at 52 mcg/m² once weekly

CHC: Children ≥5 years and Adolescents:

Week 1 to 2: Hold dose until ANC >750/mm³ then resume dose at 52 mcg/m² once weekly

Weeks 3 to 48: Hold dose until ANC >750/mm³ then resume dose at 78 mcg/m² once weekly

ANC <250/mm³ or febrile neutropenia: CHB, CHC: Children ≥3 years and Adolescents: Discontinue treatment.

Thrombocytopenia:

Platelet count 25,000 to <50,000/mm³: CHB, CHC: Children ≥3 years and Adolescents: Decrease dose to 52 mcg/m² once weekly.

Platelet count <25,000: CHB, CHC: Children ≥3 years and Adolescents: Discontinue treatment.

Dosing: Adjustment for Toxicity

Dosage modifications for adverse reactions and/or toxicity:

HBV:

Based on hematologic parameters:

ANC 500 to <750/mm³: Decrease dose to 135 mcg once weekly.

ANC <500/mm³: Suspend therapy until ANC >1,000/mm³, then restart at 90 mcg once weekly; monitor ANC.

Platelet count 25,000 to <50,000/mm³: Decrease dose to 90 mcg once weekly.

Platelet count <25,000/mm³: Discontinue therapy.

Depression (severity based on 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, discontinue or reduce dosage to 90 mcg or 135 mcg once weekly. Consider psychiatric consultation.

Moderate depression: Decrease to 90 mcg or 135 mcg once weekly; evaluate once weekly 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, discontinue permanently and obtain immediate psychiatric consultation.

Severe depression: Discontinue permanently. Obtain immediate psychiatric consultation. Utilize follow-up psychiatric therapy as needed.

Reconstitution

Do not shake vial, prefilled syringe, or autoinjector. Allow syringe, autoinjector, or vial to reach room temperature before use; wait for condensation on the outside of the syringe or autoinjector to disappear before use. The vial may be warmed by gently rolling in the palms of the hand for ~1 minute. Allow the prefilled syringe to come to room temperature by laying it on a flat, clean surface for a few minutes. Allow the autoinjector to come to room temperature on its own for ~20 minutes; do not warm autoinjector any other way. Use 180 mcg/mL vial to prepare pediatric dose; use 1 mL tuberculin syringe to withdraw dose from vial.

Administration

SubQ: Administer in the abdomen or thigh. Rotate injection site. Administration should be done on the same day and at approximately the same time each week.

Storage

Store in refrigerator at 2°C to 8°C (36°F to 46°F). Do not leave out of the refrigerator for more than 24 hours. Do not freeze or shake. Protect from light. Discard any unused portion. The following stability information has also been reported:

Intact vial: May be stored at room temperature for up to 14 days (Cohen, 2007).

Prefilled syringe: May be stored at room temperature for up to 6 days (Cohen, 2007).

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

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

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

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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

Pegloticase: May diminish the therapeutic effect of PEGylated Drug Products. Monitor therapy

Pegvaliase: PEGylated Drug Products may enhance the adverse/toxic effect of Pegvaliase. Specifically, the risk of anaphylaxis or hypersensitivity reactions may be increased. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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-2a may enhance the adverse/toxic effect of Telbivudine. Specifically, the risk for peripheral neuropathy may be increased. Avoid combination

Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Interferons (Alfa) may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

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

Adverse Reactions

>10%:

Central nervous system: Fatigue (adults: ≤56%; children and adolescents: 8%), headache (adults: 27% to 54%; children and adolescents: 21%), rigors (adults: 25% to 35%), insomnia (adults: 19%), anxiety (adults: ≤19%), irritability (adults: ≤19%), nervousness (adults: ≤19%), depression (adults: 18%), dizziness (adults: 16%; children and adolescents: 6%), pain (adults: 11%)

Dermatologic: Alopecia (adults: 18% to 23%; children and adolescents: 6%), pruritus (adults: 12%)

Endocrine & metabolic: Growth suppression (children and adolescents, percentile decrease (≥15 percentiles), weight: [11% to 43%], height: [6% to 25%])

Gastrointestinal: Nausea (adults: ≤24%; children and adolescents: 9%), vomiting (adults: ≤24%), anorexia (adults: 16% to 17%), abdominal pain (15% to 17%), diarrhea (adults: 16%)

Hematologic & oncologic: Neutropenia (adults: 21%)

Hepatic: Increased serum ALT (adults, hepatitis B: 25% to 27%; children and adolescents: 10%; adults, hepatitis C: 1%)

Local: Injection site reaction (adults: 22%)

Neuromuscular & skeletal: Weakness (adults: ≤56%; children and adolescents: 9%), myalgia (adults: 37%), arthralgia (adults: 28%)

Respiratory: Cough (children and adolescents: 15%; adults: 4%), flu-like symptoms (children and adolescents: 14%)

Miscellaneous: Fever (37% to 54%)

1% to 10%:

Central nervous system: Lack of concentration (adults: 8%), memory impairment (adults: 5%), mood changes (adults: 3%)

Dermatologic: Skin rash (5% to 10%), dermatitis (adults: 8%), diaphoresis (adults: 6%), xeroderma (adults: 4%), eczema (adults: 1%)

Endocrine & metabolic: Weight loss (adults: 4%), hypothyroidism (adults: 3% to 4%), hyperthyroidism (adults: ≤1%)

Gastrointestinal: Decreased appetite (children and adolescents: 6%), xerostomia (adults: 6%)

Hematologic & oncology: Thrombocytopenia (adults: 5%), lymphocytopenia (adults: 3%), anemia (adults: 2%)

Hepatic: Increased serum AST (children and adolescents: 10%), liver decompensation (in CHC/HIV patients; adults: 2%)

Infection: Bacterial infection (adults: ≤5%)

Neuromuscular & skeletal: Back pain (adults: 9%)

Ophthalmic: Blurred vision (adults: 4%)

Respiratory: Epistaxis (children and adolescents: 9%), upper respiratory tract infection (children and adolescents: 8%), nasopharyngitis (children and adolescents: 6%), dyspnea (adults: 4%)

≤1%, postmarketing, and/or case reports: Aggressive behavior, anaphylaxis, angina pectoris, angioedema, aplastic anemia, auditory impairment, autoimmune disorders, bipolar mood disorder, bronchiolitis obliterans, bronchoconstriction, cardiac arrhythmia, cerebral hemorrhage, chest pain, cholangitis, colitis, coma, corneal ulcer, dehydration, diabetes mellitus, dyspepsia, dyspnea on exertion, endocarditis, erythema multiforme major, exacerbation of hepatitis B, exfoliative dermatitis, gastrointestinal hemorrhage, graft rejection (hepatic, renal), hallucination, hearing loss, hematocrit decreased, hemoglobin decreased, hepatic insufficiency, hyperglycemia, hyperpigmentation, hypersensitivity reaction, hypertension, hypoglycemia, increased serum triglycerides, influenza, interstitial pneumonitis, limb abscess, liver steatosis, macular edema, mania, myocardial infarction, myositis, optic neuritis, pancreatitis, papilledema, peptic ulcer, peripheral neuropathy, pneumonia, psychiatric disturbance, psychosis, pulmonary embolism, pulmonary infiltrates, pure red cell aplasia, retinal cotton-wool spot, retinal detachment, retinal hemorrhage, retinal thrombosis (in artery or vein), retinopathy, rheumatoid arthritis, sarcoidosis, seizures, Stevens-Johnson syndrome, substance overdose, suicidal ideation, supraventricular arrhythmia, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, tongue discoloration, urticaria, vesiculobullous reaction, vision loss

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. Ribavirin may potentiate these effects. When used in combination with ribavirin, use caution with baseline neutrophil count <1,500/mm³, platelet count <90,000/mm³ or hemoglobin <10 g/dL. Discontinue therapy (at least temporarily) if ANC <500/mm³ or platelet count <25,000/mm³. Severe neutropenia and thrombocytopenia may occur with a greater incidence in HIV coinfected patients than monoinfected patients. Obtain CBC before treatment and monitor routinely during therapy.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Dermatologic effects: Serious cutaneous reactions, including vesiculobullous eruptions, Stevens-Johnson syndrome, and exfoliative dermatitis, have been reported with use, with or without ribavirin therapy; discontinue with signs or symptoms of severe skin reactions.
• Gastrointestinal effects: Gastrointestinal hemorrhage, ulcerative and hemorrhagic/ischemic colitis (may be fatal) have been observed with interferon alfa treatment; may be severe and/or life-threatening; discontinue immediately if symptoms of colitis (eg, abdominal pain, bloody diarrhea, and/or fever) develop. Colitis generally resolves within 1 to 3 weeks of discontinuation.
• Hepatic effects: Hepatic decompensation and death have been associated with the use of alpha interferons including Pegasys, in cirrhotic chronic hepatitis C patients; patients coinfected with HIV and receiving antiretroviral therapy have shown an increased risk. Monitor hepatic function closely during use; discontinue immediately if decompensation occurs (Child-Pugh score >6) in monoinfected patients and (Child-Pugh score ≥6, class B and C) in patients coinfected with HIV. Instruct patients to avoid alcohol; may increase hepatic effects.
• Hypersensitivity reactions: Severe acute hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been reported; prompt discontinuation and management is recommended.
• Neuropsychiatric disorders: [US Boxed Warning]: May cause or exacerbate life-threatening neuropsychiatric disorders; monitor closely; discontinue treatment with worsening or persistently severe signs/symptoms of neuropsychiatric disorders. In most cases these effects were reversible following discontinuation, but not all cases. Neuropsychiatric adverse effects include depression, suicidal ideation, suicide attempt, homicidal ideation, drug overdose, and relapse of drug addiction, and may occur in patients with or without a prior history of psychiatric disorder. Avoid use in severe psychiatric disorders; use with extreme caution in patients with a history of depression.
• Ophthalmic effects: Decreased or loss of vision and retinopathy, including macular edema, optic neuritis, papilledema, retinal hemorrhages, retinal detachment (serous), cotton wool spots, and retinal artery or vein thrombosis, may occur or be aggravated during treatment; if any ocular symptoms occur during use, a complete eye exam should be performed promptly. Prior to use, all patients should have a visual exam and patients with preexisting disorders (eg, diabetic or hypertensive retinopathy) should have exams periodically during therapy. Discontinue if new or worsening ophthalmologic disorders occur.
• Pancreatitis: Pancreatitis, including fatal cases, has been observed with alfa interferon and ribavirin therapy. Withhold treatment for suspected pancreatitis; discontinue therapy for confirmed pancreatitis.
• Pulmonary effects: May cause or aggravate dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, which may result in potentially fatal respiratory failure; may recur upon rechallenge with interferons. Monitor closely. Discontinue with pulmonary infiltrates or evidence of impaired pulmonary function. Use with caution in patients with pulmonary dysfunction or a history of pulmonary disease.

Disease-related concerns:

• Autoimmune disease: [US Boxed Warning]: May cause or exacerbate autoimmune disorders; monitor closely; discontinue treatment in patients with worsening or persistently severe signs/symptoms of autoimmune disease. In most cases these effects were reversible following discontinuation, but not all cases. Thyroiditis, thrombotic thrombocytopenic purpura, immune thrombocytopenia (formerly known as idiopathic thrombocytopenic purpura), rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus, myositis, hepatitis, and psoriasis have been reported with interferon therapy; use with caution in patients with autoimmune disorders.
• Cardiovascular disease: Use with caution in patients with prior cardiovascular disease; hypertension, supraventricular arrhythmias, chest pain, and MI have been observed with treatment. Patients with a history of significant or unstable cardiac disease should not receive combination treatment with ribavirin.
• Diabetes: Use with caution in patients with diabetes mellitus; hyper/hypoglycemia have been reported; may require adjustments in antidiabetic medications; discontinue if unable to effectively manage diabetes with medication.
• Hepatitis B: In hepatitis B patients, flares (transient and potentially severe increases in serum ALT) may occur during or after treatment; more frequent monitoring of LFTs and a dose reduction are recommended. Discontinue immediately if ALT elevation continues despite dose reduction or if increased bilirubin or hepatic decompensation occur.
• Infectious disorders: [US Boxed Warning]: May cause or aggravate infectious disorders; monitor closely; discontinue treatment in patients with worsening or persistently severe signs/symptoms of infectious disorders. In most cases these effects were reversible following discontinuation, but not all cases. Serious and severe infections (bacterial, viral, and fungal), some fatal, have been reported with treatment. Interferon therapy is commonly associated with flu-like symptoms, including fever; rule out other causes/infection with persistent or high fever.
• Ischemic disorders: [US Boxed Warning]: May cause or aggravate ischemic disorders and hemorrhagic cerebrovascular events; monitor closely; discontinue treatment in patients with worsening or persistent ischemia. In most cases these effects were reversible following discontinuation, but not all cases. Has been reported in patients without risk factors for stroke.
• Renal impairment: Use with caution in patients with renal dysfunction (CrCl <30 mL/minute); dosage adjustment recommended; monitor for signs/symptoms of toxicity (dosage adjustment required if toxicity occurs).
• Seizure disorders: Clinical practice chronic hepatitis B treatment guidelines do not recommend use in patients with uncontrolled seizures (AASLD [Terrault 2016]).
• Thyroid disorders: Use with caution in patients with preexisting thyroid disease; thyroid disorders (hyper- or hypothyroidism) or exacerbations have been reported; discontinue if unable to effectively manage with medication.

Concurrent drug therapy issues:

• 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.

Special populations:

• Elderly: Use with caution in the elderly; certain adverse effects (eg, neuropsychiatric, cardiac, flu-like reactions) may be more severe.
• Pediatric: Growth velocity (height and weight) was decreased in children with or without 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. Following treatment, rebound growth and weight gain occurred in most patients; however, a small percentage did not. For most children with hepatitis C, posttreatment recovery in growth at 2 years posttreatment was maintained to 6 years posttreatment; no data are available on long term follow-up for children with hepatitis B. Growth should be closely monitored in children during therapy and posttreatment until growth catch-up has occurred.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• 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 without the concurrence of their health care provider.

Other warnings/precautions:

• Appropriate use: Hepatitis B: Hepatitis B genotypes A and B are more likely to achieve HBeAg and HBsAg loss with peg-interferon than non-A/B genotypes. For patients with hepatitis B coinfected with hepatitis delta virus, pegylated interferon is the only effective therapy (AASLD [Terrault 2016]).

Monitoring Parameters

Manufacturer's labeling:

Clinical studies tested as follows:

Pediatric patients: Hematologic and biochemical assessments were made at weeks 1, 3, 5, and 8, and then every 4 weeks thereafter; TSH measured every 12 weeks.

Adults: CBC (including hemoglobin, WBC, and platelets) and chemistries (including liver function tests and uric acid) measured at weeks 1, 2, 4, 6, and 8, and then every 4-6 weeks (more frequently if abnormal); TSH measured every 12 weeks.

In addition, the following baseline values were used as entrance criteria in adults:

Platelet count ≥90,000/mm³ (as low as 75,000/mm³ in patients with cirrhosis).

ANC ≥1,500/mm³

Serum creatinine <1.5 times ULN

TSH and T₄ within normal limits or adequately controlled

CD4⁺ cell count ≥200 cells/mm³ or CD4⁺ cell count ≥100 cells/mm³

Prior to treatment, pregnancy screening should occur for women of childbearing age who are receiving treatment or who have male partners who are receiving treatment. In combination therapy with ribavirin, pregnancy tests should continue monthly up to 6 months after discontinuation of therapy. Evaluate for depression and other psychiatric symptoms before and during therapy; baseline eye examination and periodically in patients with baseline disorders; baseline echocardiogram in patients with cardiac disease. In children, growth velocity and weight should be monitored during and periodically after combination therapy is discontinued.

Alternate recommendations (AASLD [Terrault 2016]): Chronic Hepatitis B:

During therapy: CBC (monthly to every 3 months); TSH (every 3 months); monitor for autoimmune, ischemic, neuropsychiatric, and infectious complications.

Pregnancy

Pregnancy Considerations

Alfa interferon is endogenous to normal amniotic fluid (Lebon 1982); however, placenta perfusion studies note exogenous interferon alfa does not cross the placenta (Waysbort 1993). The Health and Human Services (HHS) Perinatal HIV Guidelines recommend against the use of peginterferon-alfa during pregnancy because of its antigrowth and antiproliferative effects (HHS [perinatal] 2019). Animal reproduction studies have demonstrated abortifacient effects.

Treatment of hepatitis C is not currently recommended to treat maternal infection or to decrease the risk of mother-to-child transmission during pregnancy (Tran 2016). HCV-infected females of childbearing potential should consider postponing pregnancy until therapy is complete to reduce the risk of HCV transmission (AASLD/IDSA 2017).

Verify pregnancy status prior to administration in females of reproductive potential. Disruption of the normal menstrual cycle was also observed in animal studies; therefore, the manufacturer recommends that reliable contraception is used in females of childbearing potential.

Peginterferon alfa-2a in combination with ribavirin is contraindicated in pregnant females or males whose female partners are pregnant. Combination therapy with ribavirin may cause birth defects and death in an unborn child. All warnings related to the use of ribavirin and pregnancy and/or contraception should be followed. Refer to the ribavirin monograph for additional information.

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, abdominal pain, dry mouth, muscle pain, joint pain, back pain, vomiting, diarrhea, lack of appetite, hair loss, trouble sleeping, sweating a lot, or injection site irritation. Have patient report immediately to prescriber signs of depression (thoughts of suicide, anxiety, emotional instability, confusion), homicidal ideation, sensing things that seem real but are not, psychosis, signs of infection, severe loss of strength and energy, signs of thyroid problems (change in weight without trying, anxiety, agitation, feeling very weak, hair thinning, depression, neck swelling, difficulty focusing, inability handling heat or cold, menstrual changes, tremors, or sweating), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), chest pain, fast heartbeat, abnormal heartbeat, severe headache, difficulty breathing, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, bruising, bleeding, vision changes, difficulty focusing, irritability, trouble with memory, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; diarrhea), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or 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.

Patient Education

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.