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Peginterferon Alfa-2a

Pronunciation

(peg in ter FEER on AL fa too aye)

Index Terms

  • Interferon Alfa-2a (PEG Conjugate)
  • PEG-IFN Alfa-2a
  • Pegylated Interferon Alfa-2a

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Kit, Subcutaneous [preservative free]:

Pegasys: 180 mcg/0.5 mL [contains benzyl alcohol]

Solution, Subcutaneous [preservative free]:

Pegasys: 180 mcg/mL (1 mL); 180 mcg/0.5 mL (0.5 mL) [contains benzyl alcohol, polysorbate 80]

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

Pegasys ProClick: 180 mcg/0.5 mL (0.5 mL) [contains benzyl alcohol]

Brand Names: U.S.

  • Pegasys
  • Pegasys ProClick

Pharmacologic Category

  • 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. 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.

Time to Peak

Serum: 72 to 96 hours

Half-Life Elimination

Terminal: 160 hours

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

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

Chronic hepatitis C:

Combination therapy: Treatment of adults with chronic hepatitis C (CHC) with compensated liver disease as part of a combination regiment with other hepatitis C virus (HCV) antiviral drugs; treatment of pediatric patients 5 years and older with CHC and compensated liver disease in combination with ribavirin

Monotherapy (for patients with contraindications or who are intolerant to other HCV antiviral drugs): Treatment (as a single agent) of chronic hepatitis C in patients with compensated liver disease in patients with contraindications or significant intolerance to other HCV antiviral drugs

Limitations of use: Peginterferon alfa-2a alone or in combination with ribavirin without additional HCV antiviral drugs is not recommended for treatment of patients with chronic HCV who previously failed therapy with an interferon alfa. Peginterferon alfa-2a is not recommended for treatment of patients with CHC who have had solid organ transplantation.

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 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

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

Dosage

Chronic hepatitis C: Children ≥5 years and Adolescents: SubQ: 180 mcg/1.73 m2 x body surface area (BSA) once weekly (maximum dose: 180 mcg) with ribavirin (Copegus). Note: Children who reach their 18th birthday during treatment should remain on the pediatric regimen until completion of therapy.

Duration of therapy (based on genotype):

Genotypes 1, 4, 5, 6: 48 weeks

Genotypes 2, 3: 24 weeks

Chronic hepatitis C (monoinfection or coinfection with HIV): Adults: SubQ:

Manufacturer’s labeling: 180 mcg once weekly for 48 weeks as monotherapy or in combination with ribavirin (Copegus). Note: Discontinue in patients with HCV (genotype 1) after 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.

Duration of combination therapy: Monoinfection (based on genotype):

Genotypes 1, 2: Refer to the individual agents of HCV antiviral drugs

Genotypes 3: 24 weeks if peg interferon and ribavirin are used without other HCV antiviral drugs

Genotypes 4: 48 weeks if peginterferon and ribavirin are used without other HCV antiviral drugs

Genotypes 5, 6: No dosing recommendations provided; data insufficient

Duration of therapy: Coinfection with HIV: 48 weeks regardless of HCV genotype (if used without other HCV antiviral drugs). When used in combination with other antiviral drugs, refer to individual agents for duration of therapy.

Alternative dosing:

Chronic hepatitis C (off-label uses; recommended regimens, AASLD/IDSA, 2014): Treatment naïve patients:

Genotype 1, 4, 5, or 6: Interferon eligible patients: 180 mcg once weekly in combination with sofosbuvir 400 mg once daily and ribavirin for 12 weeks:

<75 kg: Ribavirin 1000 mg daily

≥75 kg: Ribavirin 1200 mg daily

Chronic hepatitis C (off-label uses; recommended regimens, AASLD/IDSA, 2014): Treatment of relapser patients (non responders to a previous regimen of ribavirin and peginterferon without an HCV protease inhibitor):

Genotype 4, 5, or 6: Interferon eligible patients: 180 mcg once weekly in combination with sofosbuvir 400 mg once daily and ribavirin for 12 weeks

<75 kg: Ribavirin 1000 mg daily

≥75 kg: Ribavirin 1200 mg daily

Chronic hepatitis C (off-label uses; recommended regimen, AASLD/IDSA, 2014): Treatment of relapser patients (non responders to a previous regimen of ribavirin and peginterferon with or without an HCV protease inhibitor):

Genotype 1: Interferon eligible patients: 180 mcg once weekly in combination with ribavirin for 12-24 weeks total and sofosbuvir 400 mg once daily for the first 12 weeks only

<75 kg: Ribavirin 1000 mg daily

≥75 kg: Ribavirin 1200 mg daily

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

Dose modifications for adverse reactions/toxicity:

Children ≥5 years and Adolescents: HCV:

For moderate-to-severe adverse reactions: Decrease to 135 mcg/1.73 m2 x BSA once weekly for initial dose reduction; further dose reductions to 90 mcg/1.73 m2 x BSA once weekly or 45 mcg/1.73 m2 x BSA once weekly may be necessary in some cases if reaction persists or recurs. Up to 3 dosing adjustments for toxicity may be made before discontinuation is considered.

Based on hematologic parameters:

ANC 750 to 999/mm3: Week 1 to 2: 135 mcg/1.73 m2 x BSA once weekly; Weeks 3-48: No modification

ANC 500 to 749/mm3: Week 1 to 2: Delay or hold dose until ANC >750/mm3 then resume dose with 135 mcg/1.73 m2 x BSA once weekly. Assess WBC weekly for 3 weeks to verify ANC >750/mm3; Weeks 3 to 48: 135 mcg/1.73 m2 x BSA once weekly

ANC 250 to 499/mm3: Week 1 to 2: Delay or hold dose until ANC >750/mm3 then resume dose with 90 mcg/1.73 m2 x BSA once weekly; Weeks 3 to 48: Delay or hold dose until ANC >750/mm3 then resume dose with 135 mcg/1.73 m2 x BSA once weekly

ANC <250/mm3 (or febrile neutropenia): Discontinue treatment.

Platelet count <50,000/mm3: 90 mcg/1.73 m2 x BSA once weekly

Depression (severity based on DSM-IV criteria [similar to adult dosing adjustment recommendations]):

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/1.73 m2 x BSA or 135 mcg/1.73 m2 x BSA once weekly. Consider psychiatric consultation.

Moderate depression: Decrease to 90 mcg/1.73 m2 x BSA or 135 mcg/1.73 m2 x BSA once weekly; evaluate once weekly with an office visit at least every other week. If depression remains stable, consider psychiatric evaluation and continue 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 interferon permanently and obtain immediate psychiatric consultation.

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

Adults: HCV, HBV:

Based on hematologic parameters:

ANC <750/mm3: 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 <50,000/mm3: 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 interferon permanently and obtain immediate psychiatric consultation.

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

Dosage adjustment in renal impairment:

Children: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Adults:

CrCl ≥30 mL/minute: No dosage adjustment required.

CrCl <30 mL/minute: 135 mcg once weekly; monitor for toxicity

End-stage renal disease (ESRD) requiring hemodialysis: 135 mcg once weekly; monitor for toxicity. If severe adverse reactions or laboratory abnormalities occur, may reduce dose to 90 mcg once weekly until adverse reactions resolve; if intolerance persists after dosage adjustment, discontinue

Dosage adjustment in hepatic impairment:

Hepatic impairment prior to initiation: Contraindicated in autoimmune hepatitis, hepatic decompensation (Child-Pugh >6 [class B and C]) in cirrhotic patients before treatment, and hepatic decompensation with Child-Pugh ≥6 in cirrhotic HCV patients coinfected with HIV before treatment.

Hepatic impairment during treatment:

Children: HCV: Note: Immediately discontinue therapy if hepatic decompensation (Child-Pugh ≥6 [class B and C]) is observed.

ALT ≥5 but <10 x ULN: Decrease interferon dose to 135 mcg/1.73 m2 x BSA once weekly. Monitor weekly; further modify dose if needed until ALT stabilizes or decreases.

ALT ≥10 x ULN (persistent): Discontinue treatment.

Adults: Note: Immediately discontinue therapy if hepatic decompensation (Child-Pugh ≥6 [class B and C]) is observed.

HCV: ALT progressively rising above baseline: Decrease dose to 135 mcg once weekly and monitor LFTs more frequently. If ALT continues to rise despite dose reduction or ALT increase is accompanied by increased bilirubin or hepatic decompensation, discontinue therapy immediately. Therapy may resume after ALT flare subsides.

HBV:

ALT >5 x ULN: Consider decreasing dose to 135 mcg once weekly or temporarily discontinuing and monitor LFTs more frequently. If ALT continues to rise despite dose reduction or ALT increase is accompanied by increased bilirubin or hepatic decompensation, discontinue therapy immediately. Therapy may resume after ALT flare subsides.

ALT >10 x ULN: Consider discontinuing.

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 autoinjector to come to room temperature on its own for ~20 minutes; do not warm autoinjector any other way.

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.

Dietary Considerations

Avoid ethanol use in patients with hepatitis C virus.

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

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

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

Pegloticase: May diminish the therapeutic effect of Peginterferon Alfa-2a. 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: Interferons may decrease the metabolism 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 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

>10%:

Central nervous system: Headache (27% to 54%), fatigue (24% to 56%), rigors (35%; hepatitis B: 25% to 27%), insomnia (19%), anxiety (≤19%), irritability (≤19%), nervousness (≤19%), depression (18%), dizziness (16%), pain (11%)

Dermatologic: Alopecia (18% to 23%), pruritus (12%)

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

Gastrointestinal: Nausea (≤24%), vomiting (≤24%), anorexia (16% to 17%), diarrhea (16%), abdominal pain (15%)

Hematologic & oncologic: Neutropenia (21%)

Hepatic: Increased serum ALT (hepatitis B: 5 to 10x ULN: 25% to 27%; >10x ULN: 12% to 18%; hepatitis C: 5 to 10x ULN: 1%)

Local: Injection site reaction (22%)

Neuromuscular & skeletal: Weakness (≤56%), myalgia (37%), arthralgia (28%)

Miscellaneous: Fever (37%; hepatitis B: 54%)

1% to 10%:

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

Dermatologic: Dermatitis (8%), diaphoresis (6%), skin rash (5%), xeroderma (4%), eczema (1%)

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

Gastrointestinal: Xerostomia (6%)

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

Hepatic: Hepatic decompensation (2% in CHC/HIV)

Infection: Bacterial infection (3% to ≤5%)

Neuromuscular & skeletal: Back pain (9%)

Ophthalmic: Blurred vision (4%)

Respiratory: Cough (4%), dyspnea (4%)

≤1% (Limited to important or life-threatening): Aggressive behavior, angina pectoris, aplastic anemia, arrhythmia, auditory impairment, autoimmune disorders, bipolar mood disorder, bronchiolitis obliterans, cerebral hemorrhage, 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, macular edema, mania, myocardial infarction, myositis, optic neuritis, pancreatitis, papilledema, peptic ulcer, peripheral neuropathy, pneumonia, 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, suicidal ideation, supraventricular cardiac arrhythmia, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, vesiculobullous reaction, vision loss

ALERT: U.S. Boxed Warning

Risk of serious disorders:

Peginterferon alfa-2a may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor patients closely with periodic clinical and laboratory evaluations. Withdraw therapy in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all, cases, these disorders resolve after stopping peginterferon alfa-2a therapy.

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 highly active 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, 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).

• Thyroid disorders: Use with caution in patients with pre-existing 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 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. Following treatment, rebound growth and weight gain occurred in most patients; however, a small percentage did not. For most children, posttreatment recovery in growth at 2 years posttreatment was maintained to 6 years posttreatment. 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: Safety and efficacy have not been established in patients who have been coinfected with HBV and HCV or HIV, have been coinfected with HCV and HBV or HIV with a CD4+ cell count <100 cells/mm3, or been treated for >48 weeks.

Monitoring Parameters

Clinical studies tested as follows:

Children: 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 or 70,000/mm3 in patients with CHC coinfected with HIV)

ANC ≥1500/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, but <200 cells/mm3 and HIV-1 RNA <5000 copies/mL in CHC patients coinfected with HIV

Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men in CHC monoinfected patients

Hemoglobin ≥11 g/dL for women and ≥12 g/dL for men in CHC patients coinfected with HIV

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).

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.

Pregnancy Risk Factor

C / X in combination with ribavirin

Pregnancy Considerations

Reproduction studies with pegylated interferon alfa have not been conducted. Animal 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 DHHS Perinatal HIV Guidelines do not recommend that peginterferon-alfa be used during pregnancy (DHHS [perinatal], 2012). 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 (refer to Ribavirin monograph). Female patients of childbearing potential and male patients with female partners of childbearing potential must use 2 forms of contraception along with monthly pregnancy tests during therapy and for 6 months after therapy has been discontinued.

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, diarrhea, dyspepsia, lack of appetite, myalgia, arthralgia, alopecia, insomnia, or injection site irritation. Have patient report immediately to prescriber signs of depression (ie, suicidal ideation, anxiety, emotional instability, illogical thinking), signs of infection, signs of hyperglycemia, angina, tachycardia, arrhythmia, dyspnea, excessive weight gain, edema of extremities, severe dizziness, syncope, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, ecchymosis, hemorrhaging, considerable asthenia, vision changes, ophthalmalgia, significant eye irritation, blindness, paresthesia, memory impairment, signs of pulmonary disorder, signs of hepatic impairment, signs of colitis, signs of pancreatitis, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (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 healthcare 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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