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Peginterferon Alfa-2a

Pronunciation: peg-IN-ter-FEER-on AL-fa too-ay
Class: Immunomodulator

Trade Names

Pegasys
- Injection, solution 135 mcg per 0.5 mL
- Injection, solution 180 mcg per 0.5 mL
- Injection, solution 180 mcg/mL

Pharmacology

Binds to specific receptors on cell surface and initiates a complex cascade of protein-protein interactions, leading to rapid activation of gene transcription. Interferon-stimulated genes regulate many biologic effects (eg, inhibition of viral replication of infected cells, inhibition of cell proliferation, immunomodulation).

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Pharmacokinetics

Absorption

T max is 72 to 96 h. Steady state is reached within 5 to 8 wk.

Elimination

Cl is 94 mL/h; half-life is approximately 160 h.

Special Populations

Renal Function Impairment

Cl decreased 43% in those with severe renal impairment.

Elderly

AUC increased, but C max did not.

Children

Cl was nearly 4-fold lower in children 2 to 8 y of age.

Gender

Pharmacokinetics were similar in healthy male and female subjects.

Indications and Usage

Treatment of hepatitis B e antigen (HBeAg)–positive and HBeAg-negative chronic hepatitis B virus (HBV) in adult patients who have compensated liver disease and evidence of viral replication and liver inflammation; alone or in combination with ribavirin tablets for the treatment of chronic hepatitis C virus (HCV) in adults and children 5 y and older with compensated liver disease and those not treated previously with interferon alfa.

Unlabeled Uses

Chronic myelogenous leukemia; polycythemia vera; renal cell carcinoma.

Contraindications

Peginterferon alfa-2a

Hypersensitivity reactions, such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome, to alpha interferons, including peginterferon alfa-2a or any of its components; autoimmune hepatitis; hepatic decompensation (Child-Pugh score greater than 6 [classes B and C]) in cirrhotic patients before treatment; hepatic decompensation with Child-Pugh score of 6 or higher in cirrhotic chronic HCV patients coinfected with HIV before treatment; use in neonates and infants.

Combination therapy with ribavirin (additional contraindications)

Known hypersensitivity, such as urticaria, angioedema, bronchoconstriction, or anaphylaxis, to ribavirin or any component of the tablet; women who are pregnant; men whose female partners are pregnant; patients with hemoglobinopathies (eg, thalassemia major, sickle cell anemia); combination therapy with didanosine.

Dosage and Administration

Chronic Hepatitis B
Adults

Subcutaneous 180 mcg once weekly for 48 wk.

Chronic Hepatitis C
Adults Monotherapy

Subcutaneous 180 mcg once weekly for 48 wk.

Combination therapy with ribavirin

Subcutaneous For patients with HCV genotypes 1 and 4, administer 180 mcg once weekly in combination with ribavirin 1,000 mg orally daily (patient weight less than 75 kg) or 1,200 mg (patient weight 75 kg or more) in 2 divided doses for 48 wk. For patients with HCV genotypes 2 and 3, administer 180 mcg once weekly in combination with ribavirin 800 mg orally daily in 2 divided doses for 24 wk.

Children 5 y and older Combination therapy with ribavirin

Subcutaneous 180 mcg/1.73 m 2 once weekly (max, 180 mcg) in combination with ribavirin 15 mg/kg/day for 24 wk (genotypes 2 or 3) or 48 wk (other genotypes). Ribavirin oral dose for children is based on body weight. For weight 23 to 33 kg, 400 mg/day (200 mg in the morning and 200 mg in the evening); for weight 34 to 46 kg, 600 mg/day (200 mg in the morning and 400 mg in the evening); for weight 47 to 59 kg, 800 mg/day (400 mg in the morning and 400 mg in the evening); for weight 60 to 74 kg, 1,000 mg/day (400 mg in the morning and 600 mg in the evening); for weight 75 kg or more, 1,200 mg/day (600 mg in the morning and 600 mg in the evening).

Chronic Hepatitis C With HIV Coinfection
Adults

Subcutaneous 180 mcg once weekly for 48 wk. May be used as monotherapy or in combination with ribavirin 800 mg orally daily in 2 divided doses for 48 wk regardless of genotype.

Renal Function Impairment
Adults

Subcutaneous For CrCl less than 30 mL/min and patients on hemodialysis, administer peginterferon alfa-2a 135 mcg once weekly. If administering with ribavirin, administer alternating doses of ribavirin 200 and 400 mg orally every other day for CrCl 30 to 50 mL/min; for CrCl less than 30 mL/min and patients on hemodialysis, administer ribavirin 200 mg orally daily.

Children 5 y and older

Subcutaneous No data are available for children with renal impairment.

Hepatic Function Impairment
Adults

Subcutaneous If ALT increases are progressive despite dose reduction or are accompanied by increased bilirubin or evidence of hepatic decompensation, discontinue therapy immediately.

Chronic hepatitis B virus

Subcutaneous In patients with elevations in ALT (greater than 5 × ULN), monitor liver function more frequently and consider reducing the dose to 135 mcg or temporarily discontinuing treatment. After dose reduction or withholding therapy, treatment may be resumed after ALT flares subside. In patients with persistent, severe (ALT greater than 10 × above the ULN) hepatitis B flares, consider discontinuation of treatment.

Chronic hepatitis C virus

Subcutaneous In patients with progressive ALT increases above baseline values, reduce the dose to 135 mcg and monitor liver function more frequently. After dose reduction or withholding therapy, treatment may be resumed after ALT flares subside.

Children 5 y and older

Subcutaneous For persistent or increasing elevations 5 or more but less than 10 × ULN, modify dose to 135 mcg/1.73 m 2 . Monitor weekly, further modifying dose if necessary, until stable or ALT level decreases. For persistent ALT values at least 10 × ULN, discontinue treatment.

Dosage Reduction for Adverse Reactions
Adults

Subcutaneous When dose reduction is required for adverse reactions, initial dose reduction to 135 mcg generally is adequate; however, in some cases, a dose reduction to 90 mcg may be needed. The dose may be re-escalated following improvement of the adverse reactions. If severe adverse reactions or laboratory abnormalities develop during combination peginterferon alfa-2a and ribavirin therapy, modify the dose until the adverse reactions abate. If intolerance persists after dose adjustment, discontinue peginterferon alfa-2a and ribavirin therapy.

Children 5 y and older

Subcutaneous When dose modification is required for moderate to severe adverse reactions, modification to 135 mcg/1.73 m 2 is generally adequate. However, in some cases, dose modification to 90 mcg/1.73 m 2 or 45 mcg/1.73 m 2 may be needed. Up to 3 dose modifications for toxicity can be made before discontinuation is considered.

Dosage Reduction for Depression
Adults

Subcutaneous For mild depression, continue dose at 180 mcg and evaluate patient once weekly until symptoms improve or worsen; for moderate depression, decrease dose to 135 mcg (in some cases, a dose reduction to 90 mcg may be needed) and evaluate patient once weekly until symptoms improve or worsen. If symptoms improve and are stable for 4 wk, continue reduced dose or return to normal dose. If symptoms worsen (severe depression), discontinue permanently and obtain immediate psychiatric consultation.

Dosage Reduction for Hematologic Toxicity
Adults Peginterferon alfa-2a

Subcutaneous Dose reduction to 135 mcg is recommended if the neutrophil count is less than 750 cells/mm 3 . Suspend treatment in patients with an absolute neutrophil count (ANC) below 500 cells/mm 3 until the count returns to more than 1,000 cells/mm 3 . Reinstitute therapy at 90 mcg and monitor the neutrophil count. A dose reduction to 90 mcg is recommended if the platelet count is less than 50,000 cells/mm 3 . Cessation of therapy is recommended when the platelet count is below 25,000 cells/mm 3 .

Ribavirin

PO In patients without cardiac disease, reduce dose to 200 mg in the morning and 400 mg in the evening if the Hgb is less than 10 g/dL; discontinue ribavirin when Hgb is less than 8.5 g/dL. In patients with a history of stable cardiac disease, reduce dose to 200 mg in the morning and 400 mg in the evening when there is a decrease of 2 g/dL or more in Hgb during any 4-wk period treatment; discontinue ribavirin if the Hgb is less than 12 g/dL despite 4 wk at a reduced dose. Once ribavirin has been withheld because of a laboratory abnormality or clinical manifestation, an attempt may be made to restart ribavirin at 600 mg daily and further increase the dosage to 800 mg daily. However, it is not recommended that ribavirin be increased to the original dose (1,000 or 1,200 mg).

Children 5 y and older Peginterferon alfa-2a

Subcutaneous If platelets are less than 50,000 cells/mm 3 , modify dose to 90 mcg/1.73 m 2 . For ANC 750 to 999 cells/mm 3 : wk 1 to 2, immediately modify to 135 mcg/1.73 m 2 ; wk 3 to 48, no modification. For ANC 500 to 749 cells/mm 3 : wk 1 to 2, delay or hold dose until ANC is more than 750 cells/mm 3 then resume dose with a modification to 135 mcg/1.73 m 2 and assess weekly × 3 to verify WBC more than 750 cells/mm 3 ; wk 3 to 48, immediate modification to 135 mcg/1.73 m 2 . For ANC 250 to 499 cells/mm 3 : wk 1 to 2, delay or hold dose until ANC is more than 750 cells/mm 3 , then resume dose with a modification to 90 mcg/1.73 m 2 ; wk 3 to 48, delay or hold dose until more than 750 cells/mm 3 , then resume dose with a modification to 135 mcg/1.73 m 2 . For ANC less than 250 cells/mm 3 (or febrile neutropenia): discontinue treatment.

Ribavirin

PO If the Hgb is less than 10 g/dL in patients without cardiac disease or if the Hgb decreases 2 g/dL or more during any 4-wk period in children with a history of stable cardiac disease, modify the dose based on the patient's weight: for 23 to 33 kg, reduce dose to 200 mg in the morning; for weight 34 to 59 kg, reduce dose to 200 mg in the morning and 200 mg in the evening; for weight 60 kg or more, reduce dose to 200 mg in the morning and 400 mg in the evening. Discontinue ribavirin if Hgb is less than 8.5 g/dL in patients without cardiac disease or if the Hgb is less than 12 g/dL despite 4 wk at a reduced dose in patients with a history of stable cardiac disease. Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in ribavirin dose to the original dose may be attempted depending upon the health care provider's judgment. If ribavirin has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin at one-half the full dose.

General Advice

  • For subcutaneous administration only in the abdomen or thigh. Do not shake. Allow medication to come to room temperature before use.
  • For patients on combination therapy with ribavirin, ribavirin should be taken orally in divided doses with food.
  • Discontinuation of therapy should be considered if the patient has failed to demonstrate at least a 2 log 10 reduction from baseline in HCV RNA titer by 12 wk of therapy or undetectable HCV RNA after 24 wk of therapy.
  • If a dose is missed and remembered within 2 days of when the dose should have been taken, the missed dose should be taken as soon as remembered and the next dose should be taken as regularly scheduled.

Storage/Stability

Refrigerate between 36° and 46°F. Do not freeze. Protect from light. Discard any unused product.

Drug Interactions

Methadone

Methadone levels may be elevated 10% to 15%. The clinical importance of this increase is not known. Monitor for signs and symptoms of methadone toxicity.

Nucleoside reverse transcriptase inhibitors (eg, didanosine, stavudine, zidovudine)

The risk of treatment-associated toxicity (eg, hepatic decompensation, hematologic toxicity) may be increased. Closely monitor for treatment-associated toxicities. Dose reduction or discontinuation of therapy should be considered if worsening of toxicity occurs. Coadministration of didanosine and peginterferon alfa-2a with ribavirin is contraindicated.

Telbivudine

The risk of telbivudine-related peripheral neuropathy may be increased. Avoid coadministration.

Theophylline

Theophylline plasma levels may be elevated, increasing the risk of adverse reactions. Monitor theophylline concentrations and adjust dose as needed.

Adverse Reactions

CNS

Fatigue/asthenia (56%); headache (54%); insomnia, irritability/anxiety/nervousness (19%); depression (18%); dizziness (16%); mood alteration (9%); concentration impairment (8%); memory impairment (5%); seizures (postmarketing).

Dermatologic

Alopecia (23%); pruritus (12%); rash (10%); dermatitis (8%); sweating increased (6%); dry skin (4%); eczema (1%); serious skin reactions (postmarketing).

EENT

Blurred vision (4%); hearing impairment or loss (postmarketing).

GI

Nausea/vomiting (24%); anorexia (17%); diarrhea (16%); abdominal pain (15%); dry mouth (6%).

Hematologic-Lymphatic

Lymphopenia (81%); neutropenia (40%); anemia (14%); thrombocytopenia (8%); pure red aplasia (postmarketing).

Hepatic

Hepatic decompensation (2%).

Lab Tests

Decreased neutrophils (95%); decreased platelets (52%); elevated triglycerides (36%); binding antibodies to interferon alfa-2a (29%); elevated ALT (27%); decreased Hgb below 12 g/dL (17%); decreased Hgb below 10 g/dL (8%); hypothyroidism (4%); hyperthyroidism (1%).

Local

Injection-site reaction (42%).

Musculoskeletal

Myalgia (37%); rigors (35%); musculoskeletal pain (29%); arthralgia (28%); back pain (9%).

Respiratory

Cough, dyspnea (4%).

Miscellaneous

Influenza-like illness (81%); pyrexia (54%); weight decrease (16%); pain (11%); bacterial infection (5%); anaphylactic shock; dehydration, liver or renal graft rejection (postmarketing).

Precautions

Warnings

Risk of serious disorders

Alpha interferons, including 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 therapy.

Combination therapy with ribavirin

May cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia, which may result in a worsening of cardiac disease.


Monitor

Obtain standard hematologic and biochemical laboratory tests, including CrCl, for all patients before beginning therapy. After initiating therapy, obtain hematologic tests at 2 and 4 wk, biochemical tests at 4 wk, and then periodically thereafter during therapy. Increase frequency of monitoring if abnormalities are noted. Pregnancy screening for women of childbearing potential must be performed before starting therapy and monthly during combination therapy and for 6 mo following discontinuation of therapy. Monitor all patients for evidence of depression and other psychiatric symptoms. Perform ophthalmic examination before starting therapy in all patients and periodically during treatment in patients with preexisting ophthalmic disorders (eg, diabetic or hypertensive retinopathy). Before administering combination therapy with ribavirin, administer an ECG to patients with preexisting cardiac disease, and monitor during therapy. In patients with hepatic impairment, monitor clinical status and hepatic function closely.


Pregnancy

Category C . Category X when used with ribavirin.

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 5 y. Contraindicated in neonates and infants.

Elderly

Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (eg, flu-like) effects, may be more severe in elderly patients; use with caution. Peginterferon alfa-2a is known to be excreted by the kidney, and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, take care in dose selection. It may be useful to monitor renal function.

Hypersensitivity

Severe acute hypersensitivity reactions (eg, anaphylaxis, angioedema, bronchoconstriction, urticaria) have been rarely observed during alpha interferon and ribavirin therapy.

Renal Function

Use with caution and adjust dose accordingly.

Hepatic Function

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation and death when treated with peginterferon alfa-2a. Cirrhotic chronic HCV patients coinfected with HIV receiving highly active antiretroviral therapy and interferon alfa-2a with or without ribavirin appear to be at increased risk of the development of hepatic decompensation. Discontinue treatment if decompensation (Child-Pugh score at least 6) is observed.

Fertility

May impair fertility in women.

Special Risk Patients

Safety and efficacy not established in patients who are liver or other organ transplant recipients, HBV patients coinfected with HCV or HIV, or HCV patients coinfected with HBV or HIV with a CD4 + cell count less than 100 cells/mcL.

Hazardous Tasks

May cause confusion, dizziness, fatigue, and somnolence.

Autoimmune disorders

Development or exacerbation of autoimmune disorders, including hepatitis, idiopathic thrombocytopenic purpura, interstitial nephritis, myositis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, and thyroiditis have been reported. Use with caution in patients with autoimmune disorders.

Benzyl alcohol

Contains benzyl alcohol, which has been reported to be associated with an increased incidence of neurological and other complications that can be fatal in neonates and infants.

Bone marrow suppression

Bone marrow function may be suppressed; severe cytopenias may occur. Very rarely, alpha interferons may be associated with aplastic anemia. Severe neutropenia and thrombocytopenia occur with greater incidence in patients coinfected with HIV. Reduce dose in patients with hematologic abnormalities.

Cerebrovascular effects

Ischemic and hemorrhagic cerebrovascular events have been observed.

CV effects

Chest pain, hypertension, MI, and supraventricular arrhythmias have been reported during treatment; use with caution in patients with preexisting cardiac disease. Do not use in patients with a history of significant or unstable cardiac disease.

Colitis

Fatal and nonfatal ulcerative and hemorrhagic/ischemic colitis have been observed within 12 wk of starting alpha interferon treatment. Discontinue use immediately in patients who develop abdominal pain, bloody diarrhea, and fever.

Endocrine disorders

May cause or aggravate hypothyroidism and hyperthyroidism. Hyperglycemia, hypoglycemia, and diabetes mellitus have occurred during treatment; therefore, do not begin therapy in patients with these conditions at baseline who cannot be effectively treated by medication. Patients who develop these conditions during treatment and cannot be controlled by medication may require discontinuation of therapy.

Hepatitis B exacerbations

May occur and are characterized by transient and potentially severe increases in serum ALT. Consider dose reduction in patients experiencing transaminase flares. If ALT increases are progressive despite reduction of dose or are accompanied by increased bilirubin or evidence of hepatic decompensation, discontinue peginterferon alfa-2a immediately.

Infections

Serious and severe infections (bacterial, fungal, or viral), some fatal, have been observed in patients treated with alpha interferons, including peginterferon alfa-2a. Some of the infections have been associated with neutropenia. Discontinue peginterferon alfa-2a in patients who develop severe infections, and institute appropriate antibiotic therapy.

Neuropsychiatric reactions

Life-threatening or fatal neuropsychiatric reactions may manifest in patients receiving peginterferon alfa-2a therapy and include suicide, suicidal ideation, homicidal ideation, depression, relapse of drug addiction, and drug overdose. These reactions may occur in patients with or without previous psychiatric illness. Use with extreme caution in patients who report a history of depression.

Ocular effects

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, serous retinal detachment, and papilledema have been observed; discontinue therapy in patients who develop new or worsening ophthalmologic disorders.

Pancreatitis

Fatal and nonfatal cases of pancreatitis have been observed. Suspend use in patients who develop symptoms; discontinue use in patients diagnosed with pancreatitis.

Pulmonary effects

Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure and/or death, may be induced or aggravated. Suspend therapy in patients who develop pulmonary infiltrates or pulmonary function impairment.

Overdosage

Symptoms

Elevated liver enzymes, fatigue, neutropenia, thrombocytopenia.

Patient Information

  • Direct patients receiving peginterferon alfa-2a alone or in combination with ribavirin in its appropriate use, inform them of the benefits and risks associated with treatment, and refer them to the peginterferon alfa-2a and, if applicable, ribavirin Medication Guide.
  • Peginterferon alfa-2a and ribavirin combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Do not initiate ribavirin therapy until a report of a negative pregnancy test has been obtained immediately before starting therapy. Advise women of childbearing potential and men with female partners of childbearing potential of the teratogenic/embryocidal risks, and instruct them to use 2 forms of effective contraception during ribavirin therapy and for 6 mo posttherapy. Advise patients to notify their health care provider immediately in the event of a pregnancy.
  • Advise patients that laboratory evaluations are required before starting therapy and periodically thereafter. Instruct patients to remain well hydrated, especially during the initial stages of treatment. Advise patients to take ribavirin with food.
  • Question patients about history of drug abuse before initiating peginterferon alfa-2a/ribavirin because relapse of drug addiction and drug overdoses have been reported.
  • Inform patients that it is not known if therapy with peginterferon alfa-2a alone or in combination with ribavirin will prevent transmission of HBV infection to others or prevent cirrhosis, liver failure, or liver cancer that might result from HBV infection.
  • Caution patients who develop dizziness, confusion, somnolence, and fatigue to avoid driving or operating machinery.
  • Advise patients to avoid drinking alcohol.
  • Advise patients not to switch to another brand of interferon without first consulting their health care provider.
  • Advise patients to take prescribed dose once a week, on the same day each week, and at approximately the same time. Advise patients that if a dose is missed and remembered within 2 days of when the dose should have been taken, to inject the missed dose as soon as remembered and take the next dose as regularly scheduled. Instruct patients to discuss with their health care provider if more than 2 days passed and to not double the dose.
  • Instruct patients to allow the vial or prefilled syringe to come to room temperature and wait for condensation on the outside of the syringe to disappear before use. Advise patients not to shake the vial or prefilled syringe because foaming may occur.
  • Advise patients to choose a different place on either the thigh or abdomen each time they make an injection.
  • Advise patients to report any signs or symptoms of depression or suicidal ideation to their health care provider.

Copyright © 2009 Wolters Kluwer Health.

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