Peginterferon Alfa (Monograph)

Brand names: Pegasys, PegIntron, Sylatron
Drug class: Interferons
VA class: AM800

Introduction

Antiviral and antineoplastic agent; contains interferon alfa (recombinant DNA origin) covalently bound to monomethoxy polyethylene glycol (PEG). Available as peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (PegIntron) for treatment of certain viral infections; peginterferon alfa-2b also available in higher concentrations (Sylatron) for use as an antineoplastic agent.

Uses for Peginterferon Alfa

Chronic HBV Infection

Peginterferon alfa-2a (Pegasys): Treatment of chronic HBV infection in adults with hepatitis B e antigen (HBeAg)-positive or -negative infection, compensated liver disease, and evidence of viral replication and liver inflammation.

Goal of antiviral therapy is sustained suppression of HBV replication and remission of liver disease; long-term goal is prevention of cirrhosis, hepatic failure, and hepatocellular carcinoma.

Currently available therapies (e.g., interferon alfa, peginterferon alfa, adefovir, entecavir, lamivudine, telbivudine, tenofovir) do not eradicate HBV and may have only limited long-term efficacy. When making decisions regarding treatment, consider patient’s age, severity of liver disease, likelihood of response, safety and efficacy of the drug, potential for selection of resistant HBV strains, potential for adverse reactions, costs, patient’s pregnancy potential, and patient and provider preferences.

American Association for the Study of Liver Diseases (AASLD) states that drugs of choice for initial treatment of chronic HBV infection in patients with compensated liver disease are peginterferon alfa, entecavir, or tenofovir, unless contraindicated or ineffective. Efficacy of peginterferon alfa and nonconjugated interferon alfa are considered similar, but peginterferon alfa dosage schedule more convenient and generally preferred.

Although safety and efficacy not established for treatment of chronic HBV infection in patients coinfected with HIV, some experts recommend peginterferon alfa as an alternative for treatment of HBV in some adults coinfected with HIV.

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.

Chronic HCV Infection

Peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (PegIntron): Treatment of chronic HCV infection in adults and pediatric patients with compensated liver disease; used in conjunction with oral ribavirin in various multiple-drug regimens.

Usually used in conjunction with oral ribavirin in multiple-drug regimens that include an HCV direct-acting antiviral (DAA). For treatment of chronic HCV genotype 1 infection, has been used with oral ribavirin and either simeprevir (an HCV protease inhibitor) or sofosbuvir (an HCV polymerase inhibitor). For treatment of chronic HCV infection caused by other genotypes (e.g., genotypes 3, 4, 5, or 6), has been used in conjunction with oral ribavirin and sofosbuvir.

Peginterferon alfa has been used alone for treatment of chronic HCV infection in patients with compensated liver disease, but response rates better when used in conjunction with oral ribavirin. Although manufacturers state consider peginterferon alfa monotherapy only in previously untreated patients when oral ribavirin contraindicated or not tolerated, experts state peginterferon alfa monotherapy not recommend for treatment of chronic HCV infection at any time.

Safety and efficacy of peginterferon alfa alone or in conjunction with oral ribavirin not established for treatment of chronic HCV infection in patients with decompensated liver disease, HBV coinfection, or liver or other organ transplants.

Goal of antiviral therapy is sustained suppression of HCV replication and prevention of HCV-related complications (e.g., necroinflammation, fibrosis, cirrhosis, hepatocellular carcinoma) and death. When making decisions regarding treatment, consider severity of liver disease, HCV genotype, treatment history, potential for serious adverse reactions, likelihood of treatment response, presence of coexisting conditions, and patient’s readiness for treatment.

Most appropriate multiple-drug regimen depends on specific HCV genotype and patient population involved.

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].

Acute HCV Infection

Peginterferon alfa (alfa-2a, alfa-2b): Treatment of acute HCV infection^{† [off-label]} in an attempt to prevent progression to chronic HCV infection; used alone or in conjunction with oral ribavirin.

Patients with acute HCV infection have higher treatment response rates than those with chronic HCV infection, and treatment of the acute infection can reduce risk that the disease will evolve to chronic infection.

Approximately 10–50% of acute HCV patients have self-limited disease and spontaneous virus clearance without treatment; rate of spontaneous resolution depends on whether patient is asymptomatic or symptomatic, route of HCV transmission, and age at which infection acquired.

Optimum regimen (including dosage and duration of therapy) and optimum time to initiate treatment not established. Some experts suggest delaying initiation of treatment (especially in symptomatic patients) for 8–12 weeks after acute onset of hepatitis, unless HCV RNA levels are high and not declining.

Consult specialist to obtain most up-to-date information regarding treatment of acute HCV infection.

Postexposure Prophylaxis following Exposure to HCV

Peginterferon alfa-2b: Has been used in an attempt to provide postexposure prophylaxis of HCV^{† [off-label]} following occupational exposures to an HCV-positive source.

CDC and others state that postexposure prophylaxis with antivirals (e.g., peginterferon alfa or interferon alfa with or without oral ribavirin), immune globulin, or immunomodulators not recommended following occupational or other exposures known or likely to involve an HCV-positive source, including penetrating injuries or nonintact skin exposures in bombings or other mass casualty settings.

Postexposure management in exposed individuals involves early identification of HCV infection and appropriate antiviral treatment if indicated. Some experts suggest evaluating ALT concentrations and anti-HCV at time of exposure (within 7–14 days) and 4–6 months later and testing for HCV RNA at 4–6 weeks or at 2-week intervals.

Chronic HDV Infection

Peginterferon alfa-2b: Has been used for treatment of chronic hepatitis D virus (HDV) infection^{† [off-label]} in adults coinfected with HBV. Has been used alone or in conjunction with ribavirin or other antivirals (e.g., adefovir, emtricitabine, tenofovir).

HDV Infection only occurs in individuals with HBV infection since the virus depends on HBV for production of envelope proteins. Can be acquired as a coinfection with HBV or as a superinfection in HBV carriers. HDV superinfection in HBV carriers almost always results in chronic infection with both viruses and is associated with high risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma.

Hepatitis E Virus (HEV) Infection

Peginterferon alfa (alfa-2a, alfa-2b): Treatment of HEV infection^{† [off-label]}; has been used alone or in conjunction with ribavirin.

Chronic HEV infection reported almost exclusively among immunocompromised individuals, including solid organ transplant recipients, patients receiving cancer chemotherapy, and HIV patients. Optimal treatment of chronic HEV infection not identified.

Melanoma

Peginterferon alfa-2b (Sylatron): Adjuvant treatment of melanoma in adults with microscopic or gross nodal involvement who have undergone definitive surgical resection including complete lymphadenectomy. Initiate adjuvant peginterferon alfa-2b treatment in such patients within 84 days of surgery.

Coronavirus Infections

Peginterferon alfa (alfa-2a) has been used in conjunction with oral ribavirin for treatment of Middle East respiratory syndrome^{† [off-label]} (MERS) caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). No specific treatment for MERS has been identified; some evidence that regimen of oral ribavirin and peginterferon alfa-2a may improve 14-day survival rate when used in addition to usual supportive care, but 28-day survival rate not significantly improved.

MERS-CoV infections first reported in September 2012 in Saudi Arabia; as of August 28, 2015, 1,474 laboratory-confirmed cases (including 515 deaths) reported worldwide. Most reported cases to date (including 2 in the US and an outbreak in Republic of Korea) directly or indirectly linked through travel or residence to the Middle East.

Information regarding evaluation, diagnosis, and management of MERS-CoV infection and guidance for individuals traveling to areas where MERS reported (e.g., the Middle East) is available at CDC website at [Web].

Peginterferon Alfa Dosage and Administration

General

• Several peginterferon alfa subtypes (alfa-2a, alfa-2b), dosage forms, and strengths are commercially available. Ensure that correct preparation is used.

• Because there are differences in recommended indications and in potencies and dosages between the commercially available peginterferon alfa preparations, it is recommended that the peginterferon alfa preparation selected for the patient be used throughout the treatment regimen.

• Caution patients not to change brands of peginterferon alfa without consulting their clinician.

Administration

Peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (PegIntron, Sylatron) are administered by sub-Q injection once weekly.

Sub-Q injections of peginterferon alfa-2a should be made into the thigh or abdomen. Sub-Q injections of peginterferon alfa-2b should be made into the thigh, outer surface of upper arm, or abdomen. Avoid areas of the navel and waistline. Rotate injection sites.

May be self-administered if the clinician determines that the patient and/or their caregiver are competent to prepare and safely administer the drug after appropriate training and with medical follow-up as necessary.

Patients and/or their caregivers who administer peginterferon alfa in a home setting should be carefully instructed in the proper administration of the drug (including aseptic techniques), cautioned against reuse of syringes and needles, and supplied with a puncture-resistant container for proper, safe disposal of such equipment (with instructions on proper disposal of full containers).

Sub-Q Administration

Peginterferon Alfa-2a (Pegasys)

Administer undiluted.

Allow to reach room temperature before administration; do not shake. Do not keep at room temperature for >24 hours.

Solution should be clear and colorless to light yellow; do not use if solution is discolored or if particulates are present.

Vials, prefilled syringes, and autoinjectors are for single-use only; discard any unused portions.

Peginterferon Alfa-2b (PegIntron)

Reconstitute lyophilized powder for injection prior to administration using only sterile water for injection provided by the manufacturer.

Prior to reconstitution, should appear as a white to off-white powder or a tablet-shaped solid that is whole or in pieces.

Single-dose prefilled dual-chamber injection pen containing lyophilized peginterferon alfa-2b (PegIntron) and sterile water for injection: Hold upright and press the 2 halves together according to manufacturer’s directions. Gently invert to mix; do not shake. Attach the needle provided and calibrate dose according to manufacturer’s directions.

Single-dose vial containing lyophilized peginterferon alfa-2b (PegIntron): Slowly add 0.7 mL of sterile water diluent provided by the manufacturer and gently swirl vial; do not shake. Vials labeled as containing 50, 80, 120, or 150 mcg per 0.5 mL contain 74, 118.4, 177.6, or 222 mcg of lyophilized peginterferon alfa-2b, respectively.

Reconstituted solution should be clear and colorless; do not use if solution is discolored or cloudy or if particulates are present.

Vials and prefilled pens are for single-use only; discard any unused portions.

Peginterferon Alfa-2b (Sylatron)

Reconstitute lyophilized powder for injection prior to administration using only sterile water for injection provided by the manufacturer.

Single-dose vial containing lyophilized peginterferon alfa-2b (Sylatron): Slowly add 0.7 mL of sterile water diluent provided by the manufacturer and gently swirl vial; do not shake. Vials labeled as containing 200, 300, or 600 mcg per 0.5 mL contain 296, 444, or 888 mcg of lyophilized peginterferon alfa-2b, respectively.

Reconstituted solution should be clear and colorless; do not use if solution is discolored or cloudy or if particulates are present.

Do not withdraw more than 0.5 mL of reconstituted solution from each vial.

Vials are for single-use only; discard any unused portions.

Dosage

Pediatric Patients

Treatment of Chronic HCV Infection

Concomitant Peginterferon Alfa-2a (Pegasys) and Oral Ribavirin

Sub-Q

Children ≥5 years of age: 180 mcg/1.73 m² × body surface area (BSA) once weekly (maximum 180 mcg) in conjunction with oral ribavirin.

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for other HCV genotypes.

Consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log₁₀ from baseline at week 12 or are still detectable after 24 weeks of treatment.

Manufacturer states safety and efficacy beyond 48 weeks of therapy not established.

Concomitant Peginterferon Alfa-2b (PegIntron) and Oral Ribavirin

Sub-Q

Children 3–17 years of age: 60 mcg/m² once weekly in conjunction with oral ribavirin. If patient reaches 18th birthday during treatment, complete treatment using pediatric dosage.

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for genotype 1.

With the exception of HCV genotypes 2 and 3, consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log₁₀ from baseline at week 12 or remain detectable after 24 weeks of treatment.

Dosage Modification for Toxicity (Peginterferon Alfa-2a [Pegasys])

Sub-Q

If serious adverse effects or laboratory changes occur when peginterferon alfa-2a used alone or in conjunction with oral ribavirin, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Generally, if dosage modification of peginterferon alfa-2a required because of moderate to severe adverse reactions (clinical and/or laboratory), initial dosage reduction to 135 mcg/1.73 m² × BSA usually adequate; further reduction to 90 mcg/1.73 m² × BSA or 45 mcg/1.73 m² × BSA may be needed in some cases. Up to 3 dosage modifications for toxicity can be made before discontinuance is considered.

Moderate depression: Reduce peginterferon alfa-2a dosage to 135 mcg/1.73 m² × BSA; further reductions to 90 mcg/1.73 m² × BSA or 45 mcg/1.73 m² × BSA may be needed. If symptoms improve with reduced dosage and remain stable for 4 weeks, consider continuing reduced dosage or increasing to usual dosage.

Severe depression: Permanently discontinue.

Hematologic effects: If neutropenia (<1000/mm³) or decreased platelet count (<50,000/mm³) occurs, reduce dosage or discontinue (depending on severity).

Consult manufacturer's information for more specific recommendations regarding dosage modification for depression, hematologic effects, or other adverse effects.

Dosage Modification for Toxicity (Peginterferon Alfa-2b [PegIntron])

Sub-Q

If serious adverse effects or laboratory changes occur when peginterferon alfa-2b used alone or in conjunction with oral ribavirin, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Generally, if dosage modification of peginterferon alfa-2b required because of adverse reactions in those receiving usual dosage (60 mcg/m²), use 2-step dosage reduction (i.e., reduce dosage to 40 mcg/m² once weekly initially and then, if needed, reduce dosage to 20 mcg/m² once weekly).

Moderate depression: Reduce peginterferon alfa-2b dosage to 40 mcg/m² once weekly and, if needed, to 20 mcg/m² once weekly, If symptoms improve with reduced dosage and remain stable for 4 weeks, consider continuing reduced dosage or increasing to usual dosage.

Severe depression: Permanently discontinue.

Hematologic effects: If leukocyte count 1000 to <1500/mm³, neutrophil count 500 to <750/mm³, or platelet count 50,000 to <70,000/mm³, reduce dosage. Permanently discontinue if hemoglobin <8.5 g/dL, leukocyte count <1000/mm³, neutrophil count <500/mm³, or platelet count <50,000/mm³. In pediatric patients with preexisting cardiac conditions, closely monitor with weekly hematology evaluations if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).

Consult manufacturer's information for more specific recommendations regarding dosage modification for depression, hematologic effects, or other adverse effects.

Adults

Treatment of Chronic HBV Infection

Peginterferon Alfa-2a (Pegasys) Monotherapy

Sub-Q

180 mcg once weekly for 48 weeks.

Treatment of Chronic HCV Infection

Concomitant Peginterferon Alfa-2a (Pegasys) and Oral Ribavirin

Sub-Q

Adults with HCV monoinfection (without coexisting HIV infection): 180 mcg once weekly in conjunction with oral ribavirin. Recommended treatment duration depends on HCV genotype. (See Table 1.)

Adults with HCV and HIV coinfection: 180 mcg once weekly in conjunction with oral ribavirin for 48 weeks, regardless of HCV genotype.

Consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log₁₀ from baseline at week 12 or are still detectable after 24 weeks of treatment.

Manufacturer states safety and efficacy beyond 48 weeks of therapy not established.

Concomitant Peginterferon Alfa-2b (PegIntron) and Oral Ribavirin

Sub-Q

1.5 mcg/kg once weekly in conjunction with oral ribavirin.

The appropriate volume of reconstituted peginterferon alfa-2b to be administered in conjunction with oral ribavirin is based on the solution strength used and patient’s weight. (See Table 2.)

Previously untreated (treatment-naive) adults: Usual treatment duration is 24 weeks for HCV genotype 2 or 3 or 48 weeks for HCV genotype 1. Consider discontinuing HCV treatment if HCV RNA has not decreased ≥2 log₁₀ from baseline at week 12 or remains detectable after 24 weeks of treatment.

Retreatment in adults following failure of prior therapy: Usual treatment duration is 48 weeks regardless of HCV genotype. Consider discontinuing HCV treatment if HCV RNA levels are still detectable at week 12 or if HCV RNA remains detectable after 24 weeks of treatment.

Peginterferon Alfa-2a (Pegasys) Monotherapy

Sub-Q

Previously untreated (treatment-naive) adults with monoinfection (without coexisting HIV infection) who cannot receive ribavirin: 180 mcg once weekly for 48 weeks.

HCV-infected adults with HIV coinfection and clinically stable HIV disease with CD4⁺ T-cell counts >100 cells/mm³: 180 mcg once weekly for 48 weeks.

Manufacturer states safety and efficacy beyond 48 weeks of therapy not established.

Peginterferon Alfa-2b (PegIntron) Monotherapy

Sub-Q

Previously untreated (treatment-naive) adults who cannot receive ribavirin: 1 mcg/kg once weekly for 1 year.

The appropriate volume of reconstituted peginterferon alfa-2b is based on the solution strength used and the patient’s weight. (See Table 3.)

Dosage Modification for Toxicity (Peginterferon Alfa-2a [Pegasys])

Sub-Q

If serious adverse effects or laboratory changes occur when Pegasys used alone or in conjunction with oral ribavirin, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Generally, if dosage modification of peginterferon alfa-2a required because of adverse reactions (clinical and/or laboratory), initial dosage reduction to 135 mcg once weekly is recommended; further reduction to 90 mcg once weekly may be needed if adverse reaction persists or recurs. Consider dosage re-escalation if adverse reaction abates.

Moderate depression: Reduce peginterferon alfa-2a dosage to 135 mcg once weekly; further reduction to 90 mcg once weekly may be needed. If symptoms improve with reduced dosage and remain stable for 4 weeks, consider continuing reduced dosage or increasing to usual dosage.

Severe depression: Permanently discontinue.

Hematologic effects: Reduce peginterferon alfa-2a dosage to 135 mcg once weekly if ANC <750/mm³. If ANC <500/mm³, withhold the drug; If ANC increases to >1000/mm³, resume drug using reduced dosage of 90 mcg once weekly with close monitoring. If platelet counts <50,000/mm³, reduce dosage to 90 mcg once weekly; if platelet count <25,000/mm³, discontinue the drug.

Consult manufacturer's information for more specific recommendations regarding dosage modification for depression, hematologic effects, or other adverse effects.

Dosage Modification for Toxicity (Peginterferon Alfa-2b [PegIntron])

Sub-Q

If serious adverse effects or laboratory changes occur when PegIntron used alone or in conjunction with oral ribavirin, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Generally, if dosage modification of peginterferon alfa-2b required because of adverse reactions in those receiving usual dosage (1.5 mcg/kg once weekly) and concomitant oral ribavirin, use 2-step dosage reduction (i.e., initially reduce peginterferon alfa-2b dosage to 1 mcg/kg once weekly and then, if needed, reduce dosage to 0.5 mcg/kg once weekly). In those receiving usual peginterferon alfa-2b monotherapy dosage (1 mcg/kg once weekly), reduce dosage to 0.5 mcg/kg once weekly.

Moderate depression: If using peginterferon alfa-2b concomitantly with oral ribavirin, reduce peginterferon alfa-2b dosage to 1 mcg/kg once weekly and, if needed, to 0.5 mcg/kg once weekly. If using peginterferon alfa-2b monotherapy, reduce dosage to 0.5 mcg/kg once weekly. If symptoms improve with reduced dosage and remain stable for 4 weeks, consider continuing reduced dosage or increasing to usual dosage.

Severe depression: Permanently discontinue.

Hematologic effects: If leukocyte count 1000 to <1500/mm³, neutrophil count 500 to <750/mm³, or platelet count 25,000 to <50,000/mm³, reduce dosage. Permanently discontinue if hemoglobin <8.5 g/dL, leukocyte count <1000/mm³, neutrophil count <500/mm³, or platelet count <25,000/mm³. In those with history of stable cardiac disease, decrease peginterferon alfa-2b dosage by 50% if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).

Consult manufacturer's information for more specific recommendations regarding dosage modification for depression, hematologic effects, or other adverse effects.

Treatment of Acute HCV Infection†

Peginterferon Alfa-2a (Pegasys)

Sub-Q

Some experts recommend 180 mcg once weekly for 24 weeks.

Optimum time to initiate treatment and optimum regimen (e.g., with or without oral ribavirin, dosage, duration of treatment) not established. Recommended duration ranges from 12–48 weeks depending on HCV genotype, HCV RNA response, and coexisting conditions (e.g., HIV infection).

If response not obtained, some experts recommend retreatment with standard of care for chronic HCV infection.

Peginterferon Alfa-2b (PegIntron)

Sub-Q

Some experts recommend 1.5 mcg/kg once weekly for 24 weeks.

Optimum time to initiate treatment and optimum regimen (e.g., with or without oral ribavirin, dosage, duration of treatment) not established. Recommended duration ranges from 12–48 weeks depending on HCV genotype, HCV RNA response, and coexisting conditions (e.g., HIV infection).

If response not obtained, some experts recommend retreatment with standard of care for chronic HCV infection.

Treatment of Chronic HDV Infection†

Peginterferon Alfa-2a (Pegasys)

Sub-Q

Has been given in a dosage of 180 mcg once weekly for 48 weeks.

Peginterferon Alfa-2b (PegIntron)

Sub-Q

Has been given in a dosage of 1.5 mcg/kg once weekly for 48 or 52 weeks.

Melanoma

Peginterferon Alfa-2b (Sylatron)

Sub-Q

6 mcg/kg once weekly for 8 doses (induction), followed by 3 mcg/kg once weekly for up to 5 years (maintenance). Initiate peginterferon alfa-2b for adjuvant treatment of melanoma within 84 days of definitive surgical resection including complete lymphadenectomy.

Administration with antipyretic at bedtime may minimize adverse flu-like effects. Manufacturer recommends acetaminophen 0.5–1 g orally 30 minutes prior to first dose and as needed for subsequent doses.

Dosage Modification for Toxicity (Peginterferon Alfa-2b [Sylatron])

Sub-Q

Permanently discontinue if persistent or worsening severe neuropsychiatric disorders or grade 4 nonhematologic toxicity occurs or patient is unable to tolerate dosage of 1 mcg/kg once weekly or develops new or worsening retinopathy.

Withhold if ANC <500/mm³ or platelet count <50,000/mm³ or if Eastern Cooperative Oncology Group (ECOG) performance status is ≥2 or nonhematologic toxicity grade is ≥3.

May resume using reduced dosage when patient exhibits all of the following: ANC ≥500/mm³, platelet count ≥50,000/mm³, ECOG performance status 0 or 1, and nonhematologic toxicity has completely resolved or improved to grade 1.

If dosage modification required during weeks 1–8 of treatment (induction) because of adverse reactions, a 3-step decrease from original dosage (6 mcg/kg once weekly) recommended (i.e., decrease dosage to 3 mcg/kg once weekly; if needed, decrease to 2 mcg/kg once weekly; then, if needed, further decrease to 1 mcg/kg once weekly). Permanently discontinue if 1 mcg/kg once weekly not tolerated.

If dosage modification required during weeks 9–260 of treatment (maintenance) because of adverse reactions, a 2-step decrease from original dosage (3 mcg/kg once weekly) recommended (i.e., decrease dosage to 2 mcg/kg once weekly; if needed, decrease to 1 mcg/kg once weekly). Permanently discontinue if 1 mcg/kg once weekly not tolerated.

Special Populations

Hepatic Impairment

Treatment of Chronic HBV Infection

Peginterferon Alfa-2a (Pegasys)

Sub-Q

Adults with increased ALT concentrations (>5 times ULN): Consider reducing dosage to 135 mcg once weekly or temporarily discontinuing treatment and monitor hepatic function more frequently; resume treatment after ALT flares subside.

Persistent or severely increased ALT concentrations (>10 times ULN): Consider discontinuing treatment.

Progressive ALT increases despite dosage reduction: Immediately discontinue treatment.

ALT increases accompanied by increased bilirubin or evidence of hepatic decompensation: Immediately discontinue treatment.

Treatment of Chronic HCV Infection

Peginterferon Alfa-2a (Pegasys)

Sub-Q

Adults with progressive ALT increases above baseline values: Reduce dosage to 135 mcg once weekly and monitor hepatic function more frequently; resume treatment after ALT flares subside.

Progressive ALT increases despite dosage reduction: Immediately discontinue treatment.

ALT increases accompanied by increased bilirubin or evidence of hepatic decompensation: Immediately discontinue treatment.

Melanoma

Peginterferon Alfa-2b (Sylatron)

Sub-Q

Not studied for adjuvant treatment of melanoma in patients with hepatic impairment. Contraindicated in those with hepatic decompensation (Child-Pugh score >6, class B and C).

Renal Impairment

Treatment of Chronic HCV Infection

Peginterferon Alfa-2a (Pegasys)

Sub-Q

Adults with Cl_cr 30–50 mL/minute: Use usual dosage of 180 mcg once weekly.

Adults with Cl_cr <30 mL/minute (including those with end-stage renal disease requiring hemodialysis): Reduce dosage to 135 mcg once weekly.

Adults with severe adverse reactions or laboratory abnormalities: May reduce dosage to 90 mcg; discontinue if intolerance persists.

Pediatric patients with renal impairment: Data not available to make dosage recommendations.

Peginterferon Alfa-2b (PegIntron)

Sub-Q

Monotherapy in adults with Cl_cr 30–50 mL/minute: Reduce dosage by 25%.

Monotherapy in adults with Cl_cr 10–29 mL/minute (including those on hemodialysis): Reduce dosage by 50%.

Discontinue treatment if renal function decreases during treatment.

Pediatric patients with renal impairment: Discontinue treatment if S_cr >2 mg/dL.

Melanoma

Peginterferon Alfa-2b (Sylatron)

Sub-Q

Adults with Cl_cr 30–50 mL/minute per 1.73 m²: Reduce dosage for adjuvant treatment of melanoma to 4.5 mcg/kg once weekly for 8 doses (induction), followed by 2.25 mcg/kg once weekly for up to 5 years (maintenance).

Adults with Cl_cr <30 mL/minute per 1.73 m² and adults with end-stage renal disease requiring dialysis: Reduce dosage for adjuvant treatment of melanoma to 3 mcg/kg once weekly for 8 doses (induction), followed by 1.5 mcg/kg once weekly for up to 5 years (maintenance).

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal function. (See Renal Impairment under Dosage and Administration.)

Cautions for Peginterferon Alfa

Contraindications

• Known hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis) to peginterferon alfa (alfa-2a, alfa-2b) or any ingredient in the formulation.

• Autoimmune hepatitis.

• Cirrhotic patients with hepatic decompensation (Child-Pugh score >6, class B and C) prior to or during treatment.

• Use of peginterferon alfa-2a (Pegasys) in cirrhotic patients with chronic HCV infection who are coinfected with HIV and have hepatic decompensation (Child-Pugh score ≥6) prior to treatment.

• Use of peginterferon alfa-2a (Pegasys) in neonates and infants (this preparation contains benzyl alcohol). (See Pediatric Use under Cautions.)

• Concomitant use of ribavirin is contraindicated in women who are or may become pregnant, men whose female partners are pregnant, patients with known hypersensitivity (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to ribavirin or any ingredient in the formulation, patients with hemoglobinopathies (e.g., thalassemia major, sickle cell anemia), patients receiving concomitant didanosine therapy, and usually contraindicated in patients with Cl_cr <50 mL/minute.

Warnings/Precautions

Warnings

Serious Disorders

May cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Monitor closely with periodic clinical and laboratory evaluations; discontinue in those with persistently severe or worsening signs or symptoms of these disorders. In many, but not all cases, these disorders resolve after peginterferon alfa discontinuance. (See Other Warnings/Precautions under Cautions.)

Precautions Related to Combination HCV Treatment Regimens

When used in conjunction with oral ribavirin, consider cautions, precautions, and contraindications associated with both drugs.

Ribavirin may cause birth defects and/or death of the fetus. If oral ribavirin is used in conjunction with peginterferon alfa, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients.

Ribavirin causes hemolytic anemia, which can result in worsening of cardiac disease.

When used in conjunction with oral ribavirin and an HCV DAA, including simeprevir (an HCV protease inhibitor) or sofosbuvir (an HCV polymerase inhibitor), also consider cautions, precautions, and contraindications associated with the HCV DAA.

Neuropsychiatric Effects

Risk of serious depression, with suicidal ideation and completed suicides, and other serious neuropsychiatric disorders (e.g., homicidal ideation, increased risk of relapse in recovering drug addicts) are increased with alpha interferons. Psychoses, hallucinations, aggressive behavior, bipolar disorders, mania reported in patients receiving nonconjugated interferon alfa. In postmarketing experience, adverse neuropsychiatric reactions have been reported up to 6 months after discontinuance of peginterferon alfa-2b (Sylatron).

Exacerbated symptoms of psychiatric disorders may occur in patients with both psychiatric and substance use disorders. If initiated in a patient with current or prior psychiatric conditions or history of substance use disorders, consider the need for drug screening and periodic health evaluation, including psychiatric symptom monitoring. Early intervention for new or re-emergent neuropsychiatric symptoms and substance use recommended.

Use with extreme caution in any patient with history of depression or psychiatric disorder. Monitor all patients for evidence of depression and other psychiatric symptoms (every 3 weeks during first 8 weeks of treatment, every 6 months thereafter; continue monitoring for at least 6 months after last dose). Advise patients to report any sign or symptom of depression or suicidal ideation to their clinician.

If mild depression develops, usual dosage may be continued if patient is evaluated once weekly and depression remains stable or improves; dosage reduction recommended in those who develop moderate depression. (See Dosage under Dosage and Administration.)

If persistent severe depression occurs, psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior toward others is identified, discontinue immediately, provide psychiatric intervention, and refer patient for psychiatric evaluation. Do not reinitiate in such patients. These disorders may not resolve after the drug is discontinued.

Sensitivity Reactions

Serious acute hypersensitivity reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis) and cutaneous eruptions (Stevens-Johnson syndrome, toxic epidermal necrolysis) reported rarely during interferon alfa therapy.

If a hypersensitivity reaction occurs, discontinue peginterferon alfa and oral ribavirin immediately and provide appropriate supportive and symptomatic care. Transient rash does not necessitate interruption of treatment, but discontinue the drug if signs or symptoms of severe skin reactions occur.

Other Warnings/Precautions

Cardiovascular Effects

Clinically important cardiovascular effects (e.g., hypotension, hypertension, supraventricular arrhythmia, ventricular tachycardia, cardiomyopathy, angina pectoris, myocardial infarction, bundle-branch block) reported.

Use with caution and with close monitoring in those with preexisting cardiovascular disease, including history of myocardial infarction and cardiac arrhythmias. Perform ECG before initiating peginterferon alfa in such patients. Permanently discontinue if new onset ventricular arrhythmia or cardiovascular decompensation occurs.

Because cardiac disease may be worsened by ribavirin-associated anemia, patients with a history of clinically important or unstable cardiac disease should not receive concomitant oral ribavirin.

Myelosuppression

Suppresses bone marrow function and may cause severe cytopenias; aplastic anemia reported rarely. Concomitant oral ribavirin may potentiate neutropenia and lymphopenia induced by alfa interferons, including peginterferon alfa.

Severe thrombocytopenia and neutropenia occurs more frequently in patients coinfected with chronic HCV and HIV than in those not coinfected with HIV; serious infections or bleeding may occur.

Use concomitant peginterferon alfa and oral ribavirin with caution in patients with baseline neutrophil counts <1500/mm³, baseline platelet counts <90,000/mm³, baseline hemoglobin <10 g/dL, or a baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

Perform CBCs prior to and routinely during therapy. Adjust dosage or discontinue drug if necessary. (See Dosage under Dosage and Administration.)

Autoimmune Disease

Development or exacerbation of autoimmune disease (e.g., thyroiditis, thrombotic or idiopathic thrombocytopenic purpura, rheumatoid arthritis, myositis, interstitial nephritis, hepatitis, systemic lupus erythematosus, psoriasis) reported.

Use with caution in patients with autoimmune disorders.

Endocrine and Metabolic Effects

May cause or aggravate hypothyroidism, hyperthyroidism, or diabetes mellitus.

Measure TSH levels within the 4 weeks preceding initiation of peginterferon alfa-2b (Sylatron), at 3 and 6 months following initiation of the drug, and every 6 months thereafter until discontinued.

Patients with hypothyroidism, hyperthyroidism, or diabetes mellitus whose disease cannot be effectively treated should not receive peginterferon alfa.

Permanently discontinue if these conditions develop during peginterferon therapy and cannot be effectively controlled.

Ocular Effects

Decreased or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton-wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by peginterferon alfa or other interferon alfa preparations.

Perform baseline ophthalmologic examination in all patients prior to initiation of peginterferon alfa. Perform ophthalmologic examinations (e.g., visual acuity and indirect ophthalmoscopy fundus photography) periodically during treatment in those with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy).

Perform prompt and complete eye examination in any patient who develops ocular symptoms.

Permanently discontinue in patients who develop new or worsening ophthalmologic disorders.

Cerebrovascular Disorders

Ischemic and hemorrhagic cerebrovascular events reported with alfa interferons, including peginterferon alfa. Such events have occurred in patients with few or no reported risk factors for stroke, including patients <45 years of age. Estimates of frequency and causal relationship not established.

Hepatic Failure and Hepatitis Exacerbations

Patients with chronic HCV infection and cirrhosis may be at risk of hepatic decompensation and death during interferon alfa (including peginterferon alfa) therapy. Cirrhotic HCV patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) in conjunction with interferon alfa therapy (with or without oral ribavirin) appear to be at increased risk for development of hepatic decompensation compared with patients not receiving HAART. In most reported cases, patients were receiving HAART that included nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine). (See Specific Drugs under Interactions.)

Closely monitor clinical status and hepatic function. Immediately discontinue peginterferon alfa if decompensation (Child-Pugh score ≥6) occurs.

Patients with chronic HBV infection may experience HBV exacerbations (characterized by transient and potentially severe increases in ALT) during treatment. Marked transaminase flares during peginterferon alfa-2a treatment have been accompanied by other liver test abnormalities. If ALT flares occur, monitor liver function more frequently and consider dosage reduction. Immediately discontinue treatment if ALT increases are progressive despite dosage reduction or are accompanied by increased bilirubin or evidence of hepatic decompensation.

Peginterferon alfa-2b (Sylatron) increases risk of hepatic decompensation and death in patients with cirrhosis. Monitor hepatic function (i.e., serum bilirubin, ALT, AST, alkaline phosphatase, LDH) at 2 weeks, 8 weeks, 2 months, and 3 months following initiation of the drug, then every 6 months thereafter during therapy. Permanently discontinue if evidence of severe (grade 3) hepatic injury or hepatic decompensation (Child-Pugh score >6, class B and C) occurs.

Pulmonary Effects

May aggravate or induce potentially life-threatening dyspnea, pneumonia, bronchiolitis obliterans, pulmonary infiltrates, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis.

Discontinue peginterferon alfa and oral ribavirin therapy in patients who develop pulmonary infiltrates or pulmonary function impairment. Recurrence of respiratory failure has occurred with interferon rechallenge, closely monitor patient if therapy is resumed.

Use with caution in patients with history of pulmonary disease (e.g., COPD) or other debilitating conditions, since flu-like symptoms may occur.

Infectious Complications

Serious and severe infections (bacterial, viral, fungal), including some fatalities, reported in patients treated with alfa interferons, including peginterferon alfa.

While fever may be associated with the flu-like syndrome commonly reported during interferon therapy, rule out other causes of high or persistent fever, particularly in patients with neutropenia.

Initiate appropriate anti-infective therapy and consider discontinuing peginterferon alfa in patients who develop severe infections.

Colitis

Potentially life-threatening ulcerative and hemorrhagic/ischemic colitis reported within 12 weeks of initiation of interferon alfa treatment.

Discontinue immediately in patients who develop signs and symptoms of colitis (e.g., abdominal pain, bloody diarrhea, fever); colitis usually resolves within 1–3 weeks of discontinuance of interferon alfa therapy.

Pancreatitis

Potentially life-threatening pancreatitis has occurred in patients receiving interferon alfa therapy.

Discontinue in patients with suspected pancreatitis; permanently discontinue if diagnosis of pancreatitis is established.

Peripheral Neuropathy

Peripheral neuropathy reported in patients receiving telbivudine with an interferon alfa. (See Specific Drugs under Interactions.)

Triglycerides

Increased triglyceride concentrations reported in patients receiving alfa interferons, including peginterferon alfa.

Manage elevated triglycerides as clinically appropriate.

Consider discontinuing in patients with persistently elevated triglycerides (e.g., triglycerides >1000 mg/dL) and symptoms of potential pancreatitis (e.g., abdominal pain, nausea, vomiting).

Dental and Periodontal Disorders

Dental and periodontal disorders reported in patients receiving peginterferon alfa and oral ribavirin; dry mouth may contribute to damage of teeth and oral mucous membranes during long-term treatment.

Advise patients to have regular dental examinations during treatment, brush their teeth thoroughly twice daily, and rinse their mouth thoroughly after vomiting.

Antibody Formation

Neutralizing antibodies may develop in patients receiving alfa interferons, including peginterferon alfa.

Clinical and pathologic importance of development of serum neutralizing antibodies unknown. No apparent correlation of antibody development to clinical response or adverse events.

Organ Transplant Recipients

As with other alfa interferons, liver and renal graft rejections have been reported when peginterferon alfa (with or without oral ribavirin) was used in organ transplant recipients.

Safety and efficacy not established in patients with liver or other transplants.

Laboratory Monitoring

Assess organ system functions, including renal, hepatic, and hematopoietic, prior to and during peginterferon alfa therapy (with or without concomitant oral ribavirin).

Periodically monitor triglyceride concentrations.

In clinical studies in adults, CBCs and chemistries (liver function tests, uric acid) were measured at 1, 2, 4, 6, and 8 weeks or 2, 4, 8, and 12 weeks after initiation of therapy and then every 4–6 weeks or more frequently if abnormalities were found. In addition, TSH was measured every 12 weeks.

In a clinical study in pediatric patients, hematologic and chemistry assessments were performed at 1, 3, 5, and 8 weeks after initiation of peginterferon alfa and then every 4 weeks.

Perform pregnancy screening tests in all women of childbearing potential prior to initiation of treatment; in those receiving concomitant oral ribavirin, repeat pregnancy tests once monthly during and for 6 months after discontinuing therapy.

Specific Populations

Pregnancy

Peginterferon alfa monotherapy: Category C.

Concomitant peginterferon alfa and oral ribavirin: Category X. (See Concomitant Oral Ribavirin under Cautions.)

Lactation

Not known whether peginterferon alfa is distributed into human milk; studies in mice indicate mouse interferons are distributed into milk.

Discontinue nursing or the drug.

Pediatric Use

Peginterferon alfa-2a (Pegasys): Safety and efficacy not established in children <5 years of age.

Peginterferon alfa-2b (PegIntron): Safety and efficacy not established in children <3 years of age. Do not use concomitant peginterferon alfa-2b and ribavirin capsules or oral solution (Rebetol) therapy in pediatric patients with S_cr >2 mg/dL.

Peginterferon alfa-2b (Sylatron): Safety and efficacy not established in children <18 years of age.

Adverse effects reported in pediatric patients generally similar to those reported in adults. In addition, delay in weight and height increases compared with baseline reported in pediatric patients receiving peginterferon alfa and oral ribavirin.

Decreased weight and height for age z-scores as well as percentiles of the normative population reported; generally return to baseline normative growth curve percentiles for weight and height at end of 2-year follow-up after completion of treatment. May induce inhibition of growth resulting in reduced adult height in some patients.

Peginterferon alfa-2a (Pegasys): Contraindicated in neonates and infants; each mL contains 10 mg of benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity (e.g., neurologic) in neonates and infants, which is sometimes fatal.

Geriatric Use

Experience in those 65 years of age and older insufficient to determine whether they respond differently than younger adults.

Adverse reactions related to alfa interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects may be more severe in geriatric patients than in younger adults. Use with caution.

Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of drug-induced toxicity, monitor closely and adjust dosage accordingly. (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Chronic HBV patients may be at risk for transient acute exacerbations (flares) of HBV infection. (See Hepatic Failure and Hepatitis Exacerbations under Cautions.)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation and death. Closely monitor clinical status and hepatic function; immediately discontinue treatment if decompensation (Child-Pugh score ≥6) occurs. (See Hepatic Failure and Hepatitis Exacerbations under Cautions.)

If elevated plasma ALT concentrations occur, monitor hepatic function more frequently; consider dosage adjustments or discontinuance if necessary. (See Hepatic Impairment under Dosage and Administration.)

Peginterferon alfa-2b (Sylatron): Not studied in melanoma patients with moderate or severe hepatic impairment (Child-Pugh score >6, class B and C). Contraindicated in such patients; discontinue if hepatic decompensation (Child-Pugh score >6, class B and C) occurs during treatment.

Renal Impairment

Use with caution and close clinical monitoring in patients with renal impairment.

Dosage adjustments required if Cl_cr <30 mL/minute (peginterferon alfa-2a [Pegasys]) or Cl_cr ≤50 mL/minute (peginterferon alfa-2b [PegIntron, Sylatron]). (See Renal Impairment under Dosage and Administration.)

Use concomitant peginterferon alfa-2a (Pegasys) and oral ribavirin tablets (Copegus) with caution if Cl_cr ≤50 mL/minute. Other ribavirin preparations contraindicated if Cl_cr <50 mL/minute.

Concomitant peginterferon alfa-2b (PegIntron) and oral ribavirin contraindicated if Cl_cr <50 mL/minute.

Race

In studies evaluating peginterferon alfa-2b (PegIntron) for treatment of chronic HCV infection, response rates were lower in black and Hispanic patients and higher in Asian patients compared with white patients. Although black patients had a higher proportion of poor prognostic factors compared with white patients, experience with these patients was insufficient to allow meaningful conclusions about differences in response rates after adjusting for these prognostic factors.

Common Adverse Effects

Peginterferon alfa-2a (Pegasys), peginterferon alfa-2b (PegIntron): Flu-like symptoms (fatigue/asthenia, headache, myalgia, pyrexia, rigors); neuropsychiatric effects (insomnia, depression, anxiety/emotional lability/irritability); hematologic effects (neutropenia, thrombocytopenia). Almost all (>96%) of patients with chronic HCV infection receiving peginterferon alfa (alfa-2a, alfa-2b) experience adverse effects at some time during the course of treatment.

Peginterferon alfa-2b (Sylatron): Flu-like symptoms (fatigue, headache, myalgia, pyrexia, chills), anorexia, arthralgia, injection site reaction, depression, nausea, elevated AST and ALT concentrations. Essentially all patients receiving the drug for adjuvant treatment of melanoma experience adverse effects at some time during the course of treatment.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Peginterferon alfa-2a (Pegasys): May inhibit CYP1A2. Potential pharmacokinetic interactions with drugs metabolized by CYP1A2; interactions unlikely with drugs metabolized by CYP2C9, 2C19, 2D6, or 3A4.

Peginterferon alfa-2b (PegIntron): Variable effects on CYP2C8/9 and CYP2D6 activity (including possible increases); no clinically important effects on CYP1A2 or CYP3A4. Effect on CYP2C19 activity not assessed.

Peginterferon alfa-2b (Sylatron): Potential pharmacokinetic interactions with drugs metabolized by CYP2C9 or 2D6; no clinically important effects on CYP1A2 or 3A4. Effect on pharmacokinetics of drugs metabolized by CYP enzymes not studied when given at dosages recommended for adjuvant treatment of melanoma (6 mcg/kg once weekly and 3 mcg/kg once weekly).

Specific Drugs

Peginterferon Alfa Pharmacokinetics

Absorption

Bioavailability

Peginterferon alfa-2a (Pegasys): Peak serum concentrations occur 72–96 hours following sub-Q administration. In adults receiving dosages of 90–270 mcg, there is a nonlinear increase in peak serum concentrations and AUC. With once-weekly dosing, steady-state serum concentrations attained within 5–8 weeks.

Peginterferon alfa-2b (PegIntron): Mean absorption half-life is 4.6 hours. Peak serum concentrations occur 15–44 hours following sub-Q administration and are sustained for up to 48–72 hours. Peak serum concentrations and AUC increase in a dose-related manner; bioavailability is increased after multiple doses.

Peginterferon alfa-2b (Sylatron): When initiated for adjuvant treatment of melanoma in adults using dosage of 6 mcg/kg sub-Q once weekly for 8 doses (induction), peak serum concentrations are 4.4 ng/mL at week 8; mean accumulation from week 1 to week 8 is 1.7. After dosage decreased to 3 mcg/kg sub-Q once weekly (maintenance), peak serum concentrations at week 4 of lower dosage are 2.5 ng/mL.

Special Populations

Children 2–8 years of age with HCV infection (peginterferon alfa-2a): Time to reach steady-state serum concentrations is approximately 12 weeks. Steady-state trough concentrations in children receiving BSA-adjusted dosing are similar, but AUC predicted to be 25–70% higher than that reported in adults receiving fixed dose of 180 mcg.

Children 3–17 years of age with HCV infection (peginterferon alfa-2b): Systemic exposure with dosage of 60 mcg/m² once weekly may be approximately 50% higher than exposure reported in adults receiving 1.5 mcg/kg once weekly.

Adults with renal impairment (peginterferon alfa-2b [Sylatron]): After a single 4.5-mg sub-Q dose, AUC increased 1.4-fold in those with moderate renal impairment (Cl_cr 30–50 mL/minute per 1.73 m²) and increased 2.1-fold in those with severe renal impairment (Cl_cr <30 mL/minute per 1.73 m²) or with end-stage renal disease requiring dialysis compared with AUC in those with normal renal function (Cl_cr >80 mL/minute per 1.73 m²).

Adults >62 years of age (peginterferon alfa-2a): Peak serum concentrations similar, but AUC increased compared with those <62 years of age receiving 180 mcg.

Adults ≥65 years of age (peginterferon alfa-2b): Peak serum concentrations and AUC similar to values reported in younger adults (28–44 years of age).

Distribution

Extent

Not known whether peginterferon alfa-2a and peginterferon alfa-2b cross the placenta or are distributed into milk.

Elimination

Elimination Route

Renal elimination accounts for 30% of peginterferon alfa-2b clearance.

Hemodialysis does not remove clinically important amounts of peginterferon alfa-2b.

Half-life

Peginterferon alfa-2a (Pegasys): Mean terminal half-life in HCV patients is 160 hours (range 84–353 hours).

Peginterferon alfa-2b (PegIntron): Mean elimination half-life in HCV patients is 40 hours (range 22–60 hours).

Peginterferon alfa-2b (Sylatron): When used for adjuvant treatment of melanoma in adults, mean terminal half-life during induction phase (at dosage of 6 mcg/kg once weekly for 8 doses) is approximately 51 hours; and mean terminal half-life during maintenance phase (at dosage of 3 mcg/kg once weekly) is approximately 43 hours.

Special Populations

Children 2–8 years of age with HCV infection (peginterferon alfa-2a): Clearance is almost 4 times lower compared with adults.

Adults ≥65 years of age (peginterferon alfa-2b): Clearance and elimination half-life similar to values reported in younger adults (28–44 years of age).

Adults with severe renal impairment (peginterferon alfa-2a): Clearance reduced 43% compared with normal renal function.

Adults with renal impairment (peginterferon alfa-2b [PegIntron]): Clearance reduced by 17% in moderate renal impairment (Cl_cr 30–49 mL/minute) and by 44% in severe renal impairment (Cl_cr 10–29 mL/minute).

Stability

Storage

Parenteral

Injection

Vials, prefilled syringes, autoinjectors (Pegasys): 2–8°C; do not leave out of refrigerator for >24 hours. Protect from light; do not freeze or shake. For single use only; discard any unused portion.

For Injection

Prefilled dual-chamber injection pens containing lyophilized peginterferon alfa-2b and sterile water for injection (PegIntron): 2–8°C; do not freeze or expose to heat. Use immediately following reconstitution, but may be stored for up to 24 hours at 2–8°C. For single-use only; discard pen after use.

Vials (PegIntron, Sylatron): 25°C (may be exposed to 15–30°C); do not freeze or expose to heat. Use immediately following reconstitution, but may be stored for up to 24 hours at 2–8°C; do not freeze. For single-use only; discard any unused portions; do not pool.

Actions and Spectrum

• Mechanisms of antiviral activity not fully elucidated. Interferons with antiviral activity appear to bind to specific membrane receptors on cell surfaces and initiate a complex sequence of intracellular events, including induction of certain enzymes, suppression of cell proliferation, various immunomodulating activities, and inhibition of viral replication in virus-infected cells.

• Mechanism of therapeutic effects in adjuvant treatment of melanoma unknown; the drug is a pleiotropic cytokine.

Advice to Patients

• Advise patients receiving peginterferon alfa about appropriate use of the drug and the expected benefits and risks.

• Importance of taking the once-weekly dose of peginterferon alfa on the same day and approximately same time of day each week during treatment.

• If a dose of peginterferon alfa-2a (Pegasys) is missed and remembered within 2 days, take the missed dose as soon as it is remembered and take the next dose on the usually scheduled day. If a missed dose if remembered more than 2 days late, the patient should consult their clinician for instructions. Also advise patients to consult their clinician if the full dose is not received (e.g., leakage occurs around the injection site).

• Advise melanoma patients receiving peginterferon alfa-2b (Sylatron) that administration with an antipyretic at bedtime may minimize common flu-like symptoms (e.g., chills, fever, muscle aches, joint pain, headaches, tiredness).

• Importance of remaining well hydrated, especially during initial treatment.

• Importance of not reusing or sharing syringes or needles, autoinjectors, or injection pens. Importance of proper disposal of vials, syringes, needles, autoinjectors, and injection pens.

• Caution patients not to change brands of peginterferon alfa without consulting their clinician.

• Advise HBV patients that it is not known whether treatment with peginterferon alfa-2a (Pegasys) will prevent transmission of HBV infection to others or prevent HBV-associated complications (cirrhosis, liver failure, liver cancer).

• Advise HCV patients that it is not known whether treatment with peginterferon alfa-2a (Pegasys) or peginterferon alfa-2b (PegIntron) used alone or in conjunction with oral ribavirin will prevent transmission of HCV infection to others or prevent long-term HCV-associated complications (cirrhosis, liver failure, liver cancer). Importance of taking precautions to prevent transmission of HCV during treatment or in the event of treatment failure. If taking concomitant oral ribavirin, importance of taking the drug with food.

• Advise patients to avoid drinking alcohol to reduce the chance of further injury to the liver.

• Advise patients that laboratory evaluations are required before starting and periodically during treatment.

• Importance of reporting any sign or symptom of depression or suicidal ideation to clinician. Advise patients that the drug may need to be immediately discontinued and psychiatric intervention instituted in severe cases.

• Importance of immediately reporting trouble breathing, chest pain, severe stomach or lower back pain, bloody diarrhea or bloody bowel movements, high fever, bruising, bleeding, or decreased vision.

• Caution patients that dizziness, confusion, somnolence, and fatigue may occur and to avoid driving or operating machinery.

• Advise patients to maintain good oral hygiene, including brushing their teeth twice daily and rinsing their mouth after vomiting.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illness.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• If concomitant oral ribavirin is used, advise patients of the teratogenic/embryocidal risks associated with ribavirin and the necessity of females of childbearing potential and male patients with female partners of childbearing age practicing effective contraception during and for 6 months after ribavirin therapy.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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