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2/26/2001

New Interferon Alfa Formulation Licensed for Treatment of Hepatitis C

Cheryl A. Thompson

Peginterferon alfa-2b (PEG-Intron, Schering-Plough), a conjugate of the recombinant protein and polyethylene glycol, has been licensed by FDA for treatment of chronic hepatitis C in adult patients with compensated liver disease who have not previously received interferon alfa therapy. Addition of polyethylene glycol to interferon alfa-2b results in a product with a mean half-life five times as long as that of the unmodified protein, allowing for less frequent administration.

Clinical efficacy of peginterferon alfa-2b was established by a randomized study involving 1219 adults with chronic hepatitis C who not had previously received interferon alfa therapy. The group that received a once-weekly subcutaneous injection of peginterferon alfa-2b 1 or 1.5 mcg/kg for 48 weeks had a higher response rate than the group that received thrice-weekly injections of interferon alfa-2b 3 million units for the same duration. Twenty-four percent of the 1.0-mcg/kg peginterferon group had an undetectable level of viral RNA and a normal serum alanine transaminase concentration 24 weeks after the end of treatment, compared with 12% of the interferon group. Treatment with peginterferon 0.5 mcg/kg produced a response rate intermediate between the rates achieved by interferon and peginterferon 1 mcg/kg.

Labeling for peginterferon alfa-2b includes a black-box warning about the potential for interferon alfa products to cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. The appearance of signs or symptoms of any of these conditions warrants discontinuation of therapy. All patients should be carefully screened before starting therapy and closely monitored thereafter.

Peginterferon alfa-2b is contraindicated in patients hypersensitive to any component of the product, those with decompensated liver disease, and cases of autoimmune hepatitis. Therapy should stop if severe neutropenia (<0.5 x 109 cells/L) or thrombocytopenia (<50 x 109 cells/L) develops. Nearly all patients during the clinical studies had at least one adverse event, most commonly a psychiatric disorder (57%), musculoskeletal pain (56%), an application-site disorder (47%), or flu-like symptoms (46%). Flu-like symptoms may be minimized by bedtime administration of the biological or use of an antipyretic.

Thirty percent of a dose of peginterferon alfa-2b is renally eliminated. Results of a study of single-dose pharmacokinetics suggest that patients with a creatinine clearance of <50 mL/min have a 50% reduction in clearance. The product labeling does not provide specific advice on how to adjust the dosage for patients with impaired renal function. FDA has requested that the company study the potential for interactions between peginterferon alfa-2b and drugs metabolized by the liver in patients with hepatitis C.

Peginterferon alfa-2b is to be injected subcutaneously once weekly on the same day each week for one year. The recommended initial dosage is based on patient weight. A chart listing patient weights from 37 kg up to 160 kg, along with vial size and amount and volume of product to administer, is provided in the labeling. If a serious adverse reaction occurs, the clinician should tell the patient to use half of the starting dose until symptoms resolve or decrease in severity. Therapy should be discontinued if symptoms persist despite the lower dosage.

Each package of peginterferon alfa-2b contains one 100-, 160-, 240-, or 300-mcg/mL single-use vial of the lyophilized powder, one 5-mL vial of preservative-free sterile water for injection, two syringes (one for reconstitution of the powder and one for subcutaneous injection), and two alcohol swabs. Accompanying the package is an FDA-approved medication guide that pharmacists must give patients with each dispensing of peginterferon.

A dose is prepared by reconstituting the lyophilized product with 0.7 mL of the supplied diluent (gently swirl the vial) and withdrawing the appropriate volume, 0.4 or 0.5 mL. (FDA has asked the company to replace the 5-mL vial of diluent with a 1-mL vial.) Unused product should be stored at 25 degrees C; reconstituted product should be used immediately, although it can be stored for up to 24 hours at 2–8 degrees C. The product should not be frozen. Patients should be supplied with a puncture-resistant container for disposal of used syringes and needles.

The labeling for peginterferon alfa-2b states that the safety and efficacy of combination therapy with ribavirin have not been established. Unmodified interferon alfa-2b and ribavirin are used as combination treatment of chronic hepatitis C. Since approval of the initial licensing of peginterferon alfa-2b, the company announced that it had submitted a supplemental biologics license application covering combination treatment with ribavirin.