PEG-INTRON® treatment for hepatitis C

PEG-INTRON/REBETOL® (Ribavirin, USP) Capsules combination therapy has been shown in a clinical trial to be more effective in reducing hepatitis C virus to undetectable levels than REBETRON Combination Therapy containing REBETOL® and INTRON® A (Interferon alfa-2b, recombinant) Injection. The National Institutes of Health has recognized that the highest response rates in the treatment of chronic hepatitis C have been achieved with combination therapy with ribavirin and pegylated alpha interferons.

In clinical trials, 52% of previously untreated patients who were treated with PEG-INTRON/REBETOL combination therapy for 48 weeks had undetectable levels of the hepatitis C virus 6 months after treatment completion compared to 46% of patients treated with REBETRON Combination Therapy. Among patients with genotype 1, a subgroup of patients that generally responds less well to therapy than genotypes 2 and 3, 41% of those treated with PEG-INTRON/REBETOL combination therapy had undetectable levels of hepatitis C virus compared to 33% of those treated with REBETRON Combination Therapy. Another benefit of PEG-INTRON/REBETOL combination therapy is that the PEG-INTRON component only needs to be taken once per week instead of three times per week as is done with standard alpha interferon therapy. This is because the process of pegylation helps to increase the lifetime of the interferon molecule in the body so that is takes longer to be broken down and eliminated.

It is not yet known whether PEG-INTRON/REBETOL therapy cures hepatitis C or prevents cirrhosis, liver failure, or liver cancer that can result from hepatitis C virus infection. It is also not known whether combination PEG-INTRON/REBETOL therapy will prevent one person from infecting others.

WARNING
Alpha interferons, including PEG-INTRON® and INTRON® A, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping PEG-INTRON or INTRON A therapy.

REBETOL monotherapy is not effective for the treatment of chronic hepatitis C and should not be used alone for this indication.

Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL®. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.

REBETOL and combination PEG-INTRON/REBETOL or INTRON A therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination PEG-INTRON/REBETOL or INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6-month posttreatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL®. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800)727-7064.

PEG-INTRON®
There are no new adverse events specific to PEG-INTRON® as compared to INTRON® A (Interferon alfa-2b, recombinant) for Injection, however, the incidence of some (eg, injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON® were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (ie, bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON®. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON®.

Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON®, but similar to INTRON® A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON®.

PEG-INTRON®/REBETOL® is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

The following serious or clinically significant adverse events have been reported at a frequency < 1% with PEG-INTRON® or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages, and cotton wool spots.

In the PEG-INTRON/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-INTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. The incidence of severe adverse events in the PEG-INTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-INTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-INTRON® (1.5 µg/kg)/REBETOL® and in 34% of those receiving INTRON® A/REBETOL®.
REBETOL® should not be used in patients with creatinine clearance < 50 ml/min.

REBETRON Combination Therapy
The most common adverse experiences associated with therapy are "flu-like" symptoms, such as headache, fatigue, myalgia, and fever, which appear to decrease in severity as treatment continues. Severe psychiatric adverse events, including depression, psychoses, aggressive behavior, hallucinations, violent behavior (suicidal ideation, suicidal attempts, suicides), and rare instances of homicidal ideation have occurred during combination REBETOL/INTRON A therapy, both in patients with and without a previous psychiatric disorder.

INTRON® A
All patients receiving INTRON A therapy experienced mild-to-moderate side effects. Some patients experienced more severe side effects, including neutropenia, fatigue, myalgia, headache, fever, chills, and increased SGOT. Other frequently occurring side effects were nausea, vomiting, depression, alopecia, diarrhea, and thrombocytopenia. DEPRESSION AND SUICIDAL BEHAVIOR, INCLUDING SUICIDAL IDEATION, SUICIDAL ATTEMPTS, AND COMPLETED SUICIDES, HAVE BEEN REPORTED IN ASSOCIATION WITH TREATMENT WITH ALFA INTERFERONS, INCLUDING INTRON A THERAPY.