Effect on multiple sclerosis pathology as detected by MRI scans 11 meg (3MIU), 44 meg (12MIU) lycphilized powder for injection 22 meg (6MIU)/0.5mL, 44 meg (12MIU)/0.5mL liquid tormulation for injection THERAPEUTIC CLASSIFICATION Immunomodulalor ACTIONS AND CLINICAL PHARMACOLOGY Description: Rebif {Interferon beta-1a) is a purified, sterile glycoprotein product produced by recombinant DNA techniques and formulated for use by injection. The active ingredient of Rebif* is produced by genetically

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... gineered Chinese Hamster Ovary (CHO) cells. Interferon beta-1a is a highly purilied glycoprotein that has 166 amino acids and an approximate molecular weight of 22,500 daltdns. It contains a single Nlinked carbohydrate moiety attached to Asn-80 similar to that of natural human Interferon beta. The specific activity ol Rebif is apprpximately 0.2/ million international unite (MIU)/mcg Interferon beta-1a. The unit measurement is derived by comparing the antiviral activity of the product to an in-house natural hlFN-beta NIH standard that is obtained from human fibroblasts (BILS11), which has been calibrated against the NIH natural hlFN-beta standard (GB 23-902-531). General: Interferons are a family ol naturally occurring proteins, which have molecular weights ranging from 15,000 to 21,000 dallons. Three major classes of interferons have been identified: alpha, beta, gamma. INDICATIONS AND CLINICAL USE Multiple Sclerosis: Rebif (Interferon beta-1a) is indicated lor the treatment of relapsing-remitting multiple sclerosis in patients with an EDSS between 0 and 5.0, te reduce the number and severity ef clinical exacerbations, slow the progression of physical disability, reduce the reguiremenl for steroids, and reduce the number of hospitalizations tor treatment of multiple sclerosis. The elficacy has been confirmed by T, -Gd enhanced and T, (burden of disease) MRI evaluations. Evidence ol eflicacy beyond 2 years is not known since the primary evidence of eflicacy derives from 2-year trials. Condyloma acuminatum: Rebif is best suited for the patient who has less than nine lesiens, and who has failed several prior treatments. In the case of patients with nine or more lesions, it the first Rebif treatment is successful, Ihe remaining lesions could be treated with a second course ot Rebif therapy, Rebif should also be considered for the treatment ef condyloma acuminatum in patients for whom the side-effects from other treatments, e.g., scarring, are of concern. While not all patients who were treated with Rebif attained a complete response, patients whose lesions decreased in size and had at least a partial response may have also benefitted from treatment because lesion shrinkage may facilitate subsequent management with other therapies, as has been reported with IFN-alpha, CONTRAINDICATIONS: Rebif (Interferon beta-1a) is contraindicated in patients with a known hypersensitivity to natural or recombinant interferon beta, albumin (human), or any other component of the formulation, WARNINGS: Rebif (Interferon beta-1a) should be used under the supervision ol a physician, Relapsing-Remitting Multiple Sclerosis: Depression and suicidal ideation are known lo occur at an increased freguency in the multiple sclerosis population. The use of Rebif has not been associated with an increase in the incidence and/or severity of depression, or with an increased incidence ol suicide attempts or suicide. In the relapsing-remitting multiple sclerosis study, a similar incidence cf depression was seen in the placebo-treated group and in the two Rebif patient groups. Nevertheless, patients with depression should be closely monitored for signs of significant worsening of depression or suicidal ideation. The first injection should be performed under the supervision ot an appropriately qualified health care professional.