CJN volume 29 issue 2 Cover and Back matter

interferon beta-1a "Rebif 11 pg (3MIU), 44 pg (12MIU) lyophilized powder for injection 22 pg (6MIU)/0.5mL,44 pg (12MIU)/0.5mLliquid formulation tor injection THERAPEUTIC CLASSIFICATION Immunomodulator ACTIONS AND CLINICAL PHARMACOLOGYDescription: Rebif (Interferon beta-ta) is a purified, sterile glycoprotein product produced by recombinant DNA techniques and formulated lor use by injection.The active ingredient of Rebif* 1 is produced by genetically engineered Chinese Hamster Ovary fCHO) cells, interferon beta-1 a is a highly purified glycoprotein that has 166 amino acids and an approximate molecular weight of 22,500 daltons.It contains a single relinked carbohydrate moiety attached to Asn-80 similar to that of natural human Interferon beta.The specific activity of Rebif is approximately 0.27 million international units (MIU)/mcg Interferon beta-1a.The unit measurement is derived by comparing the antiviral activity of the product to an in-house natural hlFN-fi NIH standard that is obtained from human fibroblasts (BILS11), which has been calibrated against the NIH natural hlFN-6 standard (GB 23-902-531).General: Interferons are a family of naturally occurring proteins, which have molecular weights ranging from 15,000 to 21,000 dah tons.Three major classes of interferons have been identified: alpha, beta, gamma.Interferon beta, Interferon alpha and Interferon gamma have overlapping yet distinct biologic activities.Interferon beta-la acts through various mechanisms:•Immunomodulation through the induction of cell membrane components of the major histocompatibility complex i.e., MHC Class I antigens, an increase in natural killer (NK) cell activity, and an inhibition ol IFN-y induced MHC Class II antigen expression, as well as a sustained reduction in TNF level.•Antiviral effect through the induction of proteins like 2'-5' oligoadenylate synthetase and p78.•Antiproliferative effect through direct cytostatic activity and indirect through antitumoral immune response enhancement.The mechanism of action of Rebif® in relapsing-remitting multiple sclerosis is still under investigation. Relapsing-Remitting Multiple SclerosisTwo pivotal studies, including a total of 628 patients, evaluated the long-term safety and efficacy of Rebif when administered subcutaneously three times weekly to relapsing-remitting multiple sclerosis patients, The results indicate that RebiP alters the natural course of relapsing-remitting multiple sclerosis.Efficacy was demonstrated with respect to the 3 major aspects of this disease: disability (patients EDSS 0-5), exacerbations, and burden of disease and activity as measured by MRI scans. PRISMS STUDYIn the larger trial, a total of 560 patients diagnosed with clinically definite or laboratorysupported relapsing-remitting multiple sclerosis EDSS 0-5 with at least a 1-year history before study entry, were enrolled and randomized to the 3 treatments (placebo, 22 pg (6MIU) Rebif".or 44 pg (12MIU) RebiP) in a ratio of 1:1:1.About 90% of patients completed the 2 years of treatment, and very lew patients withdrew trom the study due to adverse events.The main criteria lor inclusion were:• history ol 2 or more acute exacerbations in the 2 years prior to study entry • no previous systemic treatment with interferons • no treatment with corticosteroids or ACTH in the 2 months preceding study entry • no exacerbation in the 8 weeks prior to study entry.Patients were evaluated at 3-month periods, during exacerbations and coinciding with MRI scanning.Each patient underwent cranial proton density/I>-weighted (PD/T2) MRI scans at baseline and every 6 months during the study.A subset ol patients underwent PD/T2 and ^-weighted (T1) Gd-MRI scans one month before the start of treatment, at baseline and then monthly until the end ot the lirsl 9 months of treatment.Of those, another subset ot 39 continued with the monthly scans throughout the 24 month treatment period.This study demonstrated that Rebif* at a total dose ol 66 or 132 pg weekly, signiticantly improved all 3 major outcomes, including exacerbation rate, disease activily and burden ol disease as measured by MRI scanning and progression of disability.In addition, the study showed that Rebif is effective in delaying the progression in disability in patients with an EDSS ol 4.0 or higher who are known to progress more rapidly.Also, the drug reduced the requirements lor steroids to treat multiple sclerosis and, at 132 pg weekly Rebif reduced the number of hospitalizations tor multiple sclerosis. Effect on exacerbation Efficacy parametersMean # exacertar I T .over the 2 year VJU-. 1 Percentago ot e«.u «-:i?iiii free patients at 7-JPHJ Median time to 'iM exacerbation ( i W s : INDICATIONS AND CLINICAL USE Multiple Sclerosis:Rebif (Interferon beta-1 a) is indicated for the treatment of relapsing-remitting multiple sclerosis in patients with an EDSS between 0 and 5.0, to reduce the number and severity of clinical exacerbations, slow the progression of physical disability, reduce the requirement for steroids, and reduce the number of hospitalizations for treatment ol multiple sclerosis.The ellicacy has been confirmed by T1-Gd enhanced and T2 (burden ol disease) MRI evaluations.Evidence ol efficacy beyond I years is not known since the primary evidence ol efficacy derives from 2-year trials.Condyloma acuminatum: RebiP is best suited lor the patient who has less than nine lesions, and who has failed several prior treatments.In the case of patients with nine or more lesions, il Ihe iirst Rebif treatment is successful, Ihe remaining lesions could be treated with a second course ol Rebif Iherapy.Rebif should also be considered lor the treatment of 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 RebiP attained a complete response, patients whose lesions decreased in size and had at least a partial response may have also benefitted from Ireatment because lesion shrinkage may facilitate subsequent management with other therapies, as has been reported wilh IFN-alpha.CONTRAINDICATIONS: Rebif (Interferon bela-1a) is conlraindicated in patients with a known hypersensitivity to natural or recombinant interferon beta, albumin (human), or any other component of the foimulation. WARNINGS: Rebif (Interferon bela-1a) should be used under Ihe supervision of a physician.Relapsing-Remitting Multiple Sclerosis: Depression and suicidal ideation are known to occur al an increased frequency in the multiple sclerosis population.The use ol Rebif has not been associated with an increase in the incidence and/or severity ol depression, or with an increased incidence of suicide altempfs or suicide.In the relapsing-remitting multiple sclerosis study, a similar incidence of depression was seen in the placebo-treated group and in Ihe two Rebif patient groups.Nevertheless, patients with depression should be closely monitored for signs of significant worsening ol depression or suicidal ideation.The first injection should be performed under the supervision of an appropriately qualified health care professional.Condyloma: All injections should be administered by a qualified health care professional. PRECAUTIONS General:Patients should be informed ol the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome (see Adverse Reactions).These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.Based on the results ol clinical trials of Rebif in MS, in which more than 500 patients were randomized to drug treatment, there is no indication of an increased risk of seizure disorder wilh Rebif* therapy.However, since seizures have been reported with olher interferon therapies, caution should be exercised when administering interferon-beta-1a to patients with pre-exisling seizures disorder.For patients without a pre-existing seizure disorder who develop seizures during therapy, an etiologic basis should be established and appropriate anti-convulsant therapy instituted prior to considering resuming treatment with Rebif.The ettect ot Rebif administration on the medical management ol patients with seizure disorder is unknown.Serum neutralising antibodies against Rebif (interferon beta-1a) may develop.The precise incidence and ciinical significance of antibodies is as yet uncertain (see Adverse Reactions).Hypersensitivity reactions, both local and systemic, have developed during therapy with Rebif.Intralesional injections can be painful lo some patients treated for condyloma acuminata.In such cases an anaesthetic cream such as lidocaine-prilocaine can be used.Pregnancy and Lactation: Rebif should not be administered in case ol pregnancy and lactation.There are no studies of interferon beta-ta in pregnant women.At high doses in monkeys, aborlifacienl effects were observed with other interferons.Fertile

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