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CLINICAL PHARMACOLOGY Mechanism Of Action The mechanism(s) by which REBIF (interferon beta-1a) exerts its therapeutic effects in patients with multiple sclerosis is unknown. Pharmacodynamics The relationships between serum interferon beta-1a levels and measurable pharmacodynamic activities to the mechanism(s) by which REBIF exerts its effects in multiple sclerosis are unknown. No gender-related effects on pharmacodynamic parameters have been observed. Pharmacokinetics The pharmacokinetics of REBIF (interferon beta-1a) in people with multiple sclerosis have not been evaluated. In healthy subjects, a single subcutaneous (sc) injection of 60 mcg of REBIF (liquid formulation) resulted in a peak serum concentration (Cmax) of 5.1 ± 1.7 IU/mL (mean ± SD), with a median time of peak serum concentration (Tmax) of 16 hours. The serum elimination half-life (t½) was 69 ± 37 hours, and the area under the serum concentration versus time curve (AUC) from zero to 96 hours was 294 ± 81 IU h/mL. Following every other day sc injections in healthy subjects, an increase in AUC of approximately 240% was observed, suggesting that accumulation of interferon beta-1a occurs after repeat administration. Total clearance is approximately 33-55 L/hour. There have been no observed gender-related effects on pharmacokinetic parameters. Pharmacokinetics of REBIF in pediatric and geriatric patients or patients with renal or hepatic insufficiency have not been established. Clinical Studies Two multicenter studies evaluated the safety and efficacy of REBIF in patients with relapsingremitting multiple sclerosis. Study 1 was a randomized, double-blind, placebo controlled study in patients with multiple sclerosis for at least one year, Kurtzke Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, and at least 2 acute exacerbations in the previous 2 years. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients received subcutaneous injections of either placebo (n = 187), REBIF 22 mcg (n = 189), or REBIF 44 mcg (n = 184) administered three times per week for two years. Doses of study agents were progressively increased to their target doses during the first 4 to 8 weeks for each patient in the study [see DOSAGE AND ADMINISTRATION]. The primary efficacy endpoint was the number of clinical exacerbations. Numerous secondary efficacy endpoints were also evaluated and included exacerbation-related parameters, effects of treatment on progression of disability and magnetic resonance imaging (MRI)-related parameters. Progression of disability was defined as an increase in the EDSS score of at least one point sustained for at least 3 months. Neurological examinations were completed every 3 months, during suspected exacerbations, and coincident with MRI scans. All patients underwent proton density T2-weighted (PD/T2) MRI scans at baseline and every 6 months. A subset of 198 patients underwent PD/T2 and T1-weighted gadolinium-enhanced (Gd)-MRI scans monthly for the first 9 months. Of the 560 patients enrolled, 533 (95%) provided 2 years of data and 502 (90%) received 2 years of study agent. Study results are shown in Table 4 and Figure 1. REBIF at doses of 22 mcg and 44 mcg administered three times per week significantly reduced the number of exacerbations per patient as compared to placebo. Differences between the 22 mcg and 44 mcg groups were not significant (p > 0.05). The exact relationship between MRI findings and the clinical status of patients is unknown.  Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies has not been evaluated. Table 4: Clinical and MRI Endpoints from Study 1 Placebo n = 187 REBIF 22 mcg n = 189 REBIF 44 mcg n = 184 Exacerbation-related Mean number of exacerbations per patient over 2 years1,2 (Percent reduction) 2.56 1.82** (29%) 1.73*** (32%) Percent (%) of patients exacerbation-free at 2 years3 15% 25%* 32%*** Median time to first exacerbation (months)1,4 4.5 7.6** 9 6*** MRI n = 172 n = 171 n = 171 Median percent (%) change of MRI PD-T2 lesion area at 2 years5 11.0% -1.2%*** -3.8%*** Median number of active lesions per patient per scan (PD/T2; 6 monthly)5 2.25 0.75*** 0.5*** * p < 0.05 compared to placebo ** p < 0.001 compared to placebo *** p < 0.0001 compared to placebo 1 Intent-to-treat analysis 2 Poisson regression model adjusted for center and time on study 3 Logistic regression adjusted for center. Patients lost to follow-up prior to an exacerbation were excluded from this analysis. (Analysis included 185, 183, and 184 patients for three times per week placebo, 22 mcg REBIF, and 44 mcg REBIF, respectively). 4 Cox proportional hazard model adjusted for center 5 ANOVA on ranks adjusted for center. Patients with missing scans were excluded from this analysis. The time to onset of progression in disability sustained for three months was significantly longer in patients treated with REBIF than in placebo-treated patients. The Kaplan-Meier estimates of the proportions of patients with sustained disability are depicted in Figure 1. Figure 1: Proportions of Patients with Sustained Disability Progression The safety and efficacy of treatment with REBIF beyond 2 years have not been established. Study 2 was a randomized, open-label, evaluator-blinded, active comparator study. Patients with relapsing-remitting multiple sclerosis with EDSS scores ranging from 0 to 5.5, and at least 2 exacerbations in the previous 2 years were eligible for inclusion. Patients with secondary progressive multiple sclerosis were excluded from the study. Patients were randomized to treatment with three times per week subcutaneous injections of REBIF 44 mcg (n=339) or once weekly intramuscular injections of 30 mcg AVONEX (n=338). Study duration was 48 weeks. The primary efficacy endpoint was the proportion of patients who remained exacerbation-free at 24 weeks. The principal secondary endpoint was the mean number per patient per scan of combined unique active MRI lesions through 24 weeks, defined as any lesion that was T1 active or T2 active. Neurological examinations were performed every three months by a neurologist blinded to treatment assignment. Patient visits were conducted monthly, and mid-month telephone contacts were made to inquire about potential exacerbations. If an exacerbation was suspected, the patient was evaluated with a neurological examination. MRI scans were performed monthly and analyzed in a treatment-blinded manner. Patients treated with REBIF 44 mcg three times per week were more likely to remain relapse-free at 24 and 48 weeks than were patients treated with AVONEX 30 mcg once per week (Table 5). This study does not support any conclusion regarding effects on the accumulation of physical disability. Table 5: Clinical and MRI Results from Study 2 REBIF 44 mcg AVONEX 30 mcg Absolute Difference Risk of relapse on REBIF relative to AVONEX Relapses Proportion of patients relapse-free at 24 weeks1 N=339 75%* N=338 63% 12% (95% CI: 5%, 19%) 0.68 (95% CI: 0.54, 0.86) Proportion of patients relapse-free at 48 weeks 62%** 52% 10% (95% CI: 2%, 17%) 0.81 (95% CI: 0.68, 0.96) MRI (through 24 weeks) N=325 N=325 Median of the mean number of combined unique MRI lesions per patient per scan2 (25th, 75th percentiles) 0.17* (0.00, 0.67) 0.33 (0.00, 1.25) * p < 0.001 (REBIF compared to AVONEX) ** p = 0.009 (REBIF compared to AVONEX) 1 Logistic regression model adjusted for treatment and center, intent to treat analysis 2 Nonparametric ANCOVA model adjusted for treatment and center, with baseline combined unique lesions as the single covariate

CLINICAL PHARMACOLOGY Mechanism Of Action The mechanism of action by which AVONEX exerts its effects in patients with multiple sclerosis is unknown. Pharmacodynamics Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Three major types of interferons have been defined: type I (IFN-alpha, beta, epsilon, kappa and omega), type II (IFN–gamma) and type III (IFN-lambda). Interferon-beta is a member of the type I subset of interferons. The type I interferons have considerably overlapping but also distinct biologic activities. The bioactivities of all IFNs, including IFN-beta, are induced via their binding to specific receptors on the membranes of human cells. Differences in the bioactivites induced by the three major subtypes of IFNs likely reflect differences in the signal transduction pathways induced by signaling through their cognate receptors. Interferon beta exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include 2', 5'- oligoadenylate synthetase, β2-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. Clinical studies conducted in multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased in patients treated with AVONEX compared to placebo. Serum IL-10 levels maximally were increased by 48 hours after intramuscular injection of AVONEX and remained elevated for 1 week. However, no relationship has been established between absolute levels of IL-10 and clinical outcome in multiple sclerosis. Pharmacokinetics Pharmacokinetics of AVONEX in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of AVONEX in healthy subjects following doses of 30 micrograms through 75 micrograms have been investigated. Serum levels of AVONEX as measured by antiviral activity are slightly above detectable limits following a 30 microgram intramuscular dose, and increase with higher doses. After an intramuscular dose, serum levels of AVONEX generally peak at 15 hours post-dose (range: 6-36 hours) and then decline at a rate consistent with a 19 (range: 8-54) hour elimination half-life. Subcutaneous administration of AVONEX should not be substituted for intramuscular administration as there is no data establishing that subcutaneous and intramuscular administration of AVONEX result in equivalent pharmacokinetic and pharmacodynamic parameters. Biological response markers (e.g., neopterin and β2-microglobulin) are induced by AVONEX following parenteral doses of 15 micrograms through 75 micrograms in healthy subjects and treated patients. Biological response marker levels increase within 12 hours of dosing and remain elevated for at least 4 days. Peak biological response marker levels are typically observed 48 hours after dosing. The relationship of serum AVONEX levels or levels of these induced biological response markers to the mechanisms by which AVONEX exerts its effects in multiple sclerosis is unknown. Clinical Studies The clinical effects of AVONEX in patients with relapsing forms of multiple sclerosis (MS) were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with MS (Studies 1 and 2). Safety and efficacy of treatment with AVONEX beyond 3 years is not known. In Study 1, 301 patients received either 30 micrograms of AVONEX (n=158) or placebo (n=143) by intramuscular injection once weekly. Patients received injections for up to 2 years, and continued to be followed until study completion. Two hundred eighty-two patients completed 1 year on study, and 172 patients completed 2 years on study. There were 144 patients treated with AVONEX for more than 1 year, 115 patients for more than 18 months and 82 patients for 2 years. All patients had a definite diagnosis of multiple sclerosis of at least 1 year duration and had at least 2 exacerbations in the 3 years prior to study entry (or 1 per year if the duration of disease was less than 3 years). At entry, study participants were without exacerbation during the prior 2 months and had Kurtzke Expanded Disability Status Scale (EDSS3) scores ranging from 1.0 to 3.5. The EDSS is a scale that quantifies disability in patients with MS and ranges from 0 (normal neurologic exam) to 10 (death due to MS). Patients with chronic progressive multiple sclerosis were excluded from this study. Disability The primary outcome assessment was time to progression in disability, measured as an increase in the EDSS score of at least 1 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to help distinguish permanent increase in disability from a transient increase due to an exacerbation. As shown in Figure 1, the time to onset of sustained progression in disability was significantly longer in AVONEX-treated patients than in placebo-treated patients in Study 1 (p = 0.02). The percentage of patients progressing by the end of 2 years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. This represents a 37% relative reduction in the risk of accumulating disability in the AVONEX-treated group compared to the placebo-treated group. 1Kaplan-Meier Methodology; Disability progression was defined as at least a 1 point increase in EDSS score sustained for at least 6 months. The distribution of confirmed EDSS change from study entry (baseline) to the end of the study is shown in Figure 2. There was a statistically significant difference between the AVONEX and placebo groups in confirmed change for patients with at least 2 scheduled visits (p = 0.006). Figure 2: Confirmed Change in EDSS from Study Entry to End of Study 1 Exacerbations The rate and frequency of MS exacerbations were secondary outcomes. For all patients included in the study, irrespective of time on study, the annual exacerbation rate was 0.67 per year in the AVONEX-treated group and 0.82 per year in the placebo-treated group (p = 0.04). AVONEX treatment significantly decreased the frequency of exacerbations in the subset of patients who were enrolled in the study for at least 2 years (87 placebo-treated patients and 85 AVONEX-treated patients; p = 0.03; see Table 3). MRI Results Gadolinium (Gd)-enhanced and T2-weighted magnetic resonance imaging (MRI) scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Secondary outcomes included Gd-enhanced lesion number and volume, and T2-weighted lesion volume. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. AVONEX-treated patients demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment than placebo-treated patients (p ≤ 0.05; see Table 3). The volume of Gd-enhanced lesions showed similar treatment effects in the AVONEX and placebo groups (p ≤ 0.03). Percentage change in T2-weighted lesion volume from study entry to Year 1 was significantly lower in  AVONEX-treated than placebo-treated patients (p = 0.02). A significant difference in T2- weighted lesion volume change was not seen between study entry and Year 2 in the AVONEX and placebo groups. The exact relationship between MRI findings and the clinical status of MS patients is unknown. The prognostic significance of MRI findings in these studies has not been evaluated. Summary Of Effects Of Clinical And MRI Endpoints In Study 1 A summary of the effects of AVONEX on the clinical and MRI endpoints of this study is presented in Table 3. Table 3: Clinical and MRI Endpoints in Patients with MS in Study 1 Endpoint Placebo AVONEX P-Value PRIMARY ENDPOINT: Time to sustained progression in disability (N: 143, 158)1 See Figure 1 0.022 Percentage of patients progressing in disability at 2 years (Kaplan-Meier estimate)1 35% 22% SECONDARY ENDPOINTS: DISABILITY Mean confirmed change in EDSS from study entry to end of study (N: 136, 150)1 0.50 0.20 0.0063 EXACERBATIONS Number of exacerbations in subset completing 2 years (N: 87, 85) 0 26% 38% 0.033 1 30% 31 % 2 11% 18% 3 14% 7% ≥ 4 18% 7% Percentage of patients exacerbation-free in subset completing 2 years (N: 87, 85) 26% 38% 0.104 Annual exacerbation rate (N: 143, 158)1 0.82 0.67 0.045 MRI Number of Gd-enhanced lesions: At study entry (N: 132, 141) Mean (Median) 2.3 (1.0) 3.2 (1.0) Range 0-23 0-56 Year 1 (N: 123, 134) Mean (Median) (0) .6 1.0 (0) 0.023 Range 2 2 - 0 0-28 Year 2 (N: 82, 83) Mean (Median) O CD 0.8 (0) 0.053 Range ' 6 3 .1 0 0-13 T2 lesion volume: Percentage change from study entry to Year 1 (N: 116, 123) Median -3.3% -13.1% 0.023 Percentage change from study entry to Year 2 (N: 83, 81) Median -6.5% -13.2% 0.363 Note: (N: , ) denotes the number of evaluable placebo and AVONEX patients, respectively. 1Patient data included in this analysis represent variable periods of time on study. 2Analyzed by Mantel-Cox (logrank) test. 3Analyzed by Mann-Whitney rank-sum test. 4Analyzed by Cochran-Mantel-Haenszel test. 5Analyzed by likelihood ratio test. In Study 2, 383 patients who had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical of multiple sclerosis on brain MRI, received either 30 micrograms of AVONEX (n = 193) or placebo (n = 190) by intramuscular injection once weekly. Patients were enrolled into the study over a twoyear period and followed for up to three years or until they developed a second clinical exacerbation in an anatomically distinct region of the central nervous system. Exacerbations In Study 2, the primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Time to development of a second exacerbation was significantly delayed in AVONEX-treated compared to placebo-treated patients (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 39% in the placebo group and 21% in the AVONEX group (see Figure 3). The relative rate of developing a second exacerbation in the AVONEX group was 0.56 of the rate in the placebo group (95% confidence interval 0.38 to 0.81). Figure 3: Time to onset of a Second Exacerbation in Study 21 1 Kaplan-Meier Methodology MRI Findings Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume at baseline compared to results at 18 months, and the number of Gd-enhancing lesions at 6 months. See Table 4 for the MRI results. Table 4: Brain MRI Results in Study 2 AVONEX Placebo CHANGE FROM BASELINE IN T2 VOLUME OF LESIONS AT 18 MONTHS: N = 119 N = 109 Actual Change (mm³)1* Median (25*%, 75th%) 28 (-576, 397) 313 (5, 1140) Percentage Change1* Median (25th%, 75th%) 1 (-24, 29) 16 (0, 53) NUMBER OF NEW OR ENLARGING T2 LESIONS AT 18 MONTHS1*: N = 132 N (%) N = 119 N (%) 0 62 (47) 22 (18) 1-3 41 (31) 47 (40) ≥ 4 29 (22) 50 (42) Mean (SD) 2.13 (3.2) 4.97 (7.7) NUMBER OF GD-ENHANCING LESIONS AT 6 MONTHS2*: N = 165 N (%) N = 152 N (%) 0 115 (70) 93 (61) 1 27 (16) 16 (11) > 1 23 (14) 43 (28) Mean (SD) 0.87 (2.3) 1.49 (3.1) 1 P value < 0.001 2 P value < 0.03 * P value from a Mann-Whitney rank-sum test

Find Lowest Prices on REBIF Rebif Injection DESCRIPTION REBIF (interferon beta-1a) is a purified 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of REBIF is identical to that of natural fibroblast derived human interferon beta. Natural interferon beta and interferon beta-1a (REBIF) are glycosylated with each containing a single N-linked complex carbohydrate moiety. Using a reference standard calibrated against the World Health Organization natural interferon beta standard (Second International Standard for Interferon, Human Fibroblast GB 23 902 531), REBIF has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using WISH cells and Vesicular Stomatitis virus. REBIF 8.8 mcg, 22 mcg and 44 mcg contains approximately 2.4 million international units, 6 million international units or 12 million international units, respectively, of antiviral activity using this method. REBIF (interferon beta-1a) is formulated as a sterile solution in a prefilled syringe or REBIF Rebidose autoinjector intended for subcutaneous (sc) injection. Each 0.5 mL (0.5 cc) of REBIF contains either 22 mcg or 44 mcg of interferon beta-1a, 2 mg or 4 mg albumin (human), 27.3 mg mannitol, 0.4 mg sodium acetate, and water for injection. Each 0.2 mL (0.2 cc) of REBIF contains 8.8 mcg of interferon beta-1a, 0.8 mg albumin (human), 10.9 mg mannitol, 0.16 mg sodium acetate, and water for injection.

Find Lowest Prices on AVONEX (interferon beta-1a) Intramuscular Injection DESCRIPTION AVONEX is a 166 amino acid glycoprotein with a molecular weight of approximately 22,500 daltons. It is produced by recombinant DNA technology using genetically engineered Chinese Hamster Ovary cells into which the human interferon beta gene has been introduced. The amino acid sequence of AVONEX is identical to that of natural human interferon beta. Using the World Health Organization (WHO) International Standard for Interferon, AVONEX has a specific activity of approximately 200 million international units of antiviral activity per mg of interferon beta-1a determined specifically by an in vitro cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). AVONEX 30 micrograms contains approximately 6 million international units of antiviral activity using this method. The activity against other standards is not known. Comparison of the activity of AVONEX with other interferon betas is not appropriate, because of differences in the reference standards and assays used to measure activity. AVONEX Lyophilized Powder Vial A vial of AVONEX is a sterile, white to off-white lyophilized powder for intramuscular injection after reconstitution with supplied diluent (Sterile Water for Injection, USP). Each vial of reconstituted AVONEX contains 30 micrograms of interferon beta-1a; 15 mg Albumin (Human), USP; 5.8 mg Sodium Chloride, USP; 5.7 mg Dibasic Sodium Phosphate, USP; and 1.2 mg Monobasic Sodium Phosphate, USP, in 1.0 mL at a pH of approximately 7.3. AVONEX Single-Use Prefilled Syringe A prefilled syringe of AVONEX is a sterile liquid for intramuscular injection. Each 0.5 Ml (30 microgram dose) of AVONEX in a prefilled glass syringe contains 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8. AVONEX PEN Single-Use Prefilled Autoinjector AVONEX PEN is a sterile liquid for intramuscular injection in a prefilled glass syringe surrounded by an autoinjector. Each 0.5 mL (30 microgram dose) in the AVONEX PEN contains 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8.

INDICATIONS REBIF (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. DOSAGE AND ADMINISTRATION Dosing Information The recommended dose of REBIF is either 22 mcg or 44 mcg injected subcutaneously three times per week. REBIF should be administered, if possible, at the same time (preferably in the late afternoon or evening) on the same three days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week. Generally, patients should be started at 20% of the prescribed dose three times per week and increased over a 4-week period to the targeted dose, either 22 mcg three times per week (see Table 1) or 44 mcg three times per week (see Table 2). Patients prescribed a targeted dose of 22 mcg three times per week should use the prefilled syringes for titration. A Titration Pack containing 6 doses of 8.8 mcg (0.2 mL) and 6 doses of 22 mcg (0.5 mL) is available for use during the titration period in both REBIF prefilled syringes and REBIF Rebidose autoinjectors. Table 1: Titration Schedule for a 22 mcg Prescribed Dose* Week of Use Dose Syringe to Use Amount of syringe Week 1 Titration 4.4 mcg 8.8 mcg syringe Use half of syringe Week 2 Titration 4.4 mcg 8.8 mcg syringe Use half of syringe Week 3 Titration 11 mcg 22 mcg syringe Use half of syringe Week 4 Titration 11 mcg 22 mcg syringe Use half of syringe Week 5 and after 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector *Use only prefilled syringes, not autoinjectors, to titrate to the 22 mcg Prescribed Dose Table 2: Titration Schedule for a 44 mcg Prescribed Dose** Week of Use Dose Syringe or Autoinjector to Use Amount of syringe or autoinjector Week 1 Titration 8.8 mcg 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 2 Titration 8.8 mcg 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 3 Titration 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 4 Titration 22 mcg 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 5 and after 44 mcg 44 mcg syringe or autoinjector Use full syringe or autoinjector **Prefilled syringes or autoinjectors can be used to titrate to the 44 mcg Prescribed Dose Decreased peripheral blood counts or elevated liver function tests may necessitate dose reduction or discontinuation of REBIF administration until toxicity is resolved [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Important Administration Instructions REBIF is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for selfadministering subcutaneous injections using the prefilled syringe or injection device approved for use with REBIF. Injection depth of the REBIF Rebidose autoinjector is fixed at 8 mm; the healthcare provider should determine the injection technique. The initial injection should be performed under the supervision of an appropriately qualified healthcare provider. Appropriate instruction for self-injection or injection by another person should be provided to the patient or their caregiver, including careful review of the REBIF Medication Guide and the REBIF Rebidose autoinjector Instructions for Use that accompanies the product. Users should demonstrate competency in all aspects of the injection prior to independent use. If a patient isto self-administer REBIF, the physical and cognitive ability of that patient to self-administer and properly dispose of prefilled syringes or the REBIF Rebidose autoinjectors should be assessed. Patients with severe neurological deficits should not self-administer injections without assistance from a trained caregiver. Advise Patients and Caregivers to visually inspect REBIF for particulate matter and discoloration prior to administration use aseptic technique when administering REBIF rotate site of injection with each dose to minimize the likelihood of severe injection site reactions or necrosis [see WARNINGS AND PRECAUTIONS] use a puncture-resistant container for safe disposal of used needles, prefilled syringes and REBIF Rebidose autoinjectors do not re-use needles, syringes or REBIF Rebidose autoinjectors Premedication For Flu-like Symptoms Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms associated with REBIF use on treatment days. HOW SUPPLIED Dosage Forms And Strengths Injection: 8.8 mcg per 0.2 mL in a graduated, single-dose REBIF prefilled syringe Injection: 22 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe Injection: 44 mcg per 0.5 mL in a graduated, single-dose REBIF prefilled syringe Injection: 8.8 mcg per 0.2 mL in a single-dose prefilled REBIF Rebidose autoinjector Injection: 22 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector Injection: 44 mcg per 0.5 mL in a single-dose prefilled REBIF Rebidose autoinjector Storage And Handling REBIF is supplied as a sterile solution containing no preservative available in the following package presentations: Prefilled Syringes REBIF (interferon beta -1a) Titration Pack, NDC 44087-8822-1- Six REBIF 8.8 mcg prefilled syringes and Six REBIF 22 mcg prefilled syringes REBIF (interferon beta -1a) 22 mcg Prefilled syringe One REBIF 22 mcg prefilled syringe, NDC 44087-0022-1 Twelve REBIF 22 mcg prefilled syringes, NDC 44087-0022-3 REBIF (interferon beta -1a) 44 mcg Prefilled syringe One REBIF 44 mcg prefilled syringe, NDC 44087-0044-1 Twelve REBIF 44 mcg prefilled syringes, NDC 44087-0044-3 REBIF Rebidose Autoinjectors REBIF Rebidose (interferon beta-1a) Titration Pack, NDC 44087-0188-1 Six REBIF Rebidose 8.8 mcg autoinjectors with lime-green injector buttons and Six REBIF Rebidose 22 mcg with yellow injector buttons. REBIF Rebidose (interferon beta-1a) 22 mcg Autoinjector Twelve REBIF Rebidose 22 mcg autoinjectors with yellow injector buttons, NDC 44087-3322-1 REBIF Rebidose (interferon beta-1a) 44 mcg Autoinjector Twelve REBIF Rebidose 44 mcg autoinjectors with teal-green injector buttons, NDC 44087-3344-1 REBIF should be stored refrigerated between 36°F to 46°F (2°C to 8°C). DO NOT FREEZE. If needed, REBIF may be stored between 36°F to 77°F (2°C to 25°C) for up to 30 days and away from heat and light, but refrigeration is preferred. Do not use beyond the expiration date printed on packages. REBIF contains no preservatives. Each prefilled syringe and REBIF Rebidose autoinjector is intended for a single dose. Unused portions should be discarded. Manufactured by EMD Serono, Inc. Rockland, MA 02370 U.S. License # 1773. Marketed by: EMD Serono, Inc. Pfizer Inc, Rockland, MA 02370 New York, NY 10017. Revised: Oct 2015

INDICATIONS AVONEX (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis. DOSAGE AND ADMINISTRATION Dosing Information AVONEX is administered intramuscularly. The recommended dose is 30 micrograms once a week. To reduce the incidence and severity of flu-like symptoms that may occur when initiating AVONEX therapy at a dose of 30 micrograms, AVONEX may be started at a dose of 7.5 micrograms and the dose may be increased by 7.5 micrograms each week for the next three weeks until the recommended dose of 30 micrograms is achieved (see Table 1). An AVOSTARTGRIP™ kit containing 3 titration devices can be used for titration and is to be used only with AVONEX Prefilled Syringes. Table 1: Schedule for Dose Titration AVONEX Dose1 Recommended Dose Week 1 7.5 micrograms ¼ dose Week 2 15 micrograms ½ dose Week 3 22.5 micrograms ¾ dose Week 4+ 30 micrograms full dose 1 Dosed once a week, intramuscularly Important Administration Instructions (All Dosage Forms) All AVONEX dosage forms are single-use (injection of reconstituted solution, prefilled syringe, and prefilled autoinjector). See Patient's Instructions for Use for complete administration instructions. The first AVONEX injection should be performed under the supervision of an appropriately qualified healthcare professional. If patients or caregivers are to administer AVONEX, train them in the proper intramuscular injection technique and assess their ability to inject intramuscularly to ensure the proper administration of AVONEX. Advise patients and caregivers to: Rotate sites for intramuscular injections with each injection to minimize the likelihood of injection site reactions NOT inject into an area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way Check the injection site after 2 hours for redness, swelling, or tenderness Contact their healthcare provider if they have a skin reaction and it does not clear up in a few days A 25 gauge, 1” needle for intramuscular injection with AVONEX prefilled syringe or injection of reconstituted solution may be substituted for the 23 gauge, 1 ¼” needle by the healthcare provider, if deemed appropriate. A 25 gauge, 5/8” needle specific to the prefilled autoinjector is supplied with the AVONEX PEN® Administration Dose Pack. DO NOT use any other needle with the autoinjector. Use safe disposal procedures for needles and syringes. Do not re-use needles, syringes, prefilled syringes, or autoinjectors. Following the administration of each titrated dose, discard any remaining product. Premedication For Flu-like Symptoms Concurrent use of analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms associated with AVONEX use. HOW SUPPLIED Dosage Forms And Strengths For injection: 30 micrograms lyophilized powder in a single-use vial Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled syringe Injection: 30 micrograms per 0.5 mL solution in a single-use prefilled autoinjector Storage And Handling AVONEX Lyophilized Powder Vial A vial of AVONEX is supplied as a lyophilized powder in a single-use vial containing 33 micrograms (6.6 million international units) of interferon beta-1a; 16.5 mg Albumin (Human), USP; 6.4 mg Sodium Chloride, USP; 6.3 mg Dibasic Sodium Phosphate, USP; and 1.3 mg Monobasic Sodium Phosphate, USP, and is preservative-free. Diluent is supplied in a singleuse vial (Sterile Water for Injection, USP). AVONEX lyophilized vials are available in the following package configuration (NDC 59627-111- 03): A package containing four Administration Dose Packs (each containing one vial of AVONEX, one 10 mL diluent vial, two alcohol wipes, one gauze pad, one 3 mL syringe, one MICRO PIN®* vial access pin, one 23 gauge, 1¼ inch needle, and one adhesive bandage). Vials of AVONEX should be stored in a 2°C to 8°C (36°F to 46°F) refrigerator. Should refrigeration be unavailable, vials of AVONEX can be stored at 25°C (77°F) for a period of up to 30 days. DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the vial. Following reconstitution, it is recommended the product be used as soon as possible within 6 hours stored at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE RECONSTITUTED AVONEX. AVONEX Single-Use Prefilled Syringe A prefilled syringe of AVONEX is supplied as a sterile liquid albumin-free formulation containing 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP. Each prefilled glass syringe contains 0.5 mL for Intramuscular injection. AVONEX prefilled syringes are available in the following package configuration (NDC 59627- 222-05): A package containing four Administration Dose Packs (each containing one single-use syringe of AVONEX and one 23 gauge, 1¼ inch needle), and a recloseable accessory pouch containing 4 alcohol wipes, 4 gauze pads, and 4 adhesive bandages. AVONEX in prefilled syringes should be stored in a 2°C to 8°C (36°F to 46°F) refrigerator. Once removed from the refrigerator, AVONEX in a prefilled syringe should be allowed to warm to room temperature (about 30 minutes). Do not use external heat credits such as hot water to warm AVONEX in a prefilled syringe. Should refrigeration be unavailable, AVONEX in a prefilled syringe can be stored at ≤ 25°C (77°F) for a period up to 7 days. Once the product is removed from the refrigerator, it must not be stored above 25°C (77°F). If the product has been exposed to conditions other than those recommended, DISCARD THE PRODUCT and DO NOT USE. DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the syringe. AVONEX PEN Single-Use Prefilled Autoinjector AVONEX PEN is supplied as a sterile liquid albumin-free formulation containing 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP. Each single-use prefilled autoinjector contains 0.5 mL for intramuscular injection. AVONEX PEN single-use prefilled autoinjectors are available in the following package configuration (NDC 59627-333-04): A package containing four AVONEX PEN Administration Dose Packs (each containing one AVONEX PEN autoinjector, one 25 gauge, 5/8 inch needle and an AVONEX PEN cover), and a recloseable accessory pouch containing 4 alcohol wipes, 4 gauze pads, and 4 adhesive bandages. AVONEX PEN should be stored in a 2°C to 8°C (36°F to 46°F) refrigerator. Once removed from the refrigerator, AVONEX PEN should be allowed to warm to room temperature (about 30 minutes). Do not use external heat credits such as hot water to warm AVONEX. Should refrigeration be unavailable, AVONEX PEN can be stored at ≤ 25°C (77°F) for a period up to 7 days. Once the product is removed from the refrigerator, it must not be stored above 25°C (77°F). If the product has been exposed to conditions other than those recommended, DISCARD THE PRODUCT and DO NOT USE. DO NOT EXPOSE TO HIGH TEMPERATURES. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date stamped on the prefilled autoinjector. Manufactured by: Biogen Inc., Cambridge, MA 02142 USA. Revised: Mar 2016

PATIENT INFORMATION REBIF (interferon beta-1a) Injection for Subcutaneous Use Read this Medication Guide before you start using REBIF and each time you get a refill. There may be new information. The information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about REBIF? REBIF can cause serious side effects. Tell your healthcare provider right away if you have any of the symptoms listed below while taking REBIF. 1. Behavioral health problems including depression and suicidal thoughts. You may have mood problems including: depression (feeling hopeless or feeling bad about yourself) thoughts of hurting yourself or suicide 2. Liver problems or worsening of liver problems including liver failure. Symptoms may include: nausea yellowing of your skin or the white part of your eye loss of appetite tiredness bleeding more easily than normal dark colored urine and pale stools confusion sleepiness During your treatment with REBIF you will need to see your healthcare provider regularly and have regular blood tests to check for side effects. 3. Serious allergic and skin reactions. Symptoms may include: itching swelling of your face, eyes, lips, tongue or throat trouble breathing anxiousness feeling faint skin rash, hives, sores in your mouth, or skin blisters and peels 4. Injection site problems. Symptoms at the injection site may include: redness pain swelling color changes (blue or black) drainage of fluid What is REBIF? REBIF is a prescription medicine used to treat adults with relapsing forms of multiple sclerosis (MS). It is a form of protein called beta interferon that is produced in the body. REBIF will not cure your MS but may decrease the number of flare-ups of the disease and slow the occurrence of some of the physical disability that is common in people with MS. The way REBIF works in MS is not known. It is not known if REBIF is safe and effective in children. Who should not take REBIF? Do not take REBIF if you: are allergic to interferon beta, human albumin, or any of the ingredients in REBIF. See the end of this Medication Guide for a complete list of ingredients in REBIF. What should I tell my healthcare provider before taking REBIF? Before you take REBIF, tell your healthcare provider if have or have had any of the following conditions: mental illness, including depression and suicidal behavior liver problems bleeding problems or blood clots low blood cell counts seizures (epilepsy) thyroid problems drink alcohol you are pregnant or plan to become pregnant. (It is not known if REBIF will harm your unborn baby. Tell your healthcare provider if you become pregnant during your treatment with REBIF.) you are breastfeeding or plan to breastfeed. (It is not known if REBIF passes into your breast milk. You and our healthcare provider should decide if you will use REBIF or breastfeed. You should not do both.) Tell your healthcare provider about all medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. REBIF and other medicines may affect each other causing side effects. Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use REBIF? See the Instructions for Use at the end of this Medication Guide on how to prepare and give an injection of REBIF using a prefilled syringe. For the REBIF Rebidose autoinjector, read the Instructions for Use that comes with the REBIF Rebidose autoinjector. Your healthcare provider should show you how to prepare and measure your dose of REBIF and how to inject your REBIF before you use it for the first time. REBIF is given by injection under the skin (subcutaneous injection) on the same 3 days a week, for example, Monday, Wednesday and Friday. Your injections should be at least 48 hours apart. Take them the same time each day. Inject REBIF exactly as your healthcare provider tells you. Your healthcare provider will tell you how much REBIF to inject, and may change the dose based on how your body responds. Do not inject more than your healthcare provider tells you to. Do not change your dose unless your healthcare provider tells you to. Change (rotate) your injection site you choose with each injection. This will help decrease the chance that you will have an injection site reaction. Do not inject REBIF into an area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way. REBIF comes as a: prefilled syringe (REBIF) single-use prefilled autoinjector (REBIF Rebidose autoinjector) Your healthcare provider will decide which is best for you. Always use a new, unopened, prefilled syringe of REBIF or REBIF Rebidose autoinjector for each injection. Do not reuse prefilled syringes or REBIF Rebidose autoinjectors. What are the possible side effects of REBIF? REBIF may cause serious side effects, including: See “What is the most important information I should now about REBIF?” Blood problems. REBIF can affect your bone marrow and cause low red and white blood cell, and platelet counts. In some people, these blood cell counts may fall to dangerously low levels. If your blood cell counts become very low, you can get infections and problems with bleeding and bruising. Your healthcare provider may ask you to have regular blood tests to check for blood problems. Seizures. Some people have had seizures while taking REBIF. The most common side effects of REBIF include: flu-like symptoms. You may have flu-like symptoms when you first start taking REBIF. You may be able to manage these flu-like symptoms by taking over-the-counter pain and fever reducers. For many people, these symptoms lessen or go away over time. Symptoms may include: muscle aches fever tiredness chills stomach pain change in liver blood tests Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of REBIF. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should I store REBIF? Store REBIF in the refrigerator between 36°F to 46°F (2°C to 8°C). Do not freeze REBIF. If you cannot refrigerate your REBIF, you can store your REBIF at temperatures above 36°F and below 77°°F (2°C to 25°C) for up to 30 days. Keep REBIF away from heat and light. Keep REBIF and all medicines out of the reach of children. General information about the safe and effective use of REBIF. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use REBIF for a condition for which it was not prescribed. Do not give REBIF to other people, even if they have they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about REBIF. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about REBIF that is written for healthcare professionals. For more information, go to www.REBIF.com or call toll-free 1-877-4473243. What are the ingredients in REBIF? Active ingredient: interferon beta-1a Inactive ingredients: albumin (human), mannitol, sodium acetate, water for injection Instructions for Use REBIF ( Re-bif) interferon beta-1a (in-ter-feer-on beta-one-â) Injection for subcutaneous use Prefilled Syringe Read and follow the Instructions for Use that come with your REBIF prefilled syringe before you start using it can each time you get a refill. Before you use a REBIF prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it. Important: For the REBIF Rebidose autoinjector, read the Instructions for Use that come with the REBIF Rebidose autoinjector. Parts of your REBIF Prefilled Syringe (See Figure A). Figure A Supplies needed for a REBIF Injection (See Figure B): REBIF prefilled syringe alcohol pad or cotton balls and rubbing alcohol small adhesive bandage strip if desired puncture resistant safety container for disposal of used syringes. See “Disposing of your Needles and Syringes Section” in Step 4 of the IFU. antibacterial soap an over-the-counter pain or fever reducing medicine, if your healthcare provider has recommended that you take this before, at the same time, or after you give yourself REBIF to help decrease the fever, chills, sweating and muscle aches (flu-like symptoms) that may happen. Figure B Titration (Dosing) Schedule When first starting treatment with REBIF, your healthcare provider may prescribe either the 22 mcg or 44 mcg dose of REBIF. You should gradually increase the dose over 4 weeks, starting at 20% of the prescribed dose for the first 2 weeks, half-dose for the second 2 weeks (weeks 3 and 4), and then the full dose prescribed by your healthcare provider. If your prescribed dose is 22 mcg of REBIF, a REBIF Titration Pack containing 6 prefilled syringes with 8.8 mcg and 6 prefilled syringes with 22 mcg should be prescribed to you for use during the 4-week starting period. Table 1 explains the amount to inject using the REBIF Titration Pack syringes to gradually increase to 22 mcg. Table 1: Titration Schedule for a 22 mcg Prescribed Dose* Week of Use Syringe to Use Amount of syringe Week 1 Titration 8.8 mcg syringe Use half of syringe Week 2 Titration 8.8 mcg syringe Use half of syringe Week 3 Titration 22 mcg syringe Use half of syringe Week 4 Titration 22 mcg syringe Use half of syringe Week 5 and on 22 mcg syringe or autoinjector Use full syringe or autoinjector *Only prefilled syringes can be used to titrate to the 22 mcg Prescribed Dose If your prescribed dose is 44 mcg, you may be prescribed either a REBIF Titration Pack (described above) or REBIF Rebidose Titration Pack containing 6 autoinjectors with 8.8 mcg and 6 autoinjectors with 22 mcg for use during the 4-week titration period. Table 2 explains the amount to inject using the REBIF Titration Pack or REBIF Rebidose Titration Pack to gradually increase to 44 mcg. Table 2: Titration Schedule for a 44 mcg Prescribed Dose** Week of Use Syringe or Autoinjector to Use Amount of syringe or autoinjector Week 1 Titration 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 2 Titration 8.8 mcg syringe or autoinjector Use full syringe or autoinjector Week 3 Titration 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 4 Titration 22 mcg syringe or autoinjector Use full syringe or autoinjector Week 5 and on 44 mcg syringe or autoinjector Use full syringe or autoinjector **Prefilled syringes or autoinjectors can be used to titrate to 44 mcg Prescribed Dose Step 1. Preparing for your REBIF Injection Check the expiration date. Do not use if the medication is expired. The expiration date is printed on the syringe, plastic syringe packaging and carton. Remove your REBIF syringe from the refrigerator at least 30 minutes before you plan to use it so it can warm to room temperature. Do not heat or microwave the medication. Be sure that the dose, either, 8.8 mcg, 22 mcg or 44 mcg, described on the carton is the same as the dose prescribed by your healthcare provider. Remove the REBIF syringe from the plastic packaging. Keep the needle capped. Look at the contents of the syringe carefully. The liquid should be clear to slightly yellow. Do not use if the liquid is cloudy, discolored or contains particles. Use a different syringe. Step 2. Choose and Prepare your Injection Site The best sites for giving yourself an injection are those areas with a layer of fat between the skin and muscle, like your thigh, the outer surface of your upper arm, your stomach or buttocks. Do not use the area near your waistline or within 2 inches of your navel. If you are very thin, use only the thigh or outer surface of the arm for injection. Use a different site each time you inject such as the thigh, hip, stomach or upper arm (See Figure C) Figure C Do not inject REBIF into an area of your body where the skin is irritated, reddened, bruised, infected or abnormal in any way. Wash your hands thoroughly with antibacterial soap before preparing to inject the medicine. Clean the injection site with an alcohol pad or cotton ball with rubbing alcohol using a circular motion. To avoid stinging, you should let your skin dry before you inject REBIF. Step 3. Inject your REBIF Remove the needle cap from the syringe needle. If your healthcare provider has told you to use less than the full 0.5 mL dose, slowly push the plunger in until the amount of medicine left in the syringe is the amount healthcare provider told you to use. Use your thumb and forefinger to pinch a pad of skin surrounding the cleaned injection site (See Figure D). Hold the syringe like a pencil with your other hand. Figure D While still pinching the skin, quickly insert the needle like a dart at about a 90 degree angle (just under the skin) into the pad of tissue as shown (See Figure E). Figure E After the needle is in, remove the hand that you used to pinch your skin and inject the medicine using a slow, steady push on the plunger until all the medicine is injected and the syringe is empty (See Figure  F) Figure F Withdraw the needle and apply gentle pressure to the injection site with a dry cotton ball or sterile gauze. Applying a cold compress or ice pack to the injection site after injection may help reduce local skin reactions. Put a small adhesive bandage strip over the injection site, if desired. Keep a record of the date and location of each injection. After 2 hours, check the injection site for redness, swelling, or tenderness. If you have a skin reaction and it does not clear up in a few days, call your healthcare provider. Step 4. Disposing of your Needles and Syringes Put your used needles, syringes, and autoinjectors, including REBIF, in an FDA-cleared sharps container right away after use. Do not throw away (dispose of) any syringes or autoinjectors in your household trash. If you do not have an FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, closed with a tight-fitting, puncture-resistant lid, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used autoinjectors and syringe needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. This Medication Guide and Instructions for Use has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.

OVERDOSE No information provided. CONTRAINDICATIONS REBIF is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation.

OVERDOSE No information provided. CONTRAINDICATIONS AVONEX is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation [see WARNINGS AND PRECAUTIONS]. The lyophilized vial formulation of AVONEXis contraindicated in patients with a history of hypersensitivity to albumin (human).

SIDE EFFECTS The following adverse reactions are discussed in more detail in the WARNINGS AND PRECAUTIONS section of the label: Depression and Suicide [see WARNINGS AND PRECAUTIONS] Hepatic Injury [see WARNINGS AND PRECAUTIONS] Anaphylaxis and Other Allergic Reactions [see WARNINGS AND PRECAUTIONS] Injection Site Reactions including Necrosis [see WARNINGS AND PRECAUTIONS] Decreased Peripheral Blood Counts [see WARNINGS AND PRECAUTIONS] Thrombotic Microangiopathy [see WARNINGS AND PRECAUTIONS] Seizures [see WARNINGS AND PRECAUTIONS] Laboratory Tests [see WARNINGS AND PRECAUTIONS] Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of REBIF cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. A total of 712 patients with relapsing-remitting multiple sclerosis (RRMS) in two controlled clinical trials took REBIF (22 mcg or 44 mcg given three times per week) [see Clinical Studies]. Ages ranged from 18 to 55 years. Nearly three-fourths of the patients were female, and more than 90% were Caucasian, largely reflecting the general demographics of the population of patients with multiple sclerosis. The most commonly reported adverse reactions were injection site disorders, influenza-like symptoms (headache, fatigue, fever, rigors, chest pain, back pain, myalgia), abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities. The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of REBIF, adjustment in dosage, or the need for concomitant medication to treat an adverse reaction were injection site disorders, influenza-like symptoms, depression, and elevation of liver enzymes [see WARNINGS AND PRECAUTIONS]. Study 1 was a 2-year placebo-controlled study in RRMS patients treated with REBIF 22 mcg(n=189), 44 mcg (n=184), or placebo (n=187). Table 3 enumerates adverse reactions and laboratory abnormalities that occurred at an incidence that was at least 2% more in either REBIF-treated group than was observed in the placebo group. Table 3: Adverse Reactions and Laboratory Abnormalities in Study 1 Body System Preferred Term Placebo tiw (n=187) % REBIF 22 mcg tiw (n=189) % REBIF 44 mcg tiw (n=184) % BODY AS A WHOLE Influenza-like symptoms 51 56 59 Headache 63 65 70 Fatigue 36 33 41 Fever 16 25 28 Rigors 5 6 13 Chest pain 5 6 8 Malaise 1 4 5 INJECTION SITE DISORDERS Injection Site Reaction 39 89 92 Injection Site Necrosis 0 1 3 NERVOUS SYSTEM DISORDERS Hypertonia 5 7 6 Coordination Abnormal 2 5 4 Convulsions 2 5 4 Somnolence 1 4 5 ENDOCRINE DISORDERS Thyroid Disorder 3 4 6 GASTROINTESTINAL SYSTEM DISORDERS Abdominal Pain 17 22 20 Dry Mouth 1 1 5 LIVER AND BILIARY SYSTEM DISORDERS SGPT Increased 4 20 27 SGOT Increased 4 10 17 Bilirubinemia 1 3 2 MUSCULO-SKELETAL SYSTEM DISORDERS Myalgia 20 25 25 Back Pain 20 23 25 Skeletal Pain 10 15 10 HEMATOLOGIC DISORDERS Leukopenia 14 28 36 Lymphadenopathy 8 11 12 Thrombocytopenia 2 2 8 Anemia 3 3 5 SKIN DISORDERS Rash Erythematous 3 7 5 Rash Maculo-Papular 2 5 4 Hyperhidrosis 2 4 4 URINARY SYSTEM DISORDERS Micturition Frequency 4 2 7 Urinary Incontinence 2 4 2 VISION DISORDERS Vision Abnormal 7 7 13 Xerophthalmia 0 3 1 Adverse reactions in Study 2, a 1-year active-controlled (vs. interferon beta-1a, 30 mcg once weekly intramuscular injection, n=338) study including 339 patients with MS treated with REBIF were generally similar to those in Study 1, taking into account the disparity in study durations. Immunogenicity Anaphylaxis and other allergic reactions have been observed with the use of REBIF [see WARNINGS AND PRECAUTIONS]. As with all therapeutic proteins, there is a potential for immunogenicity. In Study 1, the presence of neutralizing antibodies (NAb) to REBIF was determined by collecting and analyzing serum pre-study and at 6 month time intervals during the 2 years of the clinical trial. Serum NAb were detected in 59/189 (31%) and 45/184 (24%) of REBIF-treated patients at the 22 mcg and 44 mcg three times per week doses, respectively, at one or more times during the study. The data reflect the percentage of patients whose test results were considered positive for antibodies to REBIF using an antiviral cytopathic effect assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of NAb positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to REBIF with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post-approval use of REBIF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Autoimmune Disorders: Drug-induced lupus erythematosus, autoimmune hepatitis Eye Disorders: Retinal vascular disorders (i.e. retinopathy, cotton wool spots or obstruction of retinal artery or vein) Skin and Subcutaneous Tissue Disorders: Erythema multiforme, Stevens-Johnson syndrome DRUG INTERACTIONS No information provided.

SIDE EFFECTS The following serious adverse reactions are discussed in more detail in other sections of labeling: Depression, Suicide, and Psychotic Disorders [see WARNINGS AND PRECAUTIONS] Hepatic Injury [see WARNINGS AND PRECAUTIONS] Anaphylaxis and Other Allergic-Reactions [see WARNINGS AND PRECAUTIONS] Congestive Heart Failure [see WARNINGS AND PRECAUTIONS] Decreased Peripheral Blood Counts [see WARNINGS AND PRECAUTIONS] Thrombotic Microangiopathy [see WARNINGS AND PRECAUTIONS] Seizures [see WARNINGS AND PRECAUTIONS] Autoimmune Disorders [see WARNINGS AND PRECAUTIONS] Laboratory Tests [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of AVONEX cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. Among 351 patients with relapsing forms of MS treated with AVONEX 30 micrograms (including 319 patients treated for 6 months and 288 patients treated for greater than one year) the most commonly reported adverse reactions (at least 5% more frequent on AVONEX than on placebo) were flu-like symptoms. Symptoms can include chills, fever, myalgia and asthenia occurring within hours to days following an injection. Most people who take AVONEX have flu-like symptoms early during the course of therapy. Usually, these symptoms last for a day after the injection. For many people, these symptoms lessen or go away over time. The most frequently reported adverse reactions resulting in clinical intervention (for example, discontinuation of AVONEX or the need for concomitant medication to treat an adverse reaction symptom) were flu-like symptoms and depression. Table 2 enumerates adverse reactions that occurred with AVONEX-treated patients at an incidence of at least 2% more than that observed in the placebo-treated patients in the pooled placebo-controlled studies in patients with relapsing forms of MS [see Clinical Studies]. Table 2: Adverse Reactions in the Placebo-Controlled Studies Adverse Reaction Placebo (N = 333) AVONEX (N = 351) Body as a Whole Headache 55% 58% Flu-like symptoms (otherwise unspecified) 29% 49% Pain 21% 23% Asthenia 18% 24% Fever 9% 20% Chills 5% 19% Abdominal pain 6% 8% Injection site pain 6% 8% Infection 4% 7% Injection site inflammation 2% 6% Chest pain 2% 5% Injection site reaction 1% 3% Toothache 1% 3% Nervous System Depression 1 4% 1 8% Dizziness 1 2% 1 4% Respiratory System Upper respiratory tract infection 12% 14% Sinusitis 1 2% 1 4% Bronchitis 5% 8% Digestive System Nausea 1 9% 23% Musculoskeletal System Myalgia 22% 29% Arthralgia 6% 9% Urogenital Urinary tract infection 15% 17% Urine constituents abnormal 0% 3% Skin and Appendages Alopecia 2% 4% Special Senses Eye disorder 2% 4% Hemic and Lymphatic System Injection site ecchymosis 4% 6% Anemia 1% 4% Cardiovascular System Migraine 3% 5% Vasodilation 0% 2% Immunogenicity Anaphylaxis and other allergic reactions have occurred in AVONEX-treated patients [see WARNINGS AND PRECAUTIONS]. As with all therapeutic proteins, there is a potential for immunogenicity. In studies assessing immunogenicity in multiple sclerosis patients administered AVONEX for at least 1 year, 5% (21 of 390 patients) showed the presence of neutralizing antibodies at one or more times. These data reflect the percentage of patients whose test results were considered positive for antibodies to AVONEX using a two-tiered assay (ELISA binding assay followed by an antiviral cytopathic effect assay), and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of neutralizing activity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to AVONEX with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of AVONEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Menorrhagia and metrorrhagia Rash (including vesicular rash) Rare cases of injection site abscess or cellulitis requiring surgical intervention DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Depression and Suicide REBIF (interferon beta-1a) should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression, suicidal ideation, and suicide attempts have been reported to occur with increased frequency in patients receiving interferon compounds, including REBIF. In addition, there have been postmarketing reports of suicide in patients treated with REBIF. Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation to the prescribing physician. If a patient develops depression, cessation of treatment with REBIF should be considered. Hepatic Injury Severe liver injury, including some cases of hepatic failure requiring liver transplantation, has been reported rarely in patients taking REBIF. Symptoms of liver dysfunction began from one to six months following the initiation of REBIF. If jaundice or other symptoms of liver dysfunction appear, treatment with REBIF should be discontinued immediately due to the potential for rapid progression to liver failure. Asymptomatic elevation of hepatic transaminases (particularly SGPT) is common with interferon therapy [see ADVERSE REACTIONS]. REBIF should be initiated with caution in patients with active liver disease, alcohol abuse, increased serum SGPT ( > 2.5 times ULN), or a history of significant liver disease. Also, the potential risk of REBIF used in combination with known hepatotoxic products should be considered prior to REBIF administration, or when adding new agents to the regimen of patients already on REBIF. Reduction of REBIF dose should be considered if SGPT rises above 5 times the upper limit of normal. The dose may be gradually re-escalated when enzyme levels have normalized [see Laboratory Tests; and DOSAGE AND ADMINISTRATION]. Anaphylaxis And Other Allergic Reactions Anaphylaxis has been reported as a rare complication of REBIF use. Other allergic reactions have included skin rash and urticaria, and have ranged from mild to severe without a clear relationship to dose or duration of exposure. Several allergic reactions, some severe, have occurred after prolonged use. Discontinue REBIF if anaphylaxis occurs. Injection Site Reactions Including Necrosis In controlled clinical trials, injection site reactions occurred more frequently in REBIF-treated patients (92% in the 44 mcg group and 89% in the 22 mcg group) than in placebo-treated patients (39%) and at a higher frequency in REBIF treated patients (83%) than in AVONEX treated patients (28%). Injection site necrosis also occurred more frequently in REBIF-treated patients (3% in the 44 mcg group and 1% in the 22 mcg group) than in placebo-treated patients (0) during the two years of therapy. All events resolved with conservative management. Injection site reactions including injection site pain, erythema, edema, cellulitis, abscess, and necrosis have been reported in the postmarketing setting. Some occurred more than 2 years after initiation of REBIF. Necrosis occurred at single and at multiple injection sites. Some cases of injection site necrosis required treatment with intravenous antibiotics and surgical intervention (debridement and skin grafting). Patient understanding and use of aseptic self-injection techniques and procedures should beperiodically evaluated, particularly if injection site necrosis has occurred. Patients should be advised of the importance of rotating sites of injection with each dose and not reusing syringes. Patients should be advised against injecting an area which is inflamed, edematous, erythematous, ecchymotic, or has any other signs of infection. These signs should be reported to a healthcare professional immediately. Decreased Peripheral Blood Counts Decreased peripheral blood counts in all cell lines, including pancytopenia, have been reported in REBIF-treated patients. In controlled clinical trials, leukopenia occurred at a higher frequency in REBIF-treated patients (36% in 44 mcg group and 28% in 22 mcg group) than in placebotreated patients (14%) and at a higher frequency in REBIF-treated patients (6%) compared to the AVONEX-treated patients ( < 1%). Thrombocytopenia and anemia occurred more frequently in 44 mcg REBIF-treated patients (8% and 5%, respectively) than in placebo-treated patients (2% and 3%, respectively). In a pooled analysis of 7 placebo controlled trials with REBIF doses of 22 mcg or 44 mcg, the rate of pancytopenia (in subjects with normal baseline values who developed laboratory values less than the lower limit of normal for all 3 hematology parameters simultaneously) was higher in the total REBIF group (5.5 per 1000 subject-year) than in the placebo group (1.2 per 1000 subject-year). Patients should be monitored for symptoms or signs of decreased blood counts. Monitoring of complete blood and differential white blood cell counts is also recommended [see DOSAGE AND ADMINISTRATION and Laboratory Tests]. Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including REBIF. Cases have been reported several weeks to years after starting interferon beta products. Discontinue REBIF if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated. Seizures Caution should be exercised when administering REBIF to patients with pre-existing seizure disorders. Seizures have been temporally associated with the use of beta interferons, including REBIF, in clinical trials and in postmarketing reports. Laboratory Tests In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, blood cell counts and liver function tests are recommended at regular intervals (1, 3, and 6 months) following introduction of REBIF therapy and then periodically thereafter in the absence of clinical symptoms. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts [see DOSAGE AND ADMINISTRATION and Decreased Peripheral Blood Counts]. New or worsening thyroid abnormalities have developed in some patients treated with REBIF. Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction or as clinically indicated. Patient Counseling Information See FDA-approved patient labeling (Medication Guide). Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking REBIF. Instruct patients to take REBIF only as prescribed. Depression and Suicide Advise patients that depression, suicidal ideation, and suicide have been reported during the use of REBIF. Inform patients of the symptoms of depression and suicidal ideation and instruct patients to immediately report any of these symptoms to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Hepatic Injury Advise patients that severe liver injury, including hepatic failure, has been reported with the use of REBIF. Educate patients about the symptoms of hepatic injury and instruct patients to report them immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Anaphylaxis and Other Allergic Reactions Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see WARNINGS AND PRECAUTIONS]. Injection Site Reactions including Necrosis Advise patients that injection site reactions occur in most patients treated with REBIF and that injection site necrosis may occur [see WARNINGS AND PRECAUTIONS]. Instruct patients to promptly report any break in the skin, which may be associated with blue-black discoloration, swelling, or drainage of fluid from the injection site, prior to continuing their REBIF therapy. To minimize the likelihood of injection site reactions, inform patients of the importance of rotating injection sites with each dose and the use of aseptic injection technique [see DOSAGE AND ADMINISTRATION]. Advise patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Provide appropriate instruction for self-injection of REBIF and REBIF Rebidose, including careful review of the REBIF Medication Guide. Decreased Peripheral Blood Counts Advise patients that they may develop a lowering of their peripheral blood counts, including their white blood counts, red blood counts, and platelets, and that their blood counts will be checked during therapy with REBIF. Inform patients that they may be more likely to get infections, anemia, or be at risk for bleeding, and that they should contact their healthcare provider if they develop symptoms of these adverse reactions [see WARNINGS AND PRECAUTIONS]. Seizures Instruct patients to report seizures immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS]. Flu-like Symptoms Inform patients that flu-like symptoms are common following initiation of therapy with REBIF. Advise patients that concurrent use of analgesics and/or antipyretics may help reduce flu-like symptoms on treatment days [see DOSAGE AND ADMINISTRATION]. Risk in Pregnancy Advise patients that REBIF should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use In Specific Populations]. Therefore, inform patients that if a pregnancy is considered, or does occur, the risks and benefits of continuing REBIF should be discussed with their healthcare provider. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis REBIF has not been tested for carcinogenic potential in animals. Mutagenesis Interferon beta was negative in an in vitro bacterial reverse mutation (Ames) assay and an in vitro cytogenetic assay in human lymphocytes in the presence and absence of metabolic activation. Impairment of Fertility In studies in normally cycling female cynomolgus monkeys given daily subcutaneous injections of interferon beta for six months at doses of up to 9 times the recommended weekly human dose (based on body surface area), no effects were observed on either menstrual cycling or serum estradiol levels. In male monkeys, the same doses of interferon beta had no demonstrable adverse effects on sperm count, motility, morphology, or function. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. REBIF should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a study in pregnant cynomolgus monkeys, interferon beta was administered daily (intramuscular doses approximately 1, 2, and 7 times the maximum recommended cumulative weekly human dose, based on body surface area) either throughout the period of organogenesis or later in pregnancy (gestation day 90 to term). No adverse effects on embryofetal development were observed; however, the possibility of adverse effects cannot be ruled out because of the small number of animals tested (six per dose group at each developmental period). Nursing Mothers It is not known whether REBIF is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REBIF is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of REBIF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Depression, Suicide, And Psychotic Disorders Patients treated with AVONEX and their caregivers should be advised to report immediately any symptoms of depression, suicidal ideation, and/or psychosis to their prescribing physicians. If a patient develops depression or other severe psychiatric symptoms, cessation of AVONEX therapy should be considered. Depression and suicide have been reported to occur with increased frequency in patients receiving AVONEX. In Study 1, the incidence of depression was similar in placebo-treated and in AVONEX-treated patients, but suicidal tendency was seen more frequently in AVONEXtreated patients (4% in AVONEX group vs. 1% in placebo group). In Study 2, there was a greater incidence of depression in AVONEX-treated patients than in placebo-treated patients (20% in AVONEX group vs. 13% in placebo group) [see Clinical Studies]. Additionally, there have been postmarketing reports of depression, suicidal ideation, and/or development of new or worsening of other pre-existing psychiatric disorders, including psychosis. For some of these patients, symptoms of depression improved upon cessation of AVONEX. Hepatic Injury Severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients taking AVONEX. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge with AVONEX. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of AVONEX used in combination with known hepatotoxic drugs or other products (e.g., alcohol) should be considered prior to starting AVONEX, or before starting hepatotoxic drugs. Patients should be monitored for signs of hepatic injury [see Laboratory Tests]. Anaphylaxis And Other Allergic-Reactions Anaphylaxis has been reported as a rare complication of AVONEX use. Other allergic reactions have included dyspnea, orolingual edema, skin rash and urticaria. Discontinue AVONEX if anaphylaxis or other allergic reactions occur. Congestive Heart Failure Patients with pre-existing congestive heart failure should be monitored for worsening of their cardiac condition during initiation of and continued treatment with AVONEX. While beta interferons do not have any known direct cardiac toxicity, during the postmarketing period cases of congestive heart failure, cardiomyopathy, and cardiomyopathy with congestive heart failure have been reported in patients without known predisposition to these events, and without other etiologies being established. In some cases, these events have been temporally related to the administration of AVONEX. In some of these instances recurrence upon rechallenge was observed. Decreased Peripheral Blood Counts Decreased peripheral blood counts in all cell lines, including rare pancytopenia and thrombocytopenia, have been reported from postmarketing experience in AVONEX-treated patients [see ADVERSE REACTIONS]. In some cases, platelet counts were below 10,000/microliter. Some cases recurred with rechallenge [see ADVERSE REACTIONS]. Patients should be monitored for symptoms or signs of decreased blood counts. Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with interferon beta products, including AVONEX. Cases have been reported several weeks to years after starting interferon beta products. Discontinue AVONEX if clinical symptoms and laboratory findings consistent with TMA occur, and manage as clinically indicated. Seizures Seizures have been temporally associated with the use of beta interferons in clinical trials andpostmarketing safety surveillance. In the two placebo-controlled studies in multiple sclerosis (Studies 1 and 2), 4 patients receiving AVONEX experienced seizures, while no seizures occurred in the placebo group [see Clinical Studies]. Three of these 4 patients had no prior history of seizure [see ADVERSE REACTIONS]. It is not known whether these events were related to the effects of multiple sclerosis alone, to AVONEX, or to a combination of both. Autoimmune Disorders Postmarketing reports of autoimmune disorders of multiple target organs in AVONEX-treated patients included idiopathic thrombocytopenia, hyper- and hypothyroidism, and rare cases of autoimmune hepatitis. If AVONEX-treated patients develop a new autoimmune disorder, consider stopping the therapy. Laboratory Tests In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts, and blood chemistries, including liver function tests, are recommended during AVONEX therapy [see above]. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts. Thyroid function should be monitored periodically. If patients have or develop symptoms of thyroid dysfunction (hypo- or hyperthyroidism), thyroid function tests should be performed according to standard medical practice. Patient Counseling Information See FDA-approved patient labeling (Medication Guide and Patient's Instructions for Use). Instruct patients to carefully read the supplied AVONEX Medication Guide and caution patients not to change the AVONEX dose or schedule of administration without medical consultation. Inform patients that the Prefilled Syringe tip cap of this product contains natural rubber latex which may cause allergic reactions. Instruction on Self-injection Technique and Procedures Provide appropriate instruction for reconstitution of AVONEX and methods of self-injection, including careful review of the AVONEX Medication Guide. Instruct patients in the use of aseptic technique when administering AVONEX. Inform patients that their healthcare provider should show them or their caregiver how to prepare and inject AVONEX before administering the first dose. Their healthcare provider should watch the first AVONEX injection given. Tell patients not to re-use needles or syringes and instruct patients on safe disposal procedures. Inform patients to dispose of used needles and syringes in a puncture-resistant container and instruct the patient regarding safe disposal of full containers. Advise patients: of the importance of rotating areas of injection with each dose to minimize the likelihood of injection site reactions. [see Choose an Injection Site section of the Medication Guide]. NOT to inject area of the body where the skin is irritated, reddened, bruised, infected or scarred in any way to check the injection site after 2 hours for redness, swelling, or tenderness contact their healthcare provider if they have a skin reaction and it does not clear up in a few days Pregnancy Advise patients that AVONEX should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus [see Use in Special Population]. Depression Advise patients of the symptoms of depression, suicidal ideation, or psychotic disorders as they have been reported with the use of AVONEX and instruct patients to report them immediately to their physician [see WARNINGS AND PRECAUTIONS]. Liver Disease Advise patients that severe hepatic injury, including hepatic failure, has been reported during the use of AVONEX. Advise patients of symptoms of hepatic dysfunction, and instruct patients to report them immediately to their physician [see WARNINGS AND PRECAUTIONS]. Allergic Reactions And Anaphylaxis Advise patients of the symptoms of allergic reactions and anaphylaxis, and instruct patients to seek immediate medical attention if these symptoms occur [see WARNINGS AND PRECAUTIONS]. Congestive Heart Failure Advise patients that worsening of pre-existing congestive heart failure has been reported in patients using AVONEX. Advise patients of symptoms of worsening cardiac condition, and instruct patients to report them immediately to their physician [see WARNINGS AND PRECAUTIONS]. Seizures Advise patients that seizures have been reported in patients using AVONEX. Instruct patients to report seizures immediately to their physician [see WARNINGS AND PRECAUTIONS]. Flu-like Symptoms Inform patients that flu-like symptoms are common following initiation of therapy with AVONEX [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS]. Advise patients that starting with a lower dose than 30 micrograms and increasing the dose over 3 weeks reduces the incidence and severity of flu-like symptoms. Nonclinical Toxicology Carcinogenesis, Mutagenesis, And Impairment Of Fertility Carcinogenesis The carcinogenic potential of AVONEX has not been tested in animals. Mutagenesis Interferon beta was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test or in an in vitro cytogenetic assay in human lymphocytes. Impairment Of Fertility In monkeys administered interferon beta by subcutaneous injection (8 to 15 doses of 1.25 mcg/kg or 50 mcg/kg) over the course of one menstrual cycle, menstrual irregularities, anovulation, and decreased serum progesterone levels were observed at the higher dose. These effects were reversible after discontinuation of drug. The no-effect dose (1.25 mcg/kg) is approximately 2 times the recommended weekly dose in humans (30 mcg) on a mg/m² basis. Use In Specific Populations Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. AVONEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose (based upon a body surface area [mg/m²] comparison), no teratogenic or other adverse effects on fetal development were observed. Abortifacient activity was evident following 3 to 5 doses at this level. No abortifacient effects were observed in monkeys treated at 2 times the recommended weekly human dose (based upon mg/m²). Nursing Mothers It is not known whether AVONEX is excreted in human milk. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of AVONEX did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.