Avonex (Interferon beta-1a) is a 166 amino acid glycoprotein with a predicted 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 (Interferon beta-1a) is identical to that of natural human interferon beta.

Using the World Health Organization (WHO) natural interferon beta standard, Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531), Avonex (Interferon beta-1a) has a specific activity of approximately 200 million international units (IU) of antiviral activity per mg of Interferon beta-1a determined specifically by an cytopathic effect bioassay using lung carcinoma cells (A549) and Encephalomyocarditis virus (ECM). Avonex (Interferon beta-1a) 30 mcg contains approximately 6 million IU of antiviral activity using this method. The activity against other standards is not known. Comparison of the activity of Avonex (Interferon beta-1a) with other Interferon betas is not appropriate, because of differences in the reference standards and assays used to measure activity.

Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities in response to viral infection and other biological inducers. Three major interferons have been distinguished: alpha, beta, and gamma. Interferons alpha and beta form the Type I class of interferons, and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinct biological activities.

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, β-microglobulin, and neopterin. These products have been measured in the serum and cellular fractions of blood collected from patients treated with Avonex (Interferon beta-1a) .

The specific interferon-induced proteins and mechanisms by which Avonex (Interferon beta-1a) exerts its effects in multiple sclerosis have not been fully defined. Clinical studies conducted in multiple sclerosis patients showed that interleukin 10 (IL-10) levels in cerebrospinal fluid were increased in patients treated with Avonex (Interferon beta-1a) compared to placebo. Serum IL-10 levels were increased 48 hours after intramuscular (IM) injection of Avonex (Interferon beta-1a) 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 of Avonex (Interferon beta-1a) in multiple sclerosis patients have not been evaluated. The pharmacokinetic and pharmacodynamic profiles of Avonex (Interferon beta-1a) in healthy subjects following doses of 30 mcg through 75 mcg have been investigated. Serum levels of Avonex (Interferon beta-1a) as measured by antiviral activity are slightly above detectable limits following a 30 mcg IM dose, and increase with higher doses.

After an IM dose, serum levels of Avonex (Interferon beta-1a) typically peak between 3 and 15 hours and then decline at a rate consistent with a 10 hour elimination half-life. Serum levels of Avonex (Interferon beta-1a) may be sustained after IM administration due to prolonged absorption from the IM site. Systemic exposure, as determined by AUC and C values, is greater following IM than subcutaneous (SC) administration.

Subcutaneous administration of Avonex (Interferon beta-1a) should not be substituted for intramuscular administration. Subcutaneous and intramuscular administration have been observed to have non-equivalent pharmacokinetic and pharmacodynamic parameters following administration to healthy volunteers.

Biological response markers (e.g., neopterin and β-microglobulin) are induced by Avonex (Interferon beta-1a) following parenteral doses of 15 mcg through 75 mcg 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 (Interferon beta-1a) levels or levels of these induced biological response markers to the mechanisms by which Avonex (Interferon beta-1a) exerts its effects in multiple sclerosis is unknown.

The clinical effects of Avonex (Interferon beta-1a) in multiple sclerosis were studied in two randomized, multicenter, double-blind, placebo-controlled studies in patients with multiple sclerosis. Safety and efficacy of treatment with Avonex (Interferon beta-1a) beyond 3 years is not known.

In Study 1, 301 patients received either 30 mcg of Avonex (Interferon beta-1a) (n=158) or placebo (n=143) by IM injection once weekly. Patients were entered into the trial over a 2½ year period, 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 (Interferon beta-1a) 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 (EDSS) scores ranging from 1.0 to 3.5. Patients with chronic progressive multiple sclerosis were excluded from this study.

The primary outcome assessment was time to progression in disability, measured as an increase in the EDSS score of at least 1.0 point that was sustained for at least 6 months. An increase in EDSS score reflects accumulation of disability. This endpoint was used to ensure that progression reflected permanent increase in disability rather than a transient effect due to an exacerbation.

Secondary outcomes included exacerbation frequency and results of magnetic resonance imaging (MRI) scans including gadolinium (Gd)-enhanced lesion number and volume and T2-weighted (proton density) lesion volume. Additional secondary endpoints included 2 upper limb (tested in both arms) and 3 lower limb function tests.

Twenty-three of the 301 patients (8%) discontinued treatment prematurely. Of these, 1 patient treated with placebo (1%) and 6 patients treated with Avonex (Interferon beta-1a) (4%) discontinued treatment due to adverse events. Thirteen of these 23 patients remained on study and were evaluated for clinical endpoints.

Time to onset of sustained progression in disability was significantly longer in patients treated with Avonex (Interferon beta-1a) than in patients receiving placebo (p = 0.02). The Kaplan-Meier plots of these data are presented in . The Kaplan-Meier estimate of the percentage of patients progressing by the end of 2 years was 34.9% for placebo-treated patients and 21.9% for Avonex (Interferon beta-1a) -treated patients, indicating a slowing of the disease process. This represents a 37% relative reduction in the risk of accumulating disability in the Avonex (Interferon beta-1a) -treated group compared to the placebo-treated group.

The distribution of confirmed EDSS change from study entry (baseline) to the end of the study is shown in . There was a statistically significant difference between treatment groups in confirmed change for patients with at least 2 scheduled visits (136 placebo-treated and 150 Avonex (Interferon beta-1a) -treated patients; p = 0.006; see ).

The rate and frequency of exacerbations were determined as 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 (Interferon beta-1a) -treated group and 0.82 per year in the placebo-treated group (p = 0.04).

Avonex (Interferon beta-1a) 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 (Interferon beta-1a) -treated patients; p = 0.03; see ).

Gd-enhanced and T2-weighted (proton density) MRI scans of the brain were obtained in most patients at baseline and at the end of 1 and 2 years of treatment. Gd-enhancing lesions seen on brain MRI scans represent areas of breakdown of the blood brain barrier thought to be secondary to inflammation. Patients treated with Avonex (Interferon beta-1a) demonstrated significantly lower Gd-enhanced lesion number after 1 and 2 years of treatment (p ≤ 0.05; see ). The volume of Gd-enhanced lesions was also analyzed, and showed similar treatment effects (p ≤ 0.03). Percentage change in T2-weighted lesion volume from study entry to Year 1 was significantly lower in Avonex (Interferon beta-1a) -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.

The exact relationship between MRI findings and the clinical status of patients is unknown. The prognostic significance of MRI findings in these studies has not been evaluated.

Of the limb function tests, only 1 demonstrated a statistically significant difference between treatment groups (favoring Avonex (Interferon beta-1a) ). A summary of the effects of Avonex (Interferon beta-1a) on the clinical and MRI endpoints of this study is presented in .

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 mcg Avonex (Interferon beta-1a) (n = 193) or placebo (n = 190) by IM injection once weekly. All patients received intravenous steroid treatment for the initiating clinical exacerbation. Patients were enrolled into the study over a two-year 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. Sixteen percent of subjects on Avonex (Interferon beta-1a) and 14% of subjects on placebo withdrew from the study for a reason other than the development of a second exacerbation.

The primary outcome measure was time to development of a second exacerbation in an anatomically distinct region of the central nervous system. Secondary outcomes were brain MRI measures, including the cumulative increase in the number of new or enlarging T2 lesions, T2 lesion volume compared to baseline at 18 months, and the number of Gd-enhancing lesions at 6 months.

Time to development of a second exacerbation was significantly delayed in patients treated with Avonex (Interferon beta-1a) compared to placebo (p = 0.002). The Kaplan-Meier estimates of the percentage of patients developing an exacerbation within 24 months were 38.6% in the placebo group and 21.1% in the Avonex (Interferon beta-1a) group (). The relative rate of developing a second exacerbation in the Avonex (Interferon beta-1a) group was 0.56 of the rate in the placebo group (95% confidence interval 0.38 to 0.81). The brain MRI findings are described in .

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. Safety and efficacy in patients with chronic progressive multiple sclerosis have not been established.

Avonex (Interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation.

The lyophilized vial formulation of Avonex (Interferon beta-1a) is contraindicated in patients with a history of hypersensitivity to albumin (human).

All patients should be instructed to read the Avonex (Interferon beta-1a) Medication Guide supplied to them. Patients should be cautioned not to change the dosage or the schedule of administration without medical consultation.

Patients should be informed of the most serious (see ) and the most common adverse events associated with Avonex (Interferon beta-1a) administration, including symptoms associated with flu syndrome (see ). Symptoms of flu syndrome are most prominent at the initiation of therapy and decrease in frequency with continued treatment. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days.

Patients should be cautioned to report depression or suicidal ideation (see ).

Patients should be advised about the abortifacient potential of Avonex (Interferon beta-1a) (see ). If a woman becomes pregnant while taking Avonex (Interferon beta-1a) , she should be advised to consider enrolling in the Avonex (Interferon beta-1a) Pregnancy Registry by calling 1-800-456-2255.

When a physician determines that Avonex (Interferon beta-1a) can be used outside of the physician's office, persons who will be administering Avonex (Interferon beta-1a) should receive instruction in reconstitution and injection, including the review of the injection procedures. If a patient is to self-administer, the physical ability of that patient to self-inject intramuscularly should be assessed. The first injection should be performed under the supervision of a qualified health care professional. A puncture-resistant container for disposal of needles and syringes should be used. Patients should be instructed in the technique and importance of proper syringe and needle disposal and be cautioned against reuse of these items.

Depression, suicidal ideation, and new or worsening other psychiatric disorders have been observed to be increased in patients using interferon compounds including Avonex (Interferon beta-1a) (see ). Anaphylaxis and other allergic reactions have been reported in patients using Avonex (Interferon beta-1a) (see ). Decreased peripheral blood counts have been reported in patients using Avonex (Interferon beta-1a) (see ). Hepatic injury, including hepatic failure, hepatitis, and elevated serum hepatic enzyme levels, has been reported in post-marketing experience (see ). Seizures, cardiovascular adverse events, and autoimmune disorders also have been reported in association with the use of Avonex (Interferon beta-1a) (see ).

The adverse reactions most commonly reported in patients associated with the use of Avonex (Interferon beta-1a) were flu-like and other symptoms occurring within hours to days following an injection. Symptoms can include myalgia, fever, fatigue, headaches, chills, nausea, and vomiting. Some patients have experienced paresthesias, hypertonia and myasthenia.

The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of Avonex (Interferon beta-1a) , or the need for concomitant medication to treat an adverse reaction symptom) were flu-like symptoms and depression.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Avonex (Interferon beta-1a) cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice.

The data described below reflect exposure to Avonex (Interferon beta-1a) in 351 patients, including 319 patients exposed for 6 months, and 288 patients exposed for greater than one year in placebo-controlled trials. The mean age of patients receiving Avonex (Interferon beta-1a) was 35 years, 74% were women and 89% were Caucasian. Patients received either 30 mcg Avonex (Interferon beta-1a) or placebo.

No Avonex (Interferon beta-1a) -treated patients attempted suicide in the two placebo-controlled studies. In Study 2, Avonex (Interferon beta-1a) -treated patients were more likely to experience depression than placebo-treated patients (20% in Avonex (Interferon beta-1a) group vs. 13% in placebo group). The incidences of depression in the placebo-treated and Avonex (Interferon beta-1a) -treated patients in Study 1 were similar. In Study 1, suicidal tendency was seen more frequently in Avonex (Interferon beta-1a) -treated patients (4% in Avonex (Interferon beta-1a) group vs. 1% in placebo group) (see ).

There is no evidence that abuse or dependence occurs with Avonex (Interferon beta-1a) therapy. However, the risk of dependence has not been systematically evaluated.

Safety of doses higher than 60 mcg once a week have not been adequately evaluated. The maximum amount of Avonex (Interferon beta-1a) that can be safely administered has not been determined.

The recommended dosage of Avonex (Interferon beta-1a) is 30 mcg injected intramuscularly once a week.

Avonex (Interferon beta-1a) is intended for use under the guidance and supervision of a physician. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in intramuscular injection technique. Sites for injection include the thigh or upper arm (see ).

A 25 gauge, 1” needle for intramuscular injection may be substituted for the 23 gauge, 1 ¼” needle by the prescribing physician, if deemed appropriate.

A vial of Avonex (Interferon beta-1a) is supplied as a lyophilized powder in a single-use vial containing 33 mcg (6.6 million IU) 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 single-use vial (Sterile Water for Injection, USP).

Avonex (Interferon beta-1a) lyophilized vials are available in the following package configuration (NDC 59627-001-03): A package containing four Administration Dose Packs (each containing one vial of Avonex (Interferon beta-1a) , 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).

A prefilled syringe of Avonex (Interferon beta-1a) is supplied as a sterile liquid albumin-free formulation containing 30 mcg 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 IM injection.

Avonex (Interferon beta-1a) prefilled syringes are available in the following package configuration (NDC 59627-002-05): A package containing four Administration Dose Packs (each containing one single-use syringe of Avonex (Interferon beta-1a) and one 23 gauge, 1¼ inch needle), and a recloseable accessory pouch containing 4 alcohol wipes, 4 gauze pads, and 4 adhesive bandages.

Manufactured by:BIOGEN IDEC INC.14 Cambridge CenterCambridge, MA 02142 USA©2006 Biogen Idec Inc. All rights reserved.1-800-456-2255

U.S. Patent PendingI63005-11 (Issue Date 10/2008)

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