Interferonside effects

The following serious adverse reactions are discussed in more detail in other sections of labeling: Depression, Suicide, and Psychotic Disorders Hepatic Injury Anaphylaxis and Other Allergic-Reactions Injection Site Reactions Including Necrosis Congestive Heart Failure Decreased Peripheral Blood Counts Thrombotic Microangiopathy Pulmonary Arterial Hypertension Seizures Autoimmune Disorders Laboratory Tests The most common adverse reactions (at least 5% more frequent on AVONEX than on placebo) were flu-like symptoms including chills, fever, myalgia, and asthenia. To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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.

Table 2: Adverse Reactions in the Placebo-Controlled Studies Placebo AVONEX Adverse Reaction (N = 333) (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 14% 18% Dizziness 12% 14% Respiratory System Upper respiratory tract infection 12% 14% Sinusitis 12% 14% Bronchitis 5% 8% Digestive System Nausea 19% 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. 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.

6.2 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. Hemolytic anemia Menorrhagia and metrorrhagia Pulmonary Arterial Hypertension Rash (including vesicular rash) Rare cases of injection site abscess or cellulitis requiring surgical intervention