AVONEX

Warnings and Precautions ( 5.8 ) 7/2023

1 INDICATIONS AND USAGE AVONEX is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. AVONEX is for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION For intramuscular use only ( 2.1 ) Recommended dose: 30 micrograms once a week ( 2.1 ) AVONEX may be titrated, starting with 7.5 micrograms for first week, to reduce flu-like symptoms ( 2.1 ) Increase dose by 7.5 micrograms each week for next 3 weeks until recommended dose of 30 micrograms ( 2.1 ) See patient instructions for use for complete administration instructions ( 2.2 ) Perform first injection under the supervision of an appropriately qualified health care professional ( 2.2 ) Analgesics and/or antipyretics on treatment days may help ameliorate flu-like symptoms ( 2.3 ) 2.1 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 AVOSTARTGRIPTM 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 1 Dosed once a week, intramuscularly AVONEX Dose 1 Recommended Dose Week 1 7.5 micrograms 1/4 dose Week 2 15 micrograms 1/2 dose Week 3 22.5 micrograms 3/4 dose Week 4+ 30 micrograms full dose 2.2 Important Administration Instructions (All Dosage Forms) AVONEX dosage forms (prefilled syringe and prefilled autoinjector) are single-dose. 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 injection sites with each administration to minimize the likelihood of injection site reactions, including necrosis or localized infection [see Warnings and Precautions ( 5.4 )] 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 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A 25 gauge, 1” needle for intramuscular injection with AVONEX prefilled syringe may be substituted for the 23 gauge, 1 1⁄4” 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, prefilled syringes, or autoinjectors. Following the administration of each titrated dose, discard any remaining product. 2.3 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.

3 DOSAGE FORMS AND STRENGTHS Injection: 30 micrograms per 0.5 mL clear, colorless solution in a single-dose prefilled syringe Injection: 30 micrograms per 0.5 mL clear, colorless solution in a single-dose prefilled autoinjector Injection: 30 micrograms per 0.5 mL solution in single-dose prefilled syringe ( 3 ) Injection: 30 micrograms per 0.5 mL solution in single-dose prefilled autoinjector ( 3 )

4 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 ( 5.3 )] . The formerly available lyophilized vial formulation of AVONEX is contraindicated in patients with a history of hypersensitivity to albumin (human). History of hypersensitivity to natural or recombinant interferon beta, albumin or any other component of the formulation ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in other sections of labeling: Depression, Suicide, and Psychotic Disorders [see Warnings and Precautions ( 5.1 )] Hepatic Injury [see Warnings and Precautions ( 5.2 )] Anaphylaxis and Other Allergic-Reactions [see Warnings and Precautions ( 5.3 )] Injection Site Reactions Including Necrosis [see Warnings and Precautions ( 5.4 )] Congestive Heart Failure [see Warnings and Precautions ( 5.5 )] Decreased Peripheral Blood Counts [see Warnings and Precautions ( 5.6 )] Thrombotic Microangiopathy [see Warnings and Precautions ( 5.7 )] Pulmonary Arterial Hypertension [see Warnings and Precautions ( 5.8 )] Seizures [see Warnings and Precautions ( 5.9 )] Autoimmune Disorders [see Warnings and Precautions ( 5.10 )] Laboratory Tests [see Warnings and Precautions ( 5.11 )] 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. ( 6.1 ) 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 [see Clinical Studies ( 14 )] . 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 [see Warnings and Precautions ( 5.3 )] . 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 posi …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Epidemiological data do not suggest a clear relationship between interferon beta use and major congenital malformations, but interferon beta may cause fetal harm based on animal data. ( 8.1 ) 8.1 Pregnancy Risk Summary Data from a large population-based cohort study, as well as other published studies over several decades, have not identified a drug-associated risk of major birth defects with the use of interferon beta products during early pregnancy. Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta products in pregnancy have been inconsistent (see Data ). In a study in pregnant monkeys, administration of interferon beta during pregnancy resulted in an increased rate of abortion at doses greater than those used clinically ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Human Data The majority of observational studies reporting on pregnancies exposed to interferon beta products did not identify an association between the use of interferon beta products during early pregnancy and an increased risk of major birth defects. In a population-based cohort study conducted in Finland and Sweden, data were collected from 1996--2014 in Finland and 2005--2014 in Sweden on 2,831 pregnancy outcomes from women with MS. 797 pregnancies were in women exposed to interferon beta only. No evidence was found of an increased risk of major birth defects among women with MS exposed to interferon beta products compared to women with MS that were unexposed to any non-steroid therapy for MS (n=1,647) within the study. No increased risks were observed for miscarriages and ectopic pregnancies, though there were limitations in obtaining complete data capture for these outcomes, making the interpretation of the findings more difficult. Two small cohort studies that examined pregnancies exposed to interferon beta products (without differentiating between subtypes of interferon beta products) suggested that a decrease in mean birth weight may be associated with interferon beta exposure during pregnancy, but this finding was not confirmed in larger observational studies. Two small studies observed an increased prevalence of miscarriage, although the finding was only statistically significant in one study. Most studies enrolled patients later in pregnancy which made it difficult to ascertain the true percentage of miscarriages. In one small cohort study, a significantly increased risk of preterm birth following interferon beta exposure during pregnancy was observed. Animal Data In pregnant monkeys given interferon beta at 100 times the recommended weekly human dose (based upon a body surface area [mg/m 2 ] comparison), no adverse effects on embryofetal 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/m 2 ). 8.2 Lactation Risk Summary Limited published literature has described the presence of interferon beta-1a products in human milk at low levels. There are no data on the effects of interferon beta-1a on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AVONEX and any potential adverse effects on the breastfed infant from AVONEX or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 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.

12.1 Mechanism of Action The mechanism of action by which AVONEX exerts its effects in patients with multiple sclerosis is unknown.

11 DESCRIPTION Interferon beta-1a, an interferon beta, 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 (interferon beta-1a) injection is a sterile liquid for intramuscular injection available in a prefilled glass syringe or a prefilled glass syringe surrounded by an autoinjector. Each single-dose prefilled glass syringe or single-dose prefilled autoinjector delivers 0.5 mL of solution containing 30 micrograms of interferon beta-1a, arginine hydrochloride, USP (15.8 mg), glacial acetic acid, USP (0.25 mg), polysorbate 20 (0.025 mg), sodium acetate trihydrate, USP (0.79 mg), and Water for Injection, USP at a pH of approximately 4.8.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AVONEX (interferon beta-1a) injection is a clear, colorless solution in a single-dose prefilled glass syringe or a single-dose prefilled autoinjector for intramuscular injection available in the following packaging configurations: NDC number Contents NDC 59627-002-06 one single-dose prefilled AVONEX syringe one 23-gauge, 11⁄4-inch needle NDC 59627-222-05 four single-dose prefilled AVONEX syringes four 23-gauge, 11⁄4-inch needles four alcohol wipes four gauze pads four adhesive bandages NDC 59627-003-01 one single-dose prefilled autoinjector (AVONEX Pen) one 25-gauge, 5/8-inch needle one AVONEX Pen cover NDC 59627-333-04 four single-dose prefilled autoinjector (AVONEX Pens) four 25-gauge, 5/8-inch needles four AVONEX Pen covers four alcohol wipes four gauze pads four adhesive bandages 16.2 Storage and Handling Refrigerate AVONEX prefilled syringes and autoinjectors at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. DO NOT FREEZE. Once removed from the refrigerator, allow prefilled syringes and autoinjectors to warm to room temperature (about 30 minutes). Do not use external heat sources such as hot water to warm AVONEX. Should refrigeration be unavailable, a prefilled syringe or autoinjector may be stored at room temperature up to 25°C (77°F) for a period up to 7 days. DO NOT EXPOSE TO HIGH TEMPERATURES. 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 use beyond the expiration date. AVONEX Prefilled Syringe and AVONEX PEN contain natural rubber latex which may cause allergic reactions.