Interferon Beta-1a

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 )

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 )

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 )

Depression, Suicide, and Psychotic Disorders: advise patients to immediately report any symptoms of depression, suicidal ideation, and/or psychosis; consider discontinuation of AVONEX if depression occurs ( 5.1 ) Hepatic Injury: monitor liver function tests; monitor patients for signs and symptoms of hepatic injury; consider discontinuation of AVONEX if hepatic injury occurs ( 5.2 , 5.10 ) Injection Site Reactions: Do not administer AVONEX into affected area until fully healed; if multiple lesions occur, change injection site or discontinue AVONEX until healing of skin lesions ( 5.4 ). Anaphylaxis and Other Allergic-Reactions: Discontinue if occurs ( 5.4 ) Congestive Heart Failure: monitor patients with pre-existing significant cardiac disease for worsening of cardiac symptoms ( 5.5 ) Decreased Peripheral Blood Counts: monitor complete blood count ( 5.6 , 5.10 ) Thrombotic Microangiopathy: Cases of thrombotic microangiopathy have been reported. Discontinue AVONEX if clinical symptoms and laboratory findings consistent with TMA occur ( 5.7 ) Pulmonary Arterial Hypertension: Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including AVONEX. Discontinue AVONEX if PAH is diagnosed ( 5.8 ) Autoimmune Disorders: consider discontinuation of AVONEX if new autoimmune disorder occurs ( 5.10 , 5.11 )

5.1 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 AVONEX-treated 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 ( 14 )] . 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.

5.2 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 Warnings and Precautions ( 5.10 )] .

5.3 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.

5.4 Injection Site Reactions Including Necrosis Injection site reactions, including injection site necrosis, can occur with the use of interferon beta products, including AVONEX. In controlled clinical trials, injection site reactions (e.g., injection site pain, bruising or erythema) occurred in 18% of patients receiving AVONEX and 13% in the placebo group. These reactions included injection site inflammation (6%), injection site pain (8%), injection site mass (<1%), nonspecific reactions. Injection site abscesses and cellulitis and injection site necrosis have been reported in the postmarketing setting with interferon beta products, including AVONEX. Some cases required treatment with hospitalization for surgical drainage and intravenous antibiotics. Periodically evaluate patient understanding and use of aseptic self-injection techniques and procedures, particularly if injection site necrosis has occurred. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with AVONEX after injection site necrosis has occurred, avoid administration of AVONEX into the affected area until it is fully healed. If multiple lesions occur, change injection site or discontinue therapy until healing occurs.

5.5 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.

5.6 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 ( 6.2 )] . In some cases, platelet counts were below 10,000/microliter. Some cases recurred with rechallenge [see Adverse Reactions ( 6.2 ) ]. Patients should be monitored for symptoms or signs of decreased blood counts.

5.7 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.

5.8 Pulmonary Arterial Hypertension Cases of pulmonary arterial hypertension (PAH) have been reported in patients treated with interferon beta products, including AVONEX. PAH has occurred in patients treated with interferon beta products in the absence of other contributory factors. Many of the reported cases required hospitalization, including one case with interferon beta in which the patient underwent a lung transplant. PAH has developed at various time points after initiating therapy with interferon beta products and may occur several years after starting treatment. Patients who develop unexplained symptoms (e.g., dyspnea, new or increasing fatigue) should be assessed for PAH. If alternative etiologies have been ruled out and a diagnosis of PAH is confirmed, discontinue treatment and manage as clinically indicated.

5.9 Seizures Seizures have been temporally associated with the use of beta interferons in clinical trials and postmarketing 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 ( 14 )] . Three of these 4 patients had no prior history of seizure [see Adverse Reactions ( 6.1 )] . It is not known whether these events were related to the effects of multiple sclerosis alone, to AVONEX, or to a combination of both. […]

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 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

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.

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