Avonex Drug Information

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.

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

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 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, 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.

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.

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. 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: Immunogenicity Anaphylaxis and other allergic reactions have occurred in AVONEX-treated patients. As with all therapeutic proteins, there is a potential for immunogenicity.

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

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 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 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 ).

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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