AVONEX 30 micrograms powder and solvent for solution for injection

Each BIO-SET vial contains 30 micrograms (6 million IU) of interferon beta-1a.

Following reconstitution with the solvent (water for injections) the vial contains 1.0 ml of solution. The concentration is 30 micrograms per ml.

Using the World Health Organisation (WHO) International Standard for Interferon, 30 micrograms of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known.

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The vial contains a white to off-white cake.

AVONEX is indicated for the treatment of

• Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials, this was characterised by two or more acute exacerbations (relapses) in the previous three years without evidence of continuous progression between relapses; AVONEX slows the progression of disability and decreases the frequency of relapses.

• Patients with a single demyelinating event with an active inflammatory process, if it is severe enough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis (see section 5.1).

AVONEX should be discontinued in patients who develop progressive MS.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Adults: The recommended dosage for the treatment of relapsing MS is 30 micrograms (1 ml solution), administered by intramuscular (IM) injection once a week (see section 6.6). No additional benefit has been shown by administering a higher dose (60 micrograms) once a week.

Titration: To help patients reduce the incidence and severity of flu-like symptoms (see section 4.8), titration can be performed at the initiation of treatment. Titration using the BIOSET or pre-filled syringe can be achieved by initiating therapy on ¼ dose increments per week reaching the full dose (30 micrograms/week) by the fourth week.

An alternative titration schedule can be achieved by initiating therapy on approximately a ½ dose of AVONEX once a week before increasing to the full dose. In order to obtain adequate efficacy, a dose of 30mcg once a week should be reached and maintained after the initial titration period.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment.

Paediatric population: The safety and efficacy of AVONEX in adolescents aged 12 to 16 years have not yet been established. Currently available data are described in section 4.8 and 5.1 but no recommendation on a posology can be made.

The safety and efficacy of AVONEX in children below 12 years of age have not yet been established.

No data are available

Elderly: Clinical studies did not include a sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients. However, based on the mode of clearance of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

The intramuscular injection site should be varied each week (see section 5.3).

Doctors may prescribe a 25 mm, 25 gauge needle to patients for whom such a needle is appropriate to administer an intramuscular injection.

At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after two years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive MS.

- Initiation of treatment in pregnancy (see section 4.6).

- Patients with a history of hypersensitivity to natural or recombinant interferon -ß, human albumin or to any excipients.

- Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).

AVONEX should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Patients exhibiting depression should be monitored closely during therapy and treated appropriately. Cessation of therapy with AVONEX should be considered (see also sections 4.3 and 4.8).

AVONEX should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics (see sections 4.5 and 4.8).

Caution should be used and close monitoring considered when administering AVONEX to patients with severe renal and hepatic failure and to patients with severe myelosuppression.

Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with interferon beta in post-marketing (see section 4.8). In some cases, these reactions have occurred in the presence of other medicinal products that have been associated with hepatic injury. The potential of additive effects from multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products associated with hepatic injury.

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely monitored for worsening of their clinical condition during treatment with AVONEX. Flu-like symptoms associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions.

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with MS, complete and differential white blood cell counts, platelet counts, and blood chemistry, including liver function tests, are recommended during AVONEX therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in the in vivo biological effects of AVONEX and may potentially be associated with a reduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibody formation is reached after 12 months of treatment. Data from patients treated up to two years with AVONEX suggests that approximately 8% develop neutralising antibodies.

The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.

No formal interaction studies have been performed in humans.

The interaction of AVONEX with corticosteroids or adrenocorticotropic hormone (ACTH) has not been studied systematically. The clinical studies indicate that MS patients can receive AVONEX and corticosteroids or ACTH during relapses.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolising capabilities were observed. Caution should be exercised when AVONEX is administered in combination with medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants.

Pregnancy

There is limited information on the use of AVONEX in pregnancy. Available data indicates that there may be an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy (see section 4.3).

Women of child-bearing potential

Women of child-bearing potential have to take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking AVONEX she should be informed of the potential hazards and discontinuation of therapy should be considered (see section 5.3). In patients with a high relapse rate before treatment started, the risk of a severe relapse following discontinuation of AVONEX in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion.

Lactation

It is not known whether AVONEX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue breast-feeding or AVONEX therapy.

No studies on the effects of AVONEX on the ability to drive and use machines have been performed. Central nervous system-related adverse reactions may have a minor influence on the ability to drive and use machines in susceptible patients (see section 4.8).

The highest incidence of adverse reactions associated with AVONEX therapy is related to flu-like symptoms. The most commonly reported flu-like symptoms are myalgia, fever, chills, sweating, asthenia, headache and nausea. Titrating AVONEX at the initiation of therapy has demonstrated a reduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment.

Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms.

The frequencies of adverse reactions are expressed in patient-years, according to the following categories:

Very common (1/10 patient-years);

Common (1/100 to <1/10 patient-years);

Uncommon (1/1, 000 to <1/100 patient-years);

Rare (1/10, 000 to <1/1,000 patient-years);

Very rare (<1/10,000 patient-years);

Not known (cannot be estimated from the available data).

Patient-time is the sum of individual units of time that the patient in the study has been exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year.

Adverse reactions identified from studies (clinical trials and observational studies, with a period of follow-up ranging from two years to six years) and other adverse reactions identified through spontaneous reporting from the market, with unknown frequency, are provided in the table below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

¹Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.

²The frequency of occurrence is higher at the beginning of treatment.

³A syncope episode may occur after AVONEX injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections.

Paediatric population: Limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving AVONEX 30 micrograms IM once per week is similar to that seen in adults.

No case of overdose has been reported. However, in case of overdose, patients should be hospitalised for observation and appropriate supportive treatment given.

Pharmacotherapeutic Group: Interferons, ATC code: L03 AB07.

Interferons are a family of naturally occurring proteins that are produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities. Three major forms of interferons have been distinguished: alpha, beta and gamma. Interferons alpha and beta are classified as Type I interferons and interferon gamma is a Type II interferon. These interferons have overlapping but clearly distinguishable biological activities. They can also differ with respect to their cellular sites of synthesis.

Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (interferon beta-1a) are glycosylated and have a single N-linked complex carbohydrate moiety. Glycosylation of other proteins is known to affect their stability, activity, biodistribution, and half-life in blood. However, the effects of interferon beta that are dependent on glycosylation are not fully defined.

AVONEX 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 MHC Class I, Mx protein, 2' / 5'-oligoadenylate synthetase, β₂-microglobulin, and neopterin. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with AVONEX. After a single intramuscular dose of AVONEX, serum levels of these products remain elevated for at least four days and up to one week.

Whether the mechanism of action of AVONEX in MS is mediated by the same pathway as the biological effects described above is not known because the pathophysiology of MS is not well established.

The effects of lyophilised AVONEX in the treatment of MS were demonstrated in a placebo-controlled study of 301 patients (AVONEX n=158, placebo n=143) with relapsing MS characterised by at least 2 exacerbations in the previous 3 years or at least one exacerbation per year prior to entry when the duration of the disease was less than 3 years. Patients with an EDSS of 1.0 to 3.5 at entry were included in the clinical trial. Due to the design of the study, patients were followed for variable lengths of time. 150 AVONEX-treated patients completed one year on study and 85 completed two years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier life table analysis) by the end of two years was 35% for placebo-treated patients and 22% for AVONEX-treated patients. Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least six months. It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment.

A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX 30 micrograms n=402, AVONEX 60 micrograms n=400) has shown no statistically significant differences or trends between the 30 micrograms and the 60 micrograms doses of AVONEX in clinical and general MRI parameters.

The effects of AVONEX in the treatment of MS were also demonstrated in a randomised double-blind study performed with 383 patients (AVONEX n=193, placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the AVONEX treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in three years and 39% in two years in the placebo group and 35% (three years) and 21% (two years) in the AVONEX group. In a post-hoc analysis, those patients with a baseline MRI with at least one Gd-enhancing lesion and nine T2 lesions had a two-year risk of suffering a second event of 56% in the placebo group and 21% in the AVONEX treatment group. However, the impact of early treatment with AVONEX is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least three months after the initial scan. In any case, treatment should only be considered for patients classified at high risk.

Paediatric population: Limited data of the efficacy/safety of AVONEX 15 micrograms IM once per week (n=8) as compared to no treatment (n=8) with follow up for 4 years showed results in line to those seen in adults, although the EDSS scores increased in the treated group over the 4 year follow-up thus indicating disease progression. No direct comparison with the dose currently recommended in adults is available.

The pharmacokinetic profile of AVONEX has been investigated indirectly with an assay that measures interferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative assay techniques are not sufficiently sensitive.

Following intramuscular administration of AVONEX, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for intramuscular administration.

Carcinogenesis: No carcinogenicity data for interferon beta-1a are available in animals or humans.

Chronic Toxicity: In a 26-week, repeated-dose toxicity study in rhesus monkeys by intramuscular route once per week, administered in combination with another immunomodulating agent, an anti CD40 ligand monoclonal antibody, no immune response toward interferon beta-1a and no signs of toxicity were demonstrated.

Local Tolerance: Intramuscular irritation has not been evaluated in animals following repeated administration to the same injection site.

Mutagenesis: Limited but relevant mutagenesis tests have been carried out. The results have been negative.

Impairment of Fertility: Fertility and developmental studies in rhesus monkeys have been carried out with a related form of interferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals were observed. Similar reproductive dose-related effects have also been observed with other forms of alpha and beta interferons. No teratogenic effects or effects on foetal development have been observed, but the available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.

No information is available on the effects of interferon beta-1a on male fertility.

Human serum albumin,

Dibasic sodium phosphate,

Monobasic sodium phosphate,

Sodium chloride.

Not applicable.

2 years.

AVONEX should be administered as soon as possible after reconstitution. However, the reconstituted solution can be stored at 2 °C-8 °C for up to six hours, prior to injection.

Store below 25 °C.

DO NOT FREEZE the powder or the reconstituted product.

For storage conditions of the reconstituted medicinal product see section 6.3.

AVONEX is available as a package of four individual doses. Each dose is supplied in a 3 ml clear glass vial with BIO-SET device and a 13 mm bromobutyl rubber stopper. It is provided with a 1 ml pre-filled glass syringe of solvent for reconstitution (water for injections) and one needle.

Use the supplied pre-filled syringe of solvent to reconstitute AVONEX for injection. Do not use any other solvent. Inject the content of the syringe into the vial of AVONEX by connecting the pre-filled syringe to the BIO-SET device. Gently swirl the contents in the vial until all materials are dissolved; DO NOT SHAKE. Inspect the reconstituted product: If it contains particulate matter or is other than colourless to slightly yellow in colour, the vial must not be used. After reconstitution, draw all the liquid (1 ml) from the vial back into the syringe for the administration of 30 micrograms AVONEX. The needle for intramuscular injection is provided. The formulation does not contain a preservative. Each vial of AVONEX contains a single dose only. Discard the unused portion of any vial.

Any unused product or waste material should be disposed of in accordance with local requirements.

BIOGEN IDEC LIMITED

Innovation House

70 Norden Road

Maidenhead

Berkshire

SL6 4AY

United Kingdom

EU/1/97/033/002

Date of first authorisation: 13 March 1997

Date of latest renewal: 13 March 2007

10/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu