AVONEX 30mcg / 0.5ml PEN injection for pre-filled pen medication leaflet

AVONEX 30 micrograms/0.5ml solution for injection in pre-filled pen.

Each single-use pre-filled pen contains 30 micrograms (6 million IU) of interferon beta-1a in 0.5ml ofsolution.

The concentration is 30 micrograms per 0.5 ml.

Using the World Health Organisation (WHO) International Standard for Interferon, 30 micrograms of

AVONEX contain 6 million IU of antiviral activity. The activity against other standards is not known.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen.

Clear and colourless solution.

AVONEX is indicated for the treatment of

* Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials, this wascharacterised by two or more acute exacerbations (relapses) in the previous three-years withoutevidence of continuous progression between relapses; AVONEX slows the progression ofdisability and decreases the frequency of relapses.

* Patients with a single demyelinating event with an active inflammatory process, if it is severeenough to warrant treatment with intravenous corticosteroids, if alternative diagnoses have beenexcluded, and if they are determined to be at high risk of developing clinically definite multiplesclerosis (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 thedisease.

Adults: The recommended dosage for the treatment of relapsing MS is 30 micrograms (0.5 mlsolution), administered by intramuscular (IM) injection once a week (see section 6.6). No additionalbenefit 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 pre-filled syringe can beachieved by initiating therapy on ¼ dose increments per week reaching the full dose (30micrograms/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 doseof 30 micrograms once a week should be reached and maintained after the initial titration period.

Once a full dose is achieved patients may begin using AVONEX PEN.

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

Paediatric population: The safety and efficacy of AVONEX in adolescents aged 12 to 16 years havenot yet been established. Currently available data are described in section 4.8 and 5.1 but norecommendation 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 determinewhether they respond differently than younger patients. However, based on the mode of clearance ofthe active substance there are no theoretical reasons for any requirement for dose adjustments in theelderly.

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

AVONEX PEN is a pre-filled pen, intended for single use, and should only be used followingadequate training.

The recommended intramuscular injection site using the AVONEX PEN is the upper, outer thighmuscle. The injection site should be varied each week.

For administration of AVONEX via the AVONEX PEN, the instructions in the package leaflet shouldbe followed.

- Patients with a history of hypersensitivity to natural or recombinant interferon beta or to anyexcipients listed in section 6.1.

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

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

AVONEX should be administered with caution to patients with previous or current depressivedisorders, in particular to those with antecedents of suicidal ideation (see section 4.3). Depression andsuicidal ideation are known to occur in increased frequency in the multiple sclerosis population and inassociation with interferon use. Patients should be advised to immediately report any symptoms ofdepression 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 thosereceiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled withanti-epileptics (see sections 4.5 and 4.8).

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

Thrombotic microangiopathy (TMA): Cases of thrombotic microangiopathy, manifested as thromboticthrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS), including fatal cases, havebeen reported with interferon beta products. Events were reported at various time points duringtreatment and may occur several weeks to several years after starting treatment with interferon beta.

Early clinical features include thrombocytopenia, new onset hypertension, fever, central nervoussystem symptoms (e.g. confusion, paresis) and impaired renal function. Laboratory findingssuggestive of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH)due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood film. Therefore if clinicalfeatures of TMA are observed, further testing of blood platelet levels, serum LDH, blood films andrenal function is recommended. If TMA is diagnosed, prompt treatment is required (consideringplasma exchange) and immediate discontinuation of AVONEX is recommended.

Nephrotic Syndrome: Cases of nephrotic syndrome with different underlying nephropathies includingcollapsing focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD),membranoproliferative glomerulonephritis (MPGN) and membranous glomerulopathy (MGN) havebeen reported during treatment with interferon-beta products. Events were reported at various timepoints during treatment and may occur after several years of treatment with interferon beta. Periodicmonitoring of early signs or symptoms, e.g. oedema, proteinuria and impaired renal function isrecommended, especially in patients at higher risk of renal disease. Prompt treatment of nephroticsyndrome is required and discontinuation of treatment with AVONEX should be considered.

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

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

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

Patients may develop antibodies to AVONEX. The antibodies of some of those patients reduce theactivity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associatedwith a reduction in the in vivo biological effects of AVONEX and may potentially be associated with areduction of clinical efficacy. It is estimated that the plateau for the incidence of neutralising antibodyformation is reached after 12 months of treatment. Recent clinical studies with patients treated up tothree years with AVONEX suggest that approximately 5% to 8% develop neutralising antibodies.

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

No formal interaction studies have been performed in humans.

The interaction of AVONEX with corticosteroids or adrenocorticotropic hormone (ACTH) has notbeen studied systematically. The clinical studies indicate that MS patients can receive AVONEX andcorticosteroids or ACTH during relapses.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymesin humans and animals. The effect of high-dose AVONEX administration on P450-dependentmetabolism in monkeys was evaluated and no changes in liver metabolising capabilities wereobserved. Caution should be exercised when AVONEX is administered in combination with medicinalproducts that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome

P450 system for clearance, e.g. some classes of antiepileptics and antidepressants.

A large amount of data (more than 1000 pregnancy outcomes) from registries and post-marketingexperience indicates no increased risk of major congenital anomalies after pre-conception exposure tointerferon beta or such exposure during the first trimester of pregnancy. However, the duration ofexposure during the first trimester is uncertain, because data were collected when interferon beta usewas contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detectedand/or confirmed. Experience with exposure during the second and third trimester is very limited.

Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion.

The risk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately beevaluated based on the currently available data, but the data do not suggest an increased risk so far.

If clinically needed, the use of Avonex may be considered during pregnancy.

Limited information available on the transfer of interferon beta-1a into breast milk, together with thechemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1aexcreted in human milk are negligible. No harmful effects on the breastfed newborn/infant areanticipated.

Avonex can be used during breast-feeding.

Fertility and developmental studies in rhesus monkeys have been carried out with a related form ofinterferon beta-1a. At very high doses, anovulatory and abortifacient effects in test animals wereobserved (see section 5.3).

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

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 driveand use machines in susceptible patients (see section 4.8).

The highest incidence of adverse reactions associated with AVONEX therapy is related to flu-likesymptoms. 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 areduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be mostprominent 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 movementsmay occur at any time during treatment. These episodes are of limited duration, temporally related tothe injections and may recur after subsequent injections. In some cases these symptoms are associatedwith flu-like symptoms.

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

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 observedin 100 patients who were on treatment for one year or in 200 patients who were on treatment for half ayear.

Adverse reactions identified from studies (clinical trials and observational studies, with a period offollow-up ranging from two years to six years) and other adverse reactions identified throughspontaneous 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.

Investigationscommon lymphocyte count decreased, white blood cellcount decreased, neutrophil count decreased,hematocrit decreased, blood potassiumincreased, blood urea nitrogen increaseduncommon platelet count decreasednot known weight decreased, weight increased,liver function tests abnormal

Cardiac disordersnot known cardiomyopathy, congestive heart failure (seesection 4.4), palpitations, arrhythmia,tachycardia

Blood and lymphatic system disordersnot known pancytopenia, thrombocytopeniarare thrombotic microangiopathy includingthrombotic thrombocytopenicpurpura/haemolytic uraemic syndrome*

Nervous system disordersvery common headache2common muscle spasticity, hypoesthesianot known neurological symptoms, syncope3,hypertonia, dizziness, paraesthesia,seizures, migraine

Respiratory, thoracic and mediastinaldisorderscommon rhinorrhoearare dyspnoeanot known pulmonary arterial hypertension┼

Gastrointestinal disorderscommon vomiting, diarrhoea, nausea2

Skin and subcutaneous tissue disorderscommon rash, sweating increased, contusionuncommon alopecianot known angioneurotic oedema, pruritus, rash vesicular,urticaria, aggravation of psoriasis

Musculoskeletal and connective tissuedisorderscommon muscle cramp, neck pain, myalgia2, arthralgia,pain in extremity, back pain,muscle stiffness, musculoskeletal stiffnessnot known systemic lupus erythematosus, muscleweakness, arthritis

Renal and urinary disordersrare nephrotic syndrome, glomerulosclerosis (seesection 4.4 ‘special warnings and precautions’)

Endocrine disordersnot known hypothyroidism, hyperthyroidism

Metabolism and nutrition disorderscommon anorexia

Infections and infestationsnot known injection site abscess1

Vascular disorderscommon flushingnot known vasodilatation

General disorders and administration siteconditionsvery common flu-like symptoms, pyrexia2, chills2, sweating2injection site pain, injection site erythema,common injection site bruising, asthenia2, pain, fatigue2,malaise, night sweatsuncommon injection site burningnot known injection site reaction, injection siteinflammation, injection site cellulitis1,injection site necrosis, injection site bleeding,chest pain

Immune system disordersnot known anaphylactic reaction, anaphylactic shock,hypersensitivity reactions (angioedema,dyspnoea, urticaria, rash, pruritic rash)

Hepatobiliary disordersnot known hepatic failure (see section 4.4), hepatitis,autoimmune hepatitis

Reproductive system and breast disordersuncommon metrorrhagia, menorrhagia

Psychiatric disorderscommon depression (see section 4.4), insomnianot known suicide, psychosis, anxiety, confusion,emotional lability

*Class label for interferon beta products (see section 4.4).┼ Class label for interferon products, see below Pulmonary arterial hypertension.

1Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis thatmay 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 usuallyappears at the beginning of the treatment and does not recur with subsequent injections.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products.

Events were reported at various time points including up to several years after starting treatment withinterferon beta.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported. However, in case of overdose, patients should be hospitalisedfor 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 inresponse to viral infection and other biological inducers. Interferons are cytokines that mediateantiviral, antiproliferative, and immunomodulatory activities. Three major forms of interferons havebeen distinguished: alpha, beta, and gamma. Interferons alpha and beta are classified as Type Iinterferons, and interferon gamma is a Type II interferon. These interferons have overlapping butclearly distinguishable biological activities. They can also differ with respect to their cellular sites ofsynthesis.

Interferon beta is produced by various cell types including fibroblasts and macrophages. Naturalinterferon beta and AVONEX (interferon beta-1a) are glycosylated and have a single N-linkedcomplex 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 aredependent 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 ofnumerous 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 beenmeasured 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 atleast four days and up to one week.

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

The effects of lyophilised AVONEX in the treatment of MS were demonstrated in aplacebo-controlled study of 301 patients (AVONEX n=158, placebo n=143) with relapsing MScharacterised by at least 2 exacerbations in the previous 3 years or at least one exacerbation per yearprior to entry when the duration of the disease was less than 3 years. Patients with an EDSS of 1.0 to3.5 at entry were included in the clinical trial. Due to the design of the study, patients were followedfor variable lengths of time. 150 AVONEX-treated patients completed one year on study and 85completed two years on study. In the study, the cumulative percentage of patients who developeddisability progression (by Kaplan-Meier life table analysis) by the end of two years was 35% forplacebo-treated patients and 22% for AVONEX-treated patients. Disability progression was measuredas an increase in the Expanded Disability Status Scale (EDSS) of 1.0 point, sustained for at least sixmonths. It was also shown that there was a one-third reduction in annual relapse rate. This latterclinical effect was observed after more than one year of treatment.

A double-blind randomised dose comparison study of 802 relapsing MS patients (AVONEX30 micrograms n=402, AVONEX 60 micrograms n=400) has shown no statistically significantdifferences or trends between the 30 micrograms and the 60 micrograms doses of AVONEX inclinical and general MRI parameters.

The effects of AVONEX in the treatment of MS were also demonstrated in a randomised double-blindstudy performed with 383 patients (AVONEX n=193, placebo n=190) with a single demyelinatingevent associated with at least two compatible brain MRI lesions. A reduction of the risk ofexperiencing a second event was noted in the AVONEX treatment group. An effect on MRIparameters was also seen. The estimated risk of a second event was 50% in three years and 39% intwo years in the placebo group and 35% (three years) and 21% (two years) in the AVONEX group. Ina 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 evenin this high-risk subgroup as the study was mainly designed to assess the time to the second eventrather than the long-term evolution of the disease. Furthermore, for the time-being there is no wellestablished definition of a high risk patient although a more conservative approach is to accept at leastnine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancinglesion on a follow-up scan taken at least three months after the initial scan. In any case, treatmentshould only be considered for patients classified at high risk.

Limited data of the efficacy/safety of AVONEX 15 micrograms IM once per week (n=8) as comparedto no treatment (n=8) with follow up for 4 years showed results in line to those seen in adults, althoughthe EDSS scores increased in the treated group over the 4 year follow-up thus indicating diseaseprogression. 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 measuresinterferon antiviral activity. This assay is limited in that it is sensitive for interferon but lacksspecificity for interferon beta. Alternative assay techniques are not sufficiently sensitive.

Following intramuscular administration of AVONEX, serum antiviral activity levels peak between 5and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriateadjustment for the rate of absorption from the injection site, the calculated bioavailability isapproximately 40%. The calculated bioavailability is greater without such adjustments. Subcutaneousadministration 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 routeonce per week, administered in combination with another immunomodulating agent, an anti CD40ligand monoclonal antibody, no immune response toward interferon beta-1a and no signs of toxicitywere demonstrated.

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

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

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

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

Sodium acetate trihydrate

Acetic acid, glacial

Arginine hydrochloride

Polysorbate 20

Water for injections

Not applicable.

3 years.

Store in a refrigerator (2°C - 8°C).

DO NOT FREEZE.

The AVONEX PEN contains a pre-filled syringe of AVONEX and must be stored in the refrigerator.

Should refrigeration be unavailable, AVONEX PEN can be stored at room temperature (between 15°Cand 30°C) for up to one week.

Store the AVONEX PEN in the inner carton in order to protect from light (see section 6.5).

A pre-filled syringe of AVONEX is contained within a single-use, disposable, spring-powered peninjector called AVONEX PEN. The syringe inside the pen is a 1 ml pre-filled syringe made of glass(Type I) with a tamper evident cap and plunger stopper (bromobutyl) containing 0.5 ml of solution.

Pack size: Each single-use AVONEX PEN is packed in an individual carton, with one injection needleand a pen cover. AVONEX PEN is available in pack sizes of four or twelve.

Not all pack sizes may be marketed.

For single-use only: The solution for injection in a pre-filled syringe is contained within the AVONEX

PEN.

Once removed from the refrigerator, the AVONEX PEN should be allowed to warm to roomtemperature (15°C to 30°C) for about 30 minutes.

Do not use external heat sources such as hot water to warm AVONEX 30 micrograms solution forinjection.

Each single-use, disposable, pre-filled pen contains a single dose of AVONEX. The solution forinjection can be observed through an oval medication display window on the AVONEX PEN. If thesolution for injection contains particulate matter or if it is any colour other than clear colourless, thepre-filled pen must not be used. The injection needle is provided. The formulation does not contain apreservative.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/97/033/005

EU/1/97/033/006

Date of first authorisation: 13 March 1997

Date of latest renewal: 13 March 2007

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.