BETAFERON 250mcg / ml powder + solvent for injection medication leaflet

Betaferon 250 microgram/ml, powder and solvent for solution for injection

Recombinant interferon beta-1b* 250 microgram (8.0 million IU) per ml when reconstituted.

Betaferon contains 300 microgram (9.6 million IU) of recombinant interferon beta-1b per vial.

For the full list of excipients, see section 6.1.

* produced by genetic engineering from a strain of Escherichia coli.

Powder and solvent for solution for injection.

Sterile white to off-white powder.

Betaferon is indicated for the treatment of

* 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).

* patients with relapsing-remitting multiple sclerosis and two or more relapses within the last twoyears.

* patients with secondary progressive multiple sclerosis with active disease, evidenced byrelapses.

The treatment with Betaferon should be initiated under the supervision of a physician experienced inthe treatment of the disease.

The recommended dose of Betaferon is 250 microgram (8.0 million IU), contained in 1 ml of thereconstituted solution (see section 6.6), to be injected subcutaneously every other day.

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents.

However, limited published data suggest that the safety profile in adolescents from 12 to 16 years ofage receiving Betaferon 8.0 million IU subcutaneously every other day is similar to that seen in adults.

There is no information on the use of Betaferon in children under 12 years of age. Therefore Betaferonshould not be used in this population.

Generally, dose titration is recommended at the start of treatment.

Patients should be started at 62.5 microgram (0.25 ml) subcutaneously every other day, and increasedslowly to a dose of 250 microgram (1.0 ml) every other day (see Table A). The titration period may beadjusted, if any significant adverse reaction occurs. In order to obtain adequate efficacy, a dose of 250microgram (1.0 ml) every other day should be reached.

A titration pack composed of four triple packs is available for the titration period and the patient’sinitial treatment with Betaferon. This package meets the patient’s needs for the first 12 injections. Thetriple packs are highlighted in different colours (see section 6.5).

Table A: Schedule for dose titration*treatment day dose volume1, 3, 5 62.5 microgram 0.25 ml7, 9, 11 125 microgram 0.5 ml13, 15, 17 187.5 microgram 0.75 ml19, 21, 23 et seq. 250 microgram 1.0 ml

* The titration period may be adjusted, if any significant adverse reaction occurs.

The optimal dose has not been fully clarified.

At the present time, it is not known how long the patient should be treated for. There are follow-updata under controlled clinical conditions for patients with relapsing-remitting MS for up to 5 years andfor patients with secondary progressive MS for up to 3 years. For relapsing-remitting MS, efficacy hasbeen demonstrated for therapy for the first two years. The available data for the additional three yearsare consistent with sustained treatment efficacy of Betaferon over the whole time period.

In patients with a single clinical event suggestive of multiple sclerosis, the progression to clinicallydefinite multiple sclerosis was significantly delayed over a period of five years.

Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who haveexperienced less than 2 relapses in the previous 2 years or in patients with secondary-progressivemultiple sclerosis who have had no active disease in the previous 2 years.

If the patient fails to respond, for example a steady progression in EDSS for 6 months occurs ortreatment with at least 3 courses of ACTH or corticosteroids during a one year period is requireddespite Betaferon therapy, treatment with Betaferon should be stopped.

For subcutaneous injection.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

− Patients with a history of hypersensitivity to natural or recombinant interferon beta, humanalbumin or to any of the excipients listed in section 6.1.− Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).− Patients with decompensated liver disease (see sections 4.4, 4.5 and 4.8).

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

The administration of cytokines to patients with a pre-existing monoclonal gammopathy has beenassociated with the development of systemic capillary leak syndrome with shock-like symptoms andfatal outcome.

In rare cases, pancreatitis was observed with Betaferon use, often associated withhypertriglyceridaemia.

Betaferon 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 with increased frequency in the multiple sclerosis population andin association with interferon use. Patients treated with Betaferon should be advised to report anysymptoms of depression and/or suicidal ideation to their prescribing physician immediately. Patientsexhibiting depression should be monitored closely during therapy with Betaferon and treatedappropriately. Cessation of therapy with Betaferon should be considered (see also sections 4.3 and4.8).

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

This product contains human albumin and hence carries a potential risk for transmission of viraldiseases. A risk for transmission of Creutzfeld-Jacob disease (CJD) cannot be excluded.

Laboratory test

Thyroid function tests are recommended regularly in patients with a history of thyroid dysfunction oras clinically indicated.

In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis,complete blood and differential white blood cell counts, platelet counts, and blood chemistries,including liver function tests (e.g. AST (SGOT), ALT (SGPT) and γ-GT), are recommended prior toinitiation and at regular intervals following introduction of Betaferon therapy, and then periodicallythereafter in the absence of clinical symptoms.

Patients with anaemia, thrombocytopenia, leukopenia (alone or in any combination) may require moreintensive monitoring of complete blood cell counts, with differential and platelet counts. Patients whodevelop neutropenia should be monitored closely for the development of fever or infection. There havebeen reports of thrombocytopenia, with profound decreases in platelet count.

Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred verycommonly in patients treated with Betaferon during clinical trials. As for other beta interferons, severehepatic injury, including cases of hepatic failure, has been reported rarely in patients treated with

Betaferon. The most serious events often occurred in patients exposed to other drugs or substancesknown to be associated with hepatotoxicity or in the presence of comorbid medical conditions (e.g.metastasising malignant disease, severe infection and sepsis, alcohol abuse).

Patients should be monitored for signs of hepatic injury. The occurrence of elevations in serumtransaminases should lead to close monitoring and investigation. Withdrawal of Betaferon should beconsidered if the levels significantly increase or if they are associated with clinical symptoms such asjaundice. In the absence of clinical evidence for liver damage and after normalisation of liver enzymesa reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.

Caution should be used and close monitoring considered when administering interferon beta topatients with severe renal failure.

Nephrotic Syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focalsegmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferativeglomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported duringtreatment with interferon beta products. Events were reported at various time points during treatmentand may occur after several years of treatment with interferon beta. Periodic monitoring of early signsor symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially inpatients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required anddiscontinuation of treatment with Betaferon should be considered.

Betaferon should also be used with caution in patients who suffer from pre-existing cardiac disorders.

Patients with pre-existing significant cardiac disease, such as congestive heart failure, coronary arterydisease or arrhythmia, should be monitored for worsening of their cardiac condition, particularlyduring initiation of treatment with Betaferon.

While Betaferon does not have any known direct-acting cardiac toxicity, symptoms of the flu-likesyndrome associated with beta interferons may prove stressful to patients with pre-existing significantcardiac disease. During the post-marketing period very rare reports have been received of worseningof cardiac status in patients with pre-existing significant cardiac disease temporarily associated withthe initiation of Betaferon therapy.

Rare cases of cardiomyopathy have been reported. If this occurs and a relationship to Betaferon issuspected, treatment should be discontinued.

Thrombotic microangiopathy (TMA) and Haemolytic anaemia (HA)

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) orhaemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon betaproducts. Early clinical features include thrombocytopenia, new onset hypertension, fever, centralnervous system 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.

Additionally, cases of HA not associated with TMA, including immune HA, have been reported withinterferon beta products. Life-threatening and fatal cases have been reported. Cases of TMA and/or

HA have been reported at various time points during treatment and may occur several weeks to severalyears after starting treatment with interferon beta.

If TMA and/or HA is diagnosed and a relationship to Betaferon is suspected, prompt treatment isrequired (in case of TMA considering plasma exchange) and immediate discontinuation of Betaferonis recommended.

Serious hypersensitivity reactions (rare but severe acute reactions such as bronchospasm, anaphylaxisand urticaria) may occur. If reactions are severe, Betaferon should be discontinued and appropriatemedical intervention instituted.

Injection site necrosis has been reported in patients using Betaferon (see section 4.8). It can beextensive and may involve muscle fascia as well as fat and therefore can result in scar formation.

Occasionally debridement and, less often, skin grafting are required, and healing may take up to6 months.

If the patient experiences any break in the skin, which may be associated with swelling or drainage offluid from the injection site, the patient should be advised to consult with his/her physician beforecontinuing injections with Betaferon.

If the patient has multiple lesions Betaferon should be discontinued until healing has occurred.

Patients with single lesions may continue on Betaferon provided the necrosis is not too extensive, assome patients have experienced healing of injection site necrosis whilst on Betaferon.

To minimise the risk of injection site necrosis patients should be advised to:− use an aseptic injection technique− rotate the injection sites with each dose.

The incidence of injection site reactions may be reduced by the use of an autoinjector. In the pivotalstudy of patients with a single clinical event suggestive of multiple sclerosis an autoinjector was usedin the majority of patients. Injection site reactions as well as injection site necroses were observed lessfrequently in this study than in the other pivotal studies.

The procedure for the self-administration by the patient should be reviewed periodically especially ifinjection site reactions have occurred.

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlledclinical trials were collected every 3 months for monitoring of development of antibodies to Betaferon.

In the different controlled clinical trials in relapsing-remitting multiple sclerosis and secondaryprogressive multiple sclerosis, between 23% and 41% of the patients developed serum interferon beta-1b neutralising activity confirmed by at least two consecutive positive titres; of these patients, between43% and 55% converted to a stable antibody negative status (based on two consecutive negative titres)during the subsequent observational period of the respective study.

The development of neutralising activity in these studies is associated with a reduction in clinicalefficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger inpatients with higher titre levels of neutralising activity.

In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralisingactivity measured every 6 months was observed at least once in 32% (89) of the patients treatedimmediately with Betaferon; of these, 60% (53) returned to negative status based on the last availableassessment within the 5 year period. Within this period, the development of neutralising activity wasassociated with a significant increase in newly active lesions and T2 lesion volume on magneticresonance imaging. However, this did not seem to be associated with a reduction in clinical efficacy(with regard to time to clinically definite multiple sclerosis (CDMS), time to confirmed EDSSprogression and relapse rate).

New adverse events have not been associated with the development of neutralising activity.

It has been demonstrated in vitro that Betaferon cross-reacts with natural interferon beta. However,this has not been investigated in vivo and its clinical significance is uncertain.

There are sparse and inconclusive data on patients who have developed neutralising activity and havecompleted Betaferon therapy.

The decision to continue or discontinue treatment should be based on all aspects of the patient’sdisease status rather than on neutralising activity status alone.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

The effect of alternate-day administration of 250 microgram (8.0 million IU) of Betaferon on drugmetabolism in multiple sclerosis patients is unknown. Corticosteroid or ACTH treatment of relapsesfor periods of up to 28 days has been well tolerated in patients receiving Betaferon.

Due to the lack of clinical experience in multiple sclerosis patients, the use of Betaferon together withimmunomodulators other than corticosteroids or ACTH is not recommended.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymesin humans and animals. Caution should be exercised when Betaferon is administered in combinationwith medicinal products that have a narrow therapeutic index and are largely dependent on the hepaticcytochrome P450 system for clearance, e.g. anti-epileptics. Additional caution should be exercisedwith any co-medication which has an effect on the haematopoietic system.

No interaction studies with anti-epileptics have been carried out.

A large amount of data (more than 1000 pregnancy outcomes) from interferon beta registries, nationalregistries and post-marketing experience indicates no increased risk of major congenital anomaliesafter pre-conception exposure or exposure during the first trimester of pregnancy. However, theduration of exposure during the first trimester is uncertain, because data were collected wheninterferon beta use was contraindicated during pregnancy, and treatment likely interrupted whenpregnancy was detected and/or confirmed. Experience with exposure during the second and thirdtrimester is very limited.

Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. Therisk 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 Betaferon may be considered during pregnancy.

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

Betaferon can be used during breast-feeding.

No investigations on fertility have been conducted (see section 5.3).

No studies of the effects on the ability to drive and use machines have been performed.

Central nervous system-related adverse events associated with the use of Betaferon might influencethe ability to drive and use machines in susceptible patients.

At the beginning of treatment adverse reactions are common but in general they subside with furthertreatment. The most frequently observed adverse reactions are a flu-like symptom complex (fever,chills, arthralgia, malaise, sweating, headache, or myalgia), which is mainly due to thepharmacological effects of the medicinal product, and injection site reactions. Injection site reactionsoccurred frequently after administration of Betaferon. Redness, swelling, discolouration,inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associatedwith 250 microgram (8.0 million IU) Betaferon treatment.

The most serious adverse reactions reported include thrombotic microangiopathy (TMA) andhaemolytic anaemia (HA).

Generally, dose titration is recommended at the start of treatment in order to increase tolerability to

Betaferon (see section 4.2). Flu-like symptoms may also be reduced by administration of non-steroidalanti-inflammatory drugs. The incidence of injection site reactions may be reduced by the use of anautoinjector.

The following adverse event listing is based on reports from clinical trials (Table 1, adverse eventsand laboratory abnormalities) and from the post-marketing surveillance (Table 2, frequencies - whereknown- based on pooled clinical trials (very common ≥1/10, common ≥1/100 to <1/10, uncommon≥ 1/1,000 to < 1/100, rare ≥1/10,000 to <1/1,000, very rare < 1/10,000)) of Betaferon use. Experiencewith Betaferon in patients with MS is limited, consequently those adverse events which occur veryrarely may not yet have been observed.

Table 1: Adverse events and laboratory abnormalities with incidence rates ≥ 10% and the respectivepercentages under placebo; significantly associated side effects < 10% based on reports from clinicaltrials

System Organ Class Single Event Secondary Secondary Relapsing-suggestive of Progressive Progressive Remitting

Adverse Event Multiple Multiple Multiple Multipleand Laboratory Sclerosis Sclerosis Sclerosis Sclerosis

Abnormalities (BENEFIT) # (European (North

Study) American

Study)

Betaferon Betaferon Betaferon Betaferon250 250 250 microgram 250microgram microgram (Placebo) microgram(Placebo) (Placebo) n=317 (n=308) (Placebo)n=292 (n=176) n=360 (n=358) n=124 (n=123)

Infection 6% (3%) 13% (11%) 11% (10%) 14% (13%)

Abscess 0% (1%) 4% (2%) 4% (5%) 1% (6%)

Lymphocyte count 79% (45%) 53% (28%) 88% (68%) 82% (67%)decreased (<1,500/mm³) ×

Λ °

Absolute neutrophil count 11% (2%) 18% (5%) 4% (10%) 18% (5%)decreased (<1,500/mm³) ×

Λ * °

White blood cell count 11% (2%) 13% (4%) 13% (4%) 16% (4%)decreased (<3,000/mm³) ×

Λ * °

Lymphadenopathy 1% (1%) 3% (1%) 11% (5%) 14% (11%)

System Organ Class Single Event Secondary Secondary Relapsing-suggestive of Progressive Progressive Remitting

Adverse Event Multiple Multiple Multiple Multipleand Laboratory Sclerosis Sclerosis Sclerosis Sclerosis

Abnormalities (BENEFIT) # (European (North

Study) American

Study)

Betaferon Betaferon Betaferon Betaferon250 250 250 microgram 250microgram microgram (Placebo) microgram(Placebo) (Placebo) n=317 (n=308) (Placebo)n=292 (n=176) n=360 (n=358) n=124 (n=123)

Blood glucose decreased 3% (5%) 27% (27%) 5% (3%) 15% (13%)(<55 mg/dl) ×

Depression 10% (11%) 24% (31%) 44% (41%) 25% (24%)

Anxiety 3% (5%) 6% (5%) 10% (11%) 15% (13%)

Headache Λ 27% (17%) 47% (41%) 55% (46%) 84% (77%)

Dizziness 3% (4%) 14% (14%) 28% (26%) 35% (28%)

Insomnia 8% (4%) 12% (8%) 26% (25%) 31% (33%)

Migraine 2% (2%) 4% (3%) 5% (4%) 12% (7%)

Paraesthesia 16% (17%) 35% (39%) 40% (43%) 19% (21%)

Conjunctivitis 1% (1%) 2% (3%) 6% (6%) 12% (10%)

Abnormal vision Λ 3% (1%) 11% (15%) 11% (11%) 7% (4%)

Ear and labyrinth disorders

Ear pain 0% (1%) <1% (1%) 6% (8%) 16% (15%)

Palpitation * 1% (1%) 2% (3%) 5% (2%) 8% (2%)

Vasodilatation 0% (0%) 6% (4%) 13% (8%) 18% (17%)

Hypertension ° 2% (0%) 4% (2%) 9% (8%) 7% (2%)

Upper respiratory 18% (19%) 3% (2%)infection

Sinusitis 4% (6%) 6% (6%) 16% (18%) 36% (26%)

Cough increased 2% (2%) 5% (10%) 11% (15%) 31% (23%)

Dyspnoea * 0% (0%) 3% (2%) 8% (6%) 8% (2%)

Diarrhoea 4% (2%) 7% (10%) 21% (19%) 35% (29%)

Constipation 1% (1%) 12% (12%) 22% (24%) 24% (18%)

Nausea 3% (4%) 13% (13%) 32% (30%) 48% (49%)

Vomiting Λ 5% (1%) 4% (6%) 10% (12%) 21% (19%)

Abdominal pain ° 5% (3%) 11% (6%) 18% (16%) 32% (24%)

Alanine aminotransferase 18% (5%) 14% (5%) 4% (2%) 19% (6%)increased (SGPT> 5 timesbaseline) × Λ * °

Aspartate 6% (1%) 4% (1%) 2% (1%) 4% (0%)aminotransferaseincreased (SGOT > 5times baseline) × Λ * °

Skin disorder 1% (0%) 4% (4%) 19% (17%) 6% (8%)

System Organ Class Single Event Secondary Secondary Relapsing-suggestive of Progressive Progressive Remitting

Adverse Event Multiple Multiple Multiple Multipleand Laboratory Sclerosis Sclerosis Sclerosis Sclerosis

Abnormalities (BENEFIT) # (European (North

Study) American

Study)

Betaferon Betaferon Betaferon Betaferon250 250 250 microgram 250microgram microgram (Placebo) microgram(Placebo) (Placebo) n=317 (n=308) (Placebo)n=292 (n=176) n=360 (n=358) n=124 (n=123)

Rash Λ ° 11% (3%) 20% (12%) 26% (20%) 27% (32%)

Hypertonia° 2% (1%) 41% (31%) 57% (57%) 26% (24%)

Myalgia * ° 8% (8%) 23% (9%) 19% (29%) 44% (28%)

Myasthenia 2% (2%) 39% (40%) 57% (60%) 13% (10%)

Back pain 10% (7%) 26% (24%) 31% (32%) 36% (37%)

Pain in extremity 6% (3%) 14% (12%) 0% (0%)

Urinary retention 1% (1%) 4% (6%) 15% (13%)

Urinary protein positive 25% (26%) 14% (11%) 5% (5%) 5% (3%)(> 1+)×

Urinary frequency 1% (1%) 6% (5%) 12% (11%) 3% (5%)

Urinary incontinence 1% (1%) 8% (15%) 20% (19%) 2% (1%)

Urinary urgency 1% (1%) 8% (7%) 21% (17%) 4% (2%)

Dysmenorrhoea 2% (0%) <1% (<1%) 6% (5%) 18% (11%)

Menstrual disorder * 1% (2%) 9% (13%) 10% (8%) 17% (8%)

Metrorrhagia 2% (0%) 12% (6%) 10% (10%) 15% (8%)

Impotence 1% (0%) 7% (4%) 10% (11%) 2% (1%)

Injection site reaction 52% (11%) 78% (20%) 89% (37%) 85% (37%)(various kinds) Λ * ° §

Injection site necrosis * ° 1% (0%) 5% (0%) 6% (0%) 5% (0%)

Flu-like symptoms & Λ *° 44% (18%) 61% (40%) 43% (33%) 52% (48%)

Fever Λ * ° 13% (5%) 40% (13%) 29% (24%) 59% (41%)

Pain 4% (4%) 31% (25%) 59% (59%) 52% (48%)

Chest pain ° 1% (0%) 5% (4%) 15% (8%) 15% (15%)

Peripheral oedema 0% (0%) 7% (7%) 21% (18%) 7% (8%)

Asthenia * 22% (17%) 63% (58%) 64% (58%) 49% (35%)

Chills Λ * ° 5% (1%) 23% (7%) 22% (12%) 46% (19%)

Sweating * 2% (1%) 6% (6%) 10% (10%) 23% (11%)

Malaise * 0% (1%) 8% (5%) 6% (2%) 15% (3%)

System Organ Class Single Event Secondary Secondary Relapsing-suggestive of Progressive Progressive Remitting

Adverse Event Multiple Multiple Multiple Multipleand Laboratory Sclerosis Sclerosis Sclerosis Sclerosis

Abnormalities (BENEFIT) # (European (North

Study) American

Study)

Betaferon Betaferon Betaferon Betaferon250 250 250 microgram 250microgram microgram (Placebo) microgram(Placebo) (Placebo) n=317 (n=308) (Placebo)n=292 (n=176) n=360 (n=358) n=124 (n=123)× Laboratory abnormality

Λ Significantly associated with Betaferon treatment for patients with first event suggestive of MS,p < 0.05

* Significantly associated with Betaferon treatment for RRMS, p < 0.05° Significantly associated with Betaferon treatment for SPMS, p < 0.05§ Injection site reaction (various kinds) comprises all adverse events occurring at the injection site,i.e. the following terms: injection site haemorrhage, injection site hypersensitivity, injection siteinflammation, injection site mass, injection site necrosis, injection site pain, injection sitereaction, injection site oedema, and injection site atrophy& “Flu-like symptom complex” denotes flu syndrome and/or a combination of at least two AEsfrom fever, chills, myalgia, malaise, sweating.

# During the BENEFIT follow-up study, no change in the known risk profile of Betaferon wasobserved.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms andrelated conditions.

Table 2: Adverse drug reactions (ADRs) identified during post-marketing surveillance (frequencies -where known - calculated based on pooled clinical trial data N= 1093)

System Organ Very Common Uncommon Rare Frequency

Class common ( ≥ 1/100 to (≥ 1/1,000 to ( ≥ 1/10,000 to not known(≥ 1/10) 1 < 1/10) 1 < 1/100) 1 < 1/1,000) 1

Blood and Anaemia Thrombocytopenia Thrombotic Haemolyticlymphatic microangiopathy5 anaemia2, 5system disorders includingthromboticthrombocytopenicpurpura/ haemolyticuraemic syndrome3

Immune system Anaphylactic Capillary leakdisorders reactions syndrome inpre-existingmonoclonalgammopathy2

Endocrine Hypothyroidism Hyperthyroidism,disorders Thyroid disorders

Metabolism and Weight Blood triglycerides Anorexia2nutrition increased, increaseddisorders Weightdecreased

Psychiatric Confusional Suicide attempt (seedisorders state also section 4.4),

Emotional lability

System Organ Very Common Uncommon Rare Frequency

Class common ( ≥ 1/100 to (≥ 1/1,000 to ( ≥ 1/10,000 to not known(≥ 1/10) 1 < 1/10) 1 < 1/100) 1 < 1/1,000) 1

Nervous system Convulsiondisorders

Cardiac Tachycardia Cardiomyopathy2disorders

Respiratory, Bronchospasm2 Pulmonarythoracic and arterialmediastinal hypertension4disorders

Gastrointestinal Pancreatitisdisorders

Hepatobiliary Blood bilirubin Gamma-glutamyl- Hepatic injurydisorders increased transferase (includingincreased, hepatitis), Hepatic

Hepatitis failure2

Skin and Urticaria, Skin discolourationsubcutaneous Pruritus,tissue disorders Alopecia

Musculoskeletal Arthralgia Drug-inducedand connective lupustissue disorders erythematosus

Renal and Nephroticurinary syndrome,disorders glomerulosclerosis(see section 4.4)2, 3

Reproductive Menorrhagiasystem andbreast disorders1 frequencies based on pooled clinical trials (very common ≥1/10, common ≥1/100 to <1/10, uncommon≥ 1/1,000 to < 1/100, rare ≥1/10,000 to <1/1,000, very rare < 1/10,000).2 ADRs derived only during post-marketing3 Class label for interferon beta products (see section 4.4).4 Class label for interferon products, see below Pulmonary arterial hypertension.5 life-threatening and/or fatal cases have been reported.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms andrelated conditions.

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.

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.

Interferon beta-1b has been given without serious adverse events compromising vital functions toadult cancer patients at individual doses as high as 5,500 microgram (176 million IU) intravenouslythree times a week.

Pharmacotherapeutic group: Cytokines, Interferons,

ATC Code: L03 AB 08

Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons havemolecular weights ranging from 15,000 to 21,000 Daltons. Three major classes of interferons havebeen identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma haveoverlapping yet distinct biologic activities. The activities of interferon beta-1b are species-restrictedand therefore, the most pertinent pharmacological information on interferon beta-1b is derived fromstudies of human cells in culture or in human in vivo studies.

Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities. Themechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearlyunderstood. However, it is known that the biologic response-modifying properties of interferonbeta-1b are mediated through its interactions with specific cell receptors found on the surface ofhuman cells. The binding of interferon beta-1b to these receptors induces the expression of a numberof gene products that are believed to be the mediators of the biological actions of interferon beta-1b. Anumber of these products have been measured in the serum and cellular fractions of blood collectedfrom patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinityand enhances the internalisation and degradation of the interferon-gamma receptor. Interferon beta-1balso enhances the suppressor activity of peripheral blood mononuclear cells.

No separate investigations were performed regarding the influence of Betaferon on the cardiovascularsystem, respiratory system and the function of endocrine organs.

RR-MS

One controlled clinical trial with Betaferon in patients with relapsing-remitting multiple sclerosis andable to walk unaided (baseline EDSS 0 to 5.5) was performed. Patients receiving Betaferon showed areduction in frequency (30%) and severity of clinical relapses, as well as the number ofhospitalisations due to disease. Furthermore, there was a prolongation of the relapse-free interval.

There is no evidence of an effect of Betaferon on the duration of relapses or on symptoms in betweenrelapses, and no significant effect was seen on the progression of the disease in relapsing-remittingmultiple sclerosis.

SP-MS

Two controlled clinical trials with Betaferon involving a total of 1,657 patients with secondaryprogressive multiple sclerosis (baseline EDSS 3 to 6.5, i.e. patients were able to walk) wereperformed. Patients with mild disease and those unable to walk were not studied. The two studiesshowed inconsistent results for the primary endpoint time to confirmed progression, representing delayof disability progression:

One of the two studies demonstrated a statistically significant delay in the time to disabilityprogression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010, corresponding to a31% risk reduction due to Betaferon) and in the time to becoming wheelchair bound (Hazard Ratio =0.61, 95% confidence interval (0.44, 0.85), p=0.0036, corresponding to a 39% risk reduction due to

Betaferon) in patients who received Betaferon. This effect continued over the observation period of upto 33 months. The treatment effect occurred in patients at all levels of disability investigated andindependent of relapse activity.

In the second trial of Betaferon in secondary progressive multiple sclerosis, no delay in the time todisability progression was observed. There is evidence that the patients included in this study hadoverall less active disease than in the other study in secondary progressive multiple sclerosis.

In retrospective meta-analyses including the data of both studies, an overall treatment effect was foundwhich was statistically significant (p=0.0076; 8.0 million IU Betaferon versus all placebo patients).

Retrospective analyses in subgroups showed that a treatment effect on disability progression is mostlikely in patients with active disease before treatment commences (Hazard Ratio 0.72, 95% confidenceinterval (0.59, 0.88), p=0.0011, corresponding to a 28 % risk reduction due to Betaferon in patientswith relapses or pronounced EDSS progression, 8.0 million IU Betaferon versus all placebo patients).

From these retrospective subgroup analyses there was evidence to suggest that relapses as well aspronounced EDSS progression (EDSS >1 point or >0.5 point for EDSS ≥6 in the previous two years)can help to identify patients with active disease.

In both trials secondary progressive multiple sclerosis patients receiving Betaferon showed a reductionin frequency (30%) of clinical relapses. There is no evidence of Betaferon having an effect on theduration of relapses.

Single clinical event suggestive of MS

One controlled clinical trial with Betaferon was performed in patients with a single clinical event and

MRI features suggestive of multiple sclerosis (at least two clinically silent lesions on the T2-weighted

MRI). Patients with monofocal or multifocal onset of the disease were included (i.e. patients withclinical evidence for a single or at least two lesions, respectively, of the central nervous system). Anydisease other than multiple sclerosis that could better explain signs and symptoms of the patient had tobe excluded. This study consisted of two phases, a placebo-controlled phase followed by a pre-plannedfollow-up phase. The placebo-controlled phase lasted for 2 years or until the patient developedclinically definite multiple sclerosis (CDMS), whichever came first. After the placebo-controlledphase, patients entered a pre-planned follow-up phase with Betaferon to evaluate the effects ofimmediate versus delayed start of Betaferon treatment, comparing patients initially randomized to

Betaferon ('immediate treatment group') or to placebo ('delayed treatment group'). Patients andinvestigators remained blinded to the initial treatment allocation.

Table 3: Primary efficacy results of the BENEFIT and the BENEFIT Follow-up study

Year 2 results Year 3 results Year 5 results

Placebo-controlled Open-label follow-up Open-label follow-upphase

Betaferon Placebo Imme- Delayed Imme- Delayed250 mcg diate Betaferon diate Betaferonn=176 Betaferon 250 mcg Betaferon 250 mcgn=292 250 mcg 250 mcgn=176 n=176n=292 n=292

Number of patientscompleted the trial 271 (93%) 166 (94%) 249 (85%) 143 (81%) 235 (80%) 123 (70%)phase

Primary efficacy variables

Time to CDMS

Kaplan-Meier 28% 45% 37% 51% 46% 57%estimates

Risk reduction 47% versus placebo 41% versus delayed 37% versus delayed

Betaferon Betaferon

Hazard ratio with HR = 0.53 [0.39, 0.73] HR = 0.59 [0.42, 0.83] HR = 0.63 [0.48, 0.83]95% confidenceintervalp < 0.0001 p = 0.0011 p = 0.0027log-rank test

Betaferon prolongedthe time to CDMS by363 days, from 255days in the placebogroup to 618 days inthe Betaferon group(based on the 25thpercentiles)

Time to McDonald MS

Kaplan-Meier 69% 85% No primary endpoint No primary endpointestimates

Risk reduction 43% versus placebo

Hazard ratio with HR = 0.57 [0.46, 0.71]95% confidenceintervalp < 0.00001log-rank test

Time to confirmed EDSS progression

Kaplan-Meier No primary endpoint 16% 24% 25% 29%estimates

Risk reduction 40% versus delayed 24% versus delayed

Betaferon Betaferon

Hazard ratio with HR = 0.60 [0.39, 0.92] HR = 0.76 [0.52, 1.11]95% confidenceintervalp = 0.022 p=0.177log-rank test

In the placebo-controlled phase, Betaferon delayed the progression from the first clinical event to

CDMS in a statistically significant and clinically meaningful manner. The robustness of the treatmenteffect was also shown by the delay of progression to multiple sclerosis according to McDonald criteria(Table 3).

Subgroup analyses according to baseline factors demonstrated evidence of efficacy on progression to

CDMS in all subgroups evaluated. The risk for progression to CDMS within 2 years was higher inmonofocal patients with at least 9 T2-lesions or Gd-enhancement on brain MRI at baseline. Inmultifocal patients, the risk for CDMS was independent from MRI findings at baseline, indicating ahigh risk for CDMS because of the dissemination of the disease based on clinical findings. For thetime being there is no well-established definition of a high risk patient, although a more conservativeapproach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. Inany case, treatment should only be considered for patients classified as high risk.

Therapy with Betaferon was well accepted as indicated by a high rate of trial completion (93% in the

Betaferon group). To increase tolerability of Betaferon, a dose titration was applied and non-steroidalanti-inflammatory drugs were administered at start of therapy. Moreover, an autoinjector was used bythe majority of patients throughout the study.

In the open-label follow-up phase, the treatment effect on CDMS was still evident after 3 and 5 years(Table 3) even though the majority of patients from the placebo-group were treated with Betaferon atleast from the second year onwards. EDSS progression (confirmed increase in EDSS of at least onepoint compared to baseline) was lower in the immediate treatment group (Table 3, significant effectafter 3 years, no significant effect after 5 years). The majority of patients in both treatment groups hadno disability progression over the 5-year period. Robust evidence for benefit on this outcomeparameter could not be demonstrated for 'immediate' treatment. No benefit, attributable to immediate

Betaferon treatment, in quality of life (as measured by FAMS - Functional Assessment of MS:

Treatment Outcomes Index) was seen.

RR-MS, SP-MS and single clinical event suggestive of MS

Betaferon was effective in all multiple sclerosis studies to reduce disease activity (acute inflammationin the central nervous system and permanent tissue alterations) as measured by magnetic resonanceimaging (MRI). The relation of multiple sclerosis disease activity as measured by MRI and clinicaloutcome is currently not fully understood.

Betaferon serum levels were followed in patients and volunteers by means of a not completely specificbioassay. Maximum serum levels of about 40 IU/ml were found 1-8 hours after subcutaneous injectionof 500 microgram (16.0 million IU) interferon beta-1b. From various studies mean clearance rates andhalf-lives of disposition phases from serum were estimated to be at most 30 ml·min-1·kg-1 and 5 hours,respectively.

Betaferon injections given every other day do not lead to serum level increases, and thepharmacokinetics does not seem to change during therapy.

The absolute bioavailability of subcutaneously administered interferon beta-1b was approximately50%.

No acute toxicity studies have been carried out. As rodents do not react to human interferon beta,repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, aswell as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmentedneutrophils.

No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealedmaternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No malformationshave been observed in the surviving animals.

No investigations on fertility have been conducted. No influence on the monkey oestrous cycle hasbeen observed. Experience with other interferons suggests a potential for impairment of male andfemale fertility.

In one single genotoxicity study (Ames test), no mutagenic effect has been observed. Carcinogenicitystudies have not been performed. An in vitro cell transformation test gave no indication of tumorigenicpotential.

Vial (with powder for solution for injection):

Human albumin

Mannitol

Solvent (sodium chloride solution 5.4 mg/ml (0.54% w/v)):

Sodium chloride

Water for injection

This medicinal product must not be mixed with other medicinal products except for the suppliedsolvent mentioned in section 6.6.

2 years.

After reconstitution, immediate use is recommended. However, the in-use stability has beendemonstrated for 3 hours at 2-8 °C.

Do not store above 25°C.

Do not freeze.

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

Vial (with powder for solution for injection):3 ml clear vial (type I glass) with a butyl rubber stopper (type I) and aluminium overseal and

Solvent (with sodium chloride solution 5.4 mg/ml (0.54% w/v)):2.25 ml pre-filled syringe (type I glass) with 1.2 ml solvent.

Pack sizes− Pack with 5 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,1 vial adapter with needle, 2 alcohol wipes or− Pack with 15 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,1 vial adapter with needle, 2 alcohol wipes or− Pack with 14 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,1 vial adapter with needle, 2 alcohol wipes or− Pack with 12 single packs, each containing 1 vial with powder, 1 pre-filled syringe with solvent,1 vial adapter with needle, 2 alcohol wipes or− 2-month pack with 2x14 single packs, each containing 1 vial with powder, 1 pre-filled syringewith solvent, 1 vial adapter with needle, 2 alcohol wipes or− 3-month pack with 3x14 single packs, each containing 1 vial with powder, 1 pre-filled syringewith solvent, 1 vial adapter with needle, 2 alcohol wipes or− 3-month pack with 3x15 single packs, each containing 1 vial with powder, 1 pre-filled syringewith solvent, 1 vial adapter with needle, 2 alcohol wipes or− Titration pack for dose titration with 4 differently coloured and numbered triple packs:

- yellow, with number “1”(treatment days 1, 3 and 5; 0.25-ml syringe marking),

- red, with number “2” (treatment days 7, 9 and 11; 0.5-ml syringe marking),

- green, with number “3” (treatment days 13, 15 and 17; 0.75-ml syringe marking),

- blue, with number “4” (treatment days 19, 21 and 23; 0.25, 0.5, 0.75 and 1-ml syringemarking)

Each triple pack contains 3 vials with powder, 3 pre-filled syringes with solvent, 3 vial adapterswith pre-attached needle and 6 alcohol wipes for skin and vial cleaning.

Not all pack sizes may be marketed.

To reconstitute lyophilised interferon beta-1b for injection, connect the vial adapter with the attachedneedle on the vial. Connect the pre-filled syringe with solvent to the vial adapter and inject the 1.2 mlof the solvent (sodium chloride solution, 5.4 mg/ml (0.54% w/v)) into the Betaferon vial. Dissolve thepowder completely without shaking.

After reconstitution, draw 1.0 ml from the vial into the syringe for the administration of250 microgram Betaferon. For the dose titration at the start of treatment, draw the respective volumeas given in section 4.2.

Remove the vial with the vial adapter from the pre-filled syringe before injection.

Betaferon may also be administered with a suitable autoinjector.

Inspection prior to use

Inspect the reconstituted product visually before use. The reconstituted product is colourless to lightyellow and slightly opalescent to opalescent.

Discard the product before use if it contains particulate matter or is discoloured.

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

Bayer AG51368 Leverkusen

Germany

EU/1/95/003/005

EU/1/95/003/006

EU/1/95/003/007

EU/1/95/003/008

EU/1/95/003/009

EU/1/95/003/010

EU/1/95/003/011

EU/1/95/003/012

Date of first authorisation: 30 November 1995

Date of last renewal: 31 January 2006

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

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