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 a full list of excipients, see section 6.1.

* produced by genetic engineering from 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 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).

• patients with relapsing remitting multiple sclerosis and two or more relapses within the last two years.

• patients with secondary progressive multiple sclerosis with active disease, evidenced by relapses.

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

Adults:

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

Children and adolescents:

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 of age 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 and therefore Betaferon should 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 increased slowly to a dose of 250 microgram (1.0 ml) every other day (see Table A). The titration period may be adjusted, if any significant adverse reaction occurs. In order to obtain adequate efficacy, a dose of 250 microgram (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's initial treatment with Betaferon. This package meets the patient's needs for the first 12 injections. The triple packs are highlighted in different colours (see section 6.5).

Table A: Schedule for dose titration*

* 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-up data under controlled clinical conditions for patients with relapsing-remitting MS for up to 5 years and for patients with secondary progressive MS for up to 3 years. For relapsing-remitting MS, efficacy has been demonstrated for therapy for the first two years. The available data for the additional three years are 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 clinically definite multiple sclerosis was significantly delayed over a period of five years.

Treatment is not recommended in patients with relapsing-remitting multiple sclerosis who have experienced less than 2 relapses in the previous 2 years or in patients with secondary-progressive multiple 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 or treatment with at least 3 courses of ACTH or corticosteroids during a one year period is required despite Betaferon therapy, treatment with Betaferon should be stopped.

− Initiation of treatment in pregnancy (see section 4.6 Pregnancy and lactation).

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

− Patients with current severe depression and/or suicidal ideation (see section 4.4 Special warnings and special precautions for use and 4.8 Undesirable effects).

− Patients with decompensated liver disease (see sections 4.4, 4.5, 4.8).

Immune system disorders

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

Gastrointestinal disorders

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

Nervous system disorders

Betaferon 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 with increased frequency in the multiple sclerosis population and in association with interferon use. Patients treated with Betaferon should be advised to report any symptoms of depression and/or suicidal ideation to their prescribing physician immediately. Patients exhibiting depression should be monitored closely during therapy with Betaferon and treated appropriately. Cessation of therapy with Betaferon should be considered (see also section 4.3 and section 4.8).

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

This product contains human albumin and hence carries a potential risk for transmission of viral diseases. 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 or as 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 to initiation and at regular intervals following introduction of Betaferon therapy, and then periodically thereafter in the absence of clinical symptoms.

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

Hepato-biliary disorders

Asymptomatic elevations of serum transaminases, in most cases mild and transient, occurred very commonly in patients treated with Betaferon during clinical trials. As for other beta interferons, severe hepatic injury, including cases of hepatic failure, has been reported rarely in patients taking Betaferon. The most serious events often occurred in patients exposed to other drugs or substances known 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 serum transaminases should lead to close monitoring and investigation. Withdrawal of Betaferon should be considered if the levels significantly increase or if they are associated with clinical symptoms such as jaundices. In the absence of clinical evidence for liver damage and after normalisation of liver enzymes a reintroduction of therapy could be considered with appropriate follow-up of hepatic functions.

Renal and urinary disorders

Caution should be used and close monitoring considered when administering Interferon beta to patients with severe renal failure.

Cardiac disorders

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 artery disease or arrhythmia, should be monitored for worsening of their cardiac condition, particularly during initiation of treatment with Betaferon.

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

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

General disorders and administration site conditions

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

Injection site necrosis has been reported in patients using Betaferon (see section 4.8). It can be extensive 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 to 6 months.

If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid from the injection site, the patient should be advised to consult with his/her physician before continuing 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, as some 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 pivotal study of patients with a single clinical event suggestive of multiple sclerosis an autoinjector was used in the majority of patients. Injection site reactions as well as injection site necroses were observed less frequently in this study than in the other pivotal studies.

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

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Serum samples in controlled clinical 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 secondary progressive 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, between 43% 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 clinical efficacy only with regard to relapse activity. Some analyses suggest that this effect might be larger in patients with higher titre levels of neutralising activity.

In the study of patients with a single clinical event suggestive of multiple sclerosis, neutralising activity measured every 6 months was observed at least once in 32% (89) of the patients treated immediately with Betaferon; of these, 60% (53) returned to negative status based on the last available assessment within the 5 year period. Within this period, the development of neutralising activity was associated with a significant increase in newly active lesions and T2 lesion volume on magnetic resonance 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 EDSS progression 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 have completed Betaferon therapy.

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

No interaction studies have been performed.

The effect of alternate-day administration of 250 microgram (8.0 million IU) of Betaferon on drug metabolism in multiple sclerosis patients is unknown. Corticosteroid or ACTH treatment of relapses for 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 with immunomodulators other than corticosteroids or ACTH is not recommended.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be exercised when Betaferon 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. anti-epileptics. Additional caution should be exercised with any co-medication which has an effect on the haematopoetic system.

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

• Pregnancy

There is limited information on the use of Betaferon 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 should take appropriate contraceptive measures. If the patient becomes pregnant or plans to become pregnant while taking Betaferon, 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 Betaferon in the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion.

• Lactation

It is not known whether interferon beta-1b is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants a decision should be made on whether to discontinue breast-feeding or discontinue Betaferon therapy.

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 influence the ability to drive and use machines in susceptible patients.

a) At the beginning of treatment adverse reactions are common but in general they subside with further treatment. 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 the pharmacological effects of the medicinal product and injection site reactions. Injection site reactions occurred frequently after administration of Betaferon. Redness, swelling, discoloration, inflammation, pain, hypersensitivity, necrosis and non-specific reactions were significantly associated with 250 microgram (8 million IU) Betaferon treatment.

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-steroidal anti-inflammatory drugs. The incidence of injection site reactions may be reduced by the use of an autoinjector.

b) The following adverse event listing is based on reports from clinical trials (Table 1, adverse events and laboratory abnormalities) and from the post marketing surveillance (Table 2, reporting rates based on spontaneous adverse drug reaction reports classified as 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. Experience with Betaferon in patients with MS is limited, consequently those adverse events which occur very rarely may not yet have been observed.

Table 1 (adverse events and laboratory abnormalities with incidence rates10% and the respective percentages under placebo; significantly associated side effects < 10%).