Betaferon · 4.8 Undesirable effects · 1

HOS-083094 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile 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, discolouration, inflammation, pain, hypersensitivity, infection, necrosis and non-specific reactions were significantly associated with 250 microgram (8.0 million IU) Betaferon treatment. The most serious adverse reactions reported include thrombotic microangiopathy (TMA) and haemolytic 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-steroidal anti-inflammatory drugs. The incidence of injection site reactions may be reduced by the use of an autoinjector. Tabulated list of adverse reactions The following adverse event listing is based on reports from clinical trials and from the post-marketing surveillance (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. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Table 1: Adverse drug reactions (ADRs) based on reports from clinical trials and identified during post-marketing surveillance (frequencies - where known - calculated based on pooled clinical trial data) System Organ Very common Common Uncommon Rare Frequency Class ( 1/10) (  1/100 to ( 1/1,000 to (  1/10,000 to not known < 1/10) < 1/100) < 1/1,000) Blood and Lymphocyte Lymphadenopathy, Thrombocytopenia Thrombotic Haemolytic lymphatic count decreased Anaemia microangiopathyd anaemiaa, d system (< 1500/mm3) e, including disorders White blood cell thrombotic count decreased

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HOS-083090 · has-contraindication-information · PDF-Seite 3

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

HOS-083089 · has-indication-information · PDF-Seite 2

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.

HOS-083092 · has-interaction-information · PDF-Seite 7

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

HOS-083093 · has-pregnancy-information · PDF-Seite 7

Pregnancy A large amount of data (more than 1000 pregnancy outcomes) from interferon beta registries, national registries and post-marketing experience indicates no increased risk of major congenital anomalies after pre-conception exposure or exposure during the first trimester of pregnancy. However, the duration of exposure during the first trimester is uncertain, because data were collected when interferon beta use was contraindicated during pregnancy, and treatment likely interrupted when pregnancy was detected and/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 be evaluated 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. Breast-feeding Limited information available on the transfer of interferon beta-1b into breast milk, together with the chemical / physiological characteristics of interferon beta, suggests that levels of interferon beta-1b excreted in human milk are negligible. No harmful effects on the breastfed newborn/infant are anticipated. Betaferon can be used during breast-feeding. Fertility No investigations on fertility have been conducted (see section 5.3).

HOS-083091 · has-warning-information · PDF-Seite 3

Traceability In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. 3 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 hypertriglyceridemia. 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 sections 4.3 and 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 sections 4.5 and 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 Gamma-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

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