Tecfidera · 4.1 Therapeutic indications · 1

HOS-096440 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most common adverse reactions are flushing (35%) and gastrointestinal events (i.e. diarrhoea (14%), nausea (12%), abdominal pain (10%), abdominal pain upper (10%)). Flushing and gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and in patients who experience flushing and gastrointestinal events, these events may continue to occur intermittently throughout treatment with Tecfidera. The most commonly reported adverse reactions leading to treatment discontinuation are flushing (3%) and gastrointestinal events (4%). In phase 2 and 3 placebo-controlled and uncontrolled clinical studies, a total of 2,513 patients have received Tecfidera for periods of up to 12 years with an overall exposure equivalent to 11,318 person- years. A total of 1,169 patients have received at least 5 years of treatment with Tecfidera, and 426 patients have received at least 10 years of treatment with Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials. Tabulated list of adverse reactions Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports, are presented in the table below. The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class. The incidence of the adverse reactions below is expressed according to the following categories: - 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) - Not known (frequency cannot be estimated from the available data) MedDRA system organ class Adverse reaction Frequency category Infections and infestations Gastroenteritis Common Progressive multifocal Not known leukoencephalopathy (PML) Herpes zoster Not known Blood and lymphatic system Lymphopenia Common disorders Leucopenia Common Thrombocytopenia Uncommo

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HOS-096436 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

HOS-096435 · has-indication-information · PDF-Seite 2

Tecfidera is indicated for the treatment of adult and paediatric patients aged 13 years and older with relapsing remitting multiple sclerosis (RRMS).

HOS-096438 · has-interaction-information · PDF-Seite 7

Anti-neoplastic, immunosuppressive or corticosteroid therapies Tecfidera has not been studied in combination with anti-neoplastic or immunosuppressive therapies and caution should, therefore, be used during concomitant administration. In multiple sclerosis clinical studies, the concomitant treatment of relapses with a short course of intravenous corticosteroids was not associated with a clinically relevant increase of infection. Vaccines Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during Tecfidera therapy. In a clinical study involving a total of 71 patients with RRMS, patients on Tecfidera 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response (defined as ≥ 2-fold increase from pre- to post-vaccination titre) to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups. A positive immune response defined as a ≥ 4-fold increase in antibody titre to the three vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon. No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking Tecfidera. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating. Other fumaric acid derivatives During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided. In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemic circulation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. Potential interaction risks were not identified from in vitro CYP- inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethyl fumarate and monomethyl fumarate (the primary metabolite of dimethyl fumarate). Effects of

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HOS-096439 · has-pregnancy-information · PDF-Seite 8

Pregnancy A moderate amount of data on pregnant women are available (between 300-1,000 pregnancy outcomes), based on a pregnancy registry and post-marketing spontaneous reports. In the Tecfidera pregnancy registry, 289 prospectively collected pregnancy outcomes were documented in patients with MS who were exposed to dimethyl fumarate. The median duration of exposure to dimethyl fumarate was 4.6 gestational weeks with limited exposure after the sixth gestational week (44 pregnancy outcomes). Exposure to dimethyl fumarate during such early pregnancy indicates no malformative or foeto/neonatal toxicity compared to the general population. The risk of longer dimethyl fumarate exposure or exposure in later stages of pregnancy is not known. Animal studies have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Tecfidera during pregnancy. Tecfidera should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Tecfidera therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of dimethyl fumarate on human fertility. Data from preclinical studies do not suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility (see section 5.3). 8

HOS-096437 · has-warning-information · PDF-Seite 3

Blood/laboratory tests Renal function Changes in renal laboratory tests have been seen in clinical trials in patients treated with dimethyl fumarate (see section 4.8). The clinical implications of these changes are unknown. Assessment of renal function (e.g. creatinine, blood urea nitrogen and urinalysis) is recommended prior to treatment initiation, after 3 and 6 months of treatment, every 6 to 12 months thereafter and as clinically indicated. Hepatic function Drug-induced liver injury, including liver enzyme increase (≥ 3 times upper limit of normal (ULN)) and elevation of total bilirubin levels (≥ 2 × ULN) can result from treatment with dimethyl fumarate. The time to onset can be days, several weeks or longer. Resolution of the adverse reactions has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are 3 recommended prior to treatment initiation and during treatment as clinically indicated. Lymphocytes Patients treated with Tecfidera may develop lymphopenia (see section 4.8). Prior to initiating treatment with Tecfidera, a current complete blood count, including lymphocytes, must be performed. If lymphocyte count is found to be below the normal range, thorough assessment of possible causes should be completed prior to initiation of treatment. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients. Treatment should not be initiated in patients with severe lymphopenia (lymphocyte counts < 0.5 × 109/L). After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months. Enhanced vigilance due to an increased risk of PML is recommended in patients with lymphopenia as follows:  Treatment should be discontinued in patients with prolonged severe lymphopenia (lymphocyte counts < 0.5 × 109/L) persisting for more than 6 months.  In patients with sustained moderate reductions of absolute lymphocyte counts ≥ 0.5 × 109/L to < 0.8 × 109/L for more than 6 months, the benefit/risk balance of treatment with Tecfidera should be re-assessed.  In patients with lymphocyte counts below lower limit of normal (LLN) as defined by local laboratory reference range, regular monitoring of absolute lymphocyte counts is re

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