Lemtrada · 4.4 Special warnings and precautions for use · 1

HOS-096914 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile in clinical studies A total of 1,486 patients treated with LEMTRADA (12 mg or 24 mg) constituted the safety population in a pooled analysis of MS clinical studies with a median follow-up of 6.1 years (maximum 12 years), resulting in 8,635 patient-years of safety follow-up. The most important adverse reactions are autoimmunity (ITP, thyroid disorders, nephropathies, cytopenias), IARs, and infections. These are described in section 4.4. The most common adverse reactions with LEMTRADA (in ≥20% of patients) were rash, headache, pyrexia, and respiratory tract infections. Tabulated list of adverse reactions The table below is based on the pooled safety data on all LEMTRADA 12 mg-treated patients during all available follow up in clinical trials. Adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT). Frequencies are defined according to the following convention: 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions have been presented in order of decreasing seriousness. 13  Table 1: Adverse reactions in study 1, 2, 3 and 4 observed in LEMTRADA 12 mg treated patients and post-marketing surveillance System Organ Very Common Common Uncommon Rare Not known Class Infections and Upper respiratory Herpes zoster Onychomycosis, Listeriosis/l infestations tract infection, infections2, lower gingivitis, fungal isteria urinary tract respiratory tract skin infection, meningitis, infection, herpes infections, tonsillitis, acute Epstein- virus infection,1 gastroenteritis, sinusitis, Barr virus oral candidiasis, cellulitis, (EBV) vulvovaginal tuberculosis, infection candidiasis, cytomegalovirus

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HOS-096910 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1. Human Immunodeficiency Virus (HIV) infection. Patients with severe active infection until complete resolution. Patients with uncontrolled hypertension. Patients with a history of arterial dissection of the cervicocephalic arteries. Patients with a history of stroke. Patients with a history of angina pectoris or myocardial infarction. Patients with known coagulopathy, on anti-platelet or anti-coagulant therapy. Patients with other concomitant autoimmune diseases (besides MS).

HOS-096909 · has-indication-information · PDF-Seite 2

LEMTRADA is indicated as a single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis (RRMS) for the following patient groups: • Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT) or • Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

HOS-096912 · has-interaction-information · PDF-Seite 12

No formal drug interaction studies have been conducted with LEMTRADA using the recommended dose in patients with MS. In a controlled clinical trial in MS patients recently treated with beta interferon and glatiramer acetate were required to discontinue treatment 28 days before initiating treatment with LEMTRADA.

HOS-096913 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential Serum concentrations were low or undetectable within approximately 30 days following each treatment course. Therefore, women of childbearing potential have to use effective contraception when receiving a course of treatment with LEMTRADA and up to 4 months after each course of treatment. Pregnancy There is a limited amount of data from the use of alemtuzumab in pregnant women. LEMTRADA should be administered during pregnancy only if the potential benefit justifies the potential risk to the foetus. Human IgG is known to cross the placental barrier; alemtuzumab may cross the placental barrier as well and thus potentially pose a risk to the foetus. Animal studies have shown reproductive toxicity (see section 5.3). It is not known whether alemtuzumab can cause foetal harm when administered to pregnant women or whether it can affect reproductive capacity. Thyroid disease (see section 4.4 Thyroid Disorders) poses special risks in women who are pregnant. Without treatment of hypothyroidism during pregnancy, there is an increased risk for miscarriage and foetal effects such as mental retardation and dwarfism. In mothers with Graves’ disease, maternal thyroid stimulating hormone receptor antibodies can be transferred to a developing foetus and can cause transient neonatal Graves’ disease. Breast-feeding Alemtuzumab was detected in the milk and offspring of lactating female mice. It is unknown whether alemtuzumab is excreted in human milk. A risk to the suckling newborn/infant cannot be excluded. Therefore, breast-feeding should be discontinued during each course of treatment with LEMTRADA and for 4 months following the last infusion of each treatment course. However, benefits of 12 conferred immunity through breast-milk may outweigh the risks of potential exposure to alemtuzumab for the suckling newborn/infant. Fertility There are no adequate clinical safety data on the effect of LEMTRADA on fertility. In a sub-study in 13 male LEMTRADA-treated patients (treated with either 12 mg or 24 mg), there was no evidence of aspermia, azoospermia, consistently depressed sperm count, motility disorders or an increase in sperm morphological abnormalities. CD52 is known to be present in human and rodent reproductive tissues. Animal data have shown effects on fertility in humanised mice (see section 5.3), however a potential impact on human fertility during the period of exposure is

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HOS-096911 · has-warning-information · PDF-Seite 4

LEMTRADA is not recommended for patients with inactive disease or those stable on current therapy. Patients treated with LEMTRADA must be given the Package Leaflet, the Patient Alert Card and the Patient Guide. Before treatment, patients must be informed about the risks and benefits, and the need to commit to follow-up from treatment initiation until at least 48 months after the last infusion of the second LEMTRADA treatment course. If an additional course is administered, safety-follow up should be continued until at least 48 months after the last infusion. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Autoimmunity Treatment may result in the formation of autoantibodies and increase the risk of autoimmune mediated conditions which may be serious and life threatening. Reported autoimmune conditions, include thyroid disorders, immune thrombocytopenic purpura (ITP), nephropathies (e.g. anti-glomerular basement membrane disease), autoimmune hepatitis (AIH), acquired haemophilia A, thrombotic thrombocytopenic purpura, sarcoidosis, and autoimmune encephalitis. In the post-marketing setting, patients developing multiple autoimmune disorders after LEMTRADA treatment have been observed. Patients who develop autoimmunity should be assessed for other autoimmune mediated conditions (see section 4.3). Patients and physicians should be made aware of the potential later onset of autoimmune disorders after the 48 months monitoring period. Acquired haemophilia A Cases of acquired haemophilia A (anti-factor VIII antibodies) have been reported in both clinical trial and post-marketing setting. Patients typically present with spontaneous subcutaneous haematomas and extensive bruising although haematuria, epistaxis, gastrointestinal or other types of bleeding may occur. A 4 coagulopathy panel including aPTT must be obtained in all patients that present with such symptoms. In case of a prolonged aPTT patient should be referred to a haematologist. Educate patients on the signs and symptoms of acquired haemophilia A and to seek immediate medical attention, if any of these symptoms are observed. Thrombotic Thrombocytopenic Purpura (TTP) Development of TTP has been reported in patients treated with LEMTRADA during post-marketing use, including a fatal case. TTP is a serious condition that requires

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