Fingolimod Accord · 4.3 Contraindications · 1

HOS-099327 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile The most frequent adverse reactions (incidence ≥10%) at the 0.5 mg dose were headache (24.5%), hepatic enzyme increased (15.2%), diarrhoea (12.6%), cough (12.3%), influenza (11.4%), sinusitis (10.9%) and back pain (10.0%). Tabulated list of adverse reactions Adverse reactions reported in clinical trials and derived from post-marketing experience via spontaneous case reports or literature cases are shown below. Frequencies were defined using 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 are presented in the order of decreasing seriousness. Infections and infestations Very common: Influenza Sinusitis Common: Herpes viral infections Bronchitis Tinea versicolor Uncommon: Pneumonia Not known: Progressive multifocal leukoencephalopathy (PML)** Cryptococcal infections** Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common: Basal cell carcinoma Uncommon: Malignant melanoma**** Squamous cell carcinoma***** Rare: Lymphoma*** Very rare: Kaposi’s sarcoma**** Not known: Merkel cell carcinoma*** Blood and lymphatic system disorders Common: Lymphopenia Leucopenia Uncommon: Thrombocytopenia Not known: Autoimmune haemolytic anaemia*** Peripheral oedema*** Immune system disorders 14 Not known: Hypersensitivity reactions, including rash, urticaria and angioedema upon treatment initiation*** Immune reconstitution inflammatory syndrome (IRIS)** Psychiatric disorders Common: Depression Uncommon: Depressed mood Nervous system disorders Very common: Headache Common: Dizziness Migraine Uncommon: Seizure Rare: Posterior reversible e

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HOS-099323 · has-contraindication-information · PDF-Seite 3

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Immunodeficiency syndrome. - Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies). - Suspected or confirmed progressive multifocal leukoencephalopathy (PML) (see section 4.4). - Severe active infections, active chronic infections (hepatitis, tuberculosis). 3 - Active malignancies. - Severe liver impairment (Child-Pugh class C). - Patients who in the previous 6 months had myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure (see section 4.4). - Patients with severe cardiac arrhythmias requiring anti-arrhythmic treatment with class Ia or class III anti-arrhythmic medicinal products (see section 4.4). - Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, or sick-sinus syndrome, if they do not wear a pacemaker (see section 4.4). - Patients with a baseline QTc interval ≥ 500 msec (see section 4.4). - During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6).

HOS-099322 · has-indication-information · PDF-Seite 2

Fingolimod Accord is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older: - Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1). 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-099325 · has-interaction-information · PDF-Seite 12

Anti-neoplastic, immunomodulatory or immunosuppressive therapies Anti-neoplastic, immunomodulatory or immunosuppressive therapies should not be co-administered due to the risk of additive immune system effects (see sections 4.3 and 4.4). Caution should also be exercised when switching patients from long-acting therapies with immune effects such as natalizumab, teriflunomide or mitoxantrone (see section 4.4). In multiple sclerosis clinical studies the concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. Vaccination During and for up to two months after treatment with Fingolimod Accord vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided (see sections 4.4 and 4.8). Bradycardia-inducing substances Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was used with atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction of heart rate at fingolimod treatment initiation, an effect not seen with diltiazem. Treatment with Fingolimod Accord should not be initiated in patients receiving beta blockers, or other substances which may decrease heart rate, such as class Ia and III antiarrhythmics, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, anticholinesteratic agents or pilocarpine because of the potential additive effects on heart rate (see sections 4.4 and 4.8). If treatment with Fingolimod Accord is considered in such patients, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering medicinal products or appropriate monitoring for treatment initiation, at least overnight monitoring is recommended, if the heart-rate-lowering medication cannot be stopped. Pharmacokinetic interactions of other substances on fingolimod Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism, notably in the case of strong induction of CYP3A4. Potent inhibitors of transporter proteins are not expected to influence fingolimod disposition. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC) by inhibition of CYP4F2. Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithrom

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HOS-099326 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential/Contraception in females Fingolimod is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for 2 months after discontinuation of Fingolimod Accord, since fingolimod takes approximately 2 months to eliminate from the body after treatment discontinuation (see section 4.4). Specific measures are also included in the Physician Information Pack. These measures must be implemented before fingolimod is prescribed to female patients and during treatment. When stopping fingolimod therapy for planning a pregnancy the possible return of disease activity should be considered (see section 4.4). Pregnancy Based on human experience, post-marketing data suggest that use of fingolimod is associated with a 2- fold increased risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population (2-3%; EUROCAT). The following major malformations were most frequently reported: - Congenital heart disease such as atrial and ventricular septal defects, tetralogy of Fallot - Renal abnormalities - Musculoskeletal abnormalities There are no data on the effects of fingolimod on labour and delivery. Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably persistent truncus arteriosus and ventricular septal defect (see section 5.3). Furthermore, the receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. Consequently, fingolimod is contraindicated during pregnancy (see section 4.3). Fingolimod should be stopped 2 months before planning a pregnancy (see section 4.4). If a woman becomes pregnant during treatment, fingolimod must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed. Breast-feeding Fingolimod is excreted in milk of treated animals during lactation (see section 5.3). Due to the potential for serious adverse reactions to fingolimod in nursing infants, women receiving Fingolimod Ac

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HOS-099324 · has-warning-information · PDF-Seite 4

Bradyarrhythmia Initiation of treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously resolving complete AV block (see sections 4.8 and 5.1). After the first dose, the decline in heart rate starts within one hour, and is maximal within 6 hours. This post-dose effect persists over the following days, although usually to a milder extent, and usually abates over the next weeks. With continued administration, the average heart rate returns towards baseline within one month. However, individual patients may not return to baseline heart rate by the end of the first month. Conduction abnormalities were typically transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours on treatment. If necessary, the decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline. All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after the first dose of Fingolimod Accord. All patients should be monitored for a period of 6 hours for signs and symptoms of bradycardia with hourly heart rate and blood pressure measurement. Continuous (real time) ECG monitoring during this 6-hour period is recommended. The same precautions as for the first dose are recommended when patients are switched from the 0.25 mg to the 0.5 mg daily dose. Should post-dose bradyarrhythmia-related symptoms occur, appropriate clinical management should be initiated and monitoring should be continued until the symptoms have resolved. Should a patient require pharmacological intervention during the first-dose monitoring, overnight monitoring in a medical facility should be instituted and the first-dose monitoring should be repeated after the second dose of Fingolimod Accord. If the heart rate at 6 hours is the lowest since the first dose was administered (suggesting that the maximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should be extended by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heart rate is <45 bpm in adults, <55 bpm in paediatric patients aged 12 years and above, or <60 bpm in paediatric patients aged 10 to below 12 years, or the ECG shows new onset second degree or higher grade AV block or a QTc interval ≥500 msec, extended monitoring (at least ov

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