Zeposia · 4.3 Contraindications · 1

HOS-098799 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most commonly reported adverse reactions are nasopharyngitis (12.3%), alanine aminotransferase (ALT) increased (5%), and gamma-glutamyl transferase (GGT) increased (5.4%). Initiation of ozanimod may result in transient bradycardia that usually resolves by the end of the first week. Other serious adverse reactions include serious opportunistic infections (PML has been reported in patients treated with ozanimod), macular oedema (see section 4.4), hypertension, and rare cases of clinically significant liver injury (see section 4.4). The most common adverse reactions leading to discontinuation were related to liver enzyme elevations (1.1%) in the MS clinical studies. Liver enzyme elevations leading to discontinuation occurred in 0.4% of patients, in UC controlled clinical studies. The overall safety profile was similar for patients with multiple sclerosis and ulcerative colitis. Tabulated list of adverse reactions The adverse reactions observed in patients treated with ozanimod in MS and UC clinical studies and from post-marketing experience including spontaneous case reports are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. 10 Frequencies are defined 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). Table 2: Adverse reactions SOC Frequency Adverse reaction Very common Nasopharyngitis Pharyngitis Viral respiratory tract infection***** Infections and infestations Common Urinary tract infection*,***** Herpes zoster***** Herpes simplex***** Rare Progressive multifocal leukoencephalopathy Blood and lymphatic system Very common Lymphopenia***** disorders Immune system disorders Uncommon Hypersensitivity (including rash and urticaria*)

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HOS-098795 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Immunodeficient state predisposing to systemic opportunistic infections (see section 4.4). • Patients who in the last 6 months experienced myocardial infarction (MI), unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation or New York Heart Association (NYHA) Class III/IV heart failure. • Patients with history or presence of second-degree atrioventricular (AV) block Type II or third- degree AV block or sick sinus syndrome unless the patient has a functioning pacemaker. • Severe active infections, active chronic infections such as hepatitis and tuberculosis (see section 4.4). • Active malignancies. • Severe hepatic impairment (Child-Pugh class C). • During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6).

HOS-098794 · has-indication-information · PDF-Seite 2

Multiple sclerosis Zeposia is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease as defined by clinical or imaging features. 2 Ulcerative colitis Zeposia is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent.

HOS-098797 · has-interaction-information · PDF-Seite 8

Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies should not be coadministered due to the risk of additive immune system effects (see sections 4.3 and 4.4). 8 Vaccination During and for up to 3 months after treatment with ozanimod, vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided during and for up to 3 months after treatment with ozanimod (see section 4.4). Effect of inhibitors of monoamine oxidase (MAO) on ozanimod The potential for clinical interaction with MAO inhibitors has not been studied. However, the coadministration with Monoamine oxidase B (MAO-B) inhibitors may decrease exposure of the major active metabolites and may result in reduced clinical response. The coadministration of MAO inhibitors (e.g., selegiline, phenelzine) with ozanimod is not recommended (see section 4.4). Effect of inducers of CYP2C8 on ozanimod The coadministration of rifampicin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ozanimod 0.92 mg reduced exposure (AUC) of major active metabolites by approximately 60% via CYP2C8 induction which may result in reduced clinical response. The coadministration of CYP2C8 inducers (i.e. rifampicin) with ozanimod is not recommended (see section 4.4). Effects of ozanimod on medicinal products that slow heart rate or atrioventricular conduction (e.g., beta-blockers or calcium channel blockers) In healthy subjects, a single dose of ozanimod 0.23 mg with steady state propranolol long acting 80 mg once daily or diltiazem 240 mg once daily did not result in any additional clinically meaningful changes in HR and PR interval compared to either propranolol or diltiazem alone. Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta-blocker or a calcium- channel blocker (see section 4.4). Patients on other bradycardic medicinal products and on antiarrhythmic medicinal products (which have been associated with cases of torsades de pointes in patients with bradycardia) have not been studied with ozanimod. Effect of inhibitors of CYP2C8 on ozanimod The coadministration of gemfibrozil (a strong inhibitor of CYP2C8) 600 mg twice daily at steady state and a single dose of oza

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HOS-098798 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in females Zeposia 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 confirmed and repeated at suitable intervals. Counselling should be provided regarding the risk to the foetus. Women of childbearing potential must use effective contraception during ozanimod treatment and for 3 months after treatment discontinuation (see section 4.4). 9 Specific measures are also included in the Healthcare Professional checklist. These measures must be implemented before ozanimod is prescribed to female patients and during treatment. When stopping ozanimod therapy for planning a pregnancy the possible return of disease activity should be considered (see section 4.4). Pregnancy There are no or limited amount of data from the use of ozanimod in pregnant women. Studies in animals have shown reproductive toxicity including foetal loss and anomalies, notably malformations of blood vessels, generalised oedema (anasarca), and malpositioned testes and vertebrae (see section 5.3). Sphingosine 1-phosphate is known to be involved in vascular formation during embryogenesis (see section 5.3). Consequently, Zeposia is contraindicated during pregnancy (see section 4.3). Zeposia should be stopped 3 months before planning a pregnancy (see section 4.4). If a woman becomes pregnant during treatment, Zeposia 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 Ozanimod/metabolites are excreted in milk of treated animals during lactation (see section 5.3). Due to the potential for serious adverse reactions to ozanimod/metabolites in nursing infants, women receiving ozanimod should not breastfeed. Fertility No fertility data are available in humans. In animal studies, no adverse effects on fertility were observed (see section 5.3).

HOS-098796 · has-warning-information · PDF-Seite 4

Bradyarrhythmia Initiation of treatment with ozanimod Prior to treatment initiation with ozanimod, an electrocardiogram (ECG) in all patients should be obtained to determine whether any pre-existing cardiac abnormalities are present. In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below). Initiation of ozanimod may result in transient reductions in heart rate (HR) (see sections 4.8 and 5.1), and, therefore the initial dose escalation regimen to reach the maintenance dose (0.92 mg) on day 8 should be followed (see section 4.2). After the initial dose of ozanimod 0.23 mg, the HR decrease started at Hour 4, with the greatest mean reduction at Hour 5, returning towards baseline at Hour 6. With continued dose escalation, there were no clinically relevant HR decreases. Heart rates below 40 beats per minute were not observed. If necessary, the decrease in HR induced by ozanimod can be reversed by parenteral doses of atropine or isoprenaline. Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta- blocker or a calcium-channel blocker (e.g. diltiazem and verapamil) because of the potential for additive effects on lowering HR. Beta-blockers and calcium-channel blockers treatment can be initiated in patients receiving stable doses of ozanimod. The co-administration of ozanimod in patients on a beta-blocker in combination with a calcium channel blocker has not been studied (see section 4.5). First dose monitoring in patients with certain pre-existing cardiac conditions Due to the risk of transient decreases in HR with the initiation of ozanimod, first-dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR < 55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure (see section 4.3). Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended. Additional monitoring is recommended in patients if at hour 6 post-dose: • heart rate is less than 45 bpm 4 • heart rate is the lowest value post-dose, suggesting that the maximum decrease in HR may not have occurred yet • there is evidence of a new onset second-degree or higher AV block at the 6-hour post-dose ECG • QTc interval ≥ 500 msec In these

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