Velsipity

HOS-100371 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The most common adverse reactions are lymphopenia (11%) and headache (7%). Tabulated list of adverse reactions The adverse reactions observed in patients treated with etrasimod are listed below by system organ class (SOC) and frequency category. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. 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 1: Adverse reactions System organ class Very common Common Uncommon (SOC) Infections and Urinary tract infectiona, infestations lower respiratory tract infectionb Blood and lymphatic Lymphopeniac Neutropenia system disorders 10  Metabolism and Hypercholesterolaemiad nutrition disorders Nervous system Headache, dizziness disorders Eye disorders Visual impairment Macular oedema Cardiac disorders Bradycardiae Atrioventricular blockf Vascular disorders Hypertension Hepatobiliary Hepatic enzyme increased disorders a Urinary tract infection includes urinary tract infection and cystitis. b Lower respiratory tract infection includes bronchitis and pneumonia. c Lymphopenia includes lymphopenia, lymphocyte count decreased, and lymphocyte percentage decreased. d Hypercholesterolaemia includes hypercholesterolaemia and blood cholesterol increased. e Bradycardia includes bradycardia and sinus bradycardia. See “Description of selected adverse reactions” below. f Atrioventricular block includes first- or second-degree Mobitz type I. See “Description of selected adverse reactions” below. Description of selected adverse reactions Bradyarrhythmia In ELEVATE UC 52 and ELEVATE UC 12, bradycardia was reported as an AE on the day of treatment initiation in 1.5% of patients treated with etrasimod. On Day 2, bradycardia was reported as an AE in 0.4% of patients treated with etrasimod. Bradycardia was recorded more frequently on ECG monitoring (see sect

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HOS-100367 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Immunodeficient state (see section 4.4). • Patients who in the last 6 months experienced myocardial infarction, unstable angina pectoris, 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 Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker. • Severe active infections, active chronic infections such as hepatitis or tuberculosis (see section 4.4). • Active malignancies. • Severe hepatic impairment. • During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6). 3

HOS-100366 · has-indication-information · PDF-Seite 2

Velsipity is indicated for the treatment of patients 16 years of age and older 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 biological agent.

HOS-100369 · has-interaction-information · PDF-Seite 8

Effect of inhibitors of CYP2C8, CYP2C9, and CYP3A4 on etrasimod The co-administration of etrasimod with steady state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased exposure (AUC) of etrasimod by 84%. Co-administration of etrasimod with a therapeutic agent or a combination of agents that are moderate to strong inhibitors of two or more of the following CYP enzymes (CYP2C8, CYP2C9, and CYP3A4) (e.g., fluconazole) increases the exposure of etrasimod and is not recommended (see section 4.4). Effect of inducers of CYP2C8, CYP2C9, and CYP3A4 on etrasimod The co-administration of etrasimod with rifampicin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased exposure (AUC) of etrasimod by 49%. Co-administration of etrasimod with a therapeutic agent or a combination of agents that are moderate to strong inducers of two or more of the following CYP enzymes (CYP2C8, CYP2C9, and CYP3A4) (e.g., rifampicin, enzalutamide) decreases the exposure of etrasimod and is not recommended (see section 4.4). Effect of CYP2C9 polymorphism Due to the potential for increased exposure of etrasimod, co-administration of etrasimod in patients who are known or suspected to be CYP2C9 poor metabolisers (< 5% of the population) and who take medicinal products that are moderate or strong inhibitors of CYP2C8 and/or CYP3A4 is not recommended (see section 4.4). Beta blockers and calcium channel blockers The initiation of a beta blocker with stable treatment of etrasimod has not been studied. The effect of co-administration of etrasimod and a calcium channel blocker has not been studied. Caution is recommended for patients receiving medicinal products that slow heart rate or atrioventricular conduction because of the potential additive effects on lowering heart rate (see section 4.4). 8 Anti-arrhythmic medicinal products, QT prolonging medicinal products, medicinal products that may decrease heart rate Etrasimod has not been studied in patients taking QT prolonging medicinal products. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic medicinal products have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with etrasimod is considered in patients on Class Ia or Class III anti-arrhythmic medicinal products, advice from a cardiologist should be sought (see section 4.4). Due to the potential additive effects on heart

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HOS-100370 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception in females Velsipity 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. Due to the time it takes to eliminate etrasimod from the body after stopping treatment, the potential risk to the foetus may persist and women of childbearing potential must use effective contraception during etrasimod treatment and for at least 14 days after treatment discontinuation (see section 4.4). Specific measures are also included in the Healthcare Professional checklist. These measures must be implemented before etrasimod is prescribed to female patients and during treatment. 9 Pregnancy There is a limited amount of data from the use of etrasimod in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Clinical experience with another sphingosine-1-phosphate receptor modulator indicated a 2-fold higher risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population. Based on human experience etrasimod may cause congenital malformations when administered during the first trimester of pregnancy. The limited human data available for etrasimod also suggest an increased risk of abnormal pregnancy outcomes. Consequently, Velsipity is contraindicated during pregnancy (see section 4.3). Etrasimod should be stopped at least 14 days before a pregnancy is planned (see section 4.4). If a woman becomes pregnant during treatment, etrasimod must be immediately discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and follow-up examinations should be performed. Breast-feeding It is unknown whether etrasimod is excreted in human milk. A study in lactating rats has indicated excretion of etrasimod in milk (see section 5.3). A risk to newborns/infants cannot be excluded. Etrasimod should not be used during breast-feeding. Fertility The effect of etrasimod on human fertility has not been evaluated. In animal studies, no adverse effects on fertility were observed (see section 5.3).

HOS-100368 · has-warning-information · PDF-Seite 4

Bradyarrhythmia and atrioventricular conduction delays Treatment initiation with etrasimod Prior to treatment initiation with etrasimod, an electrocardiogram (ECG) should be obtained in all patients to assess for pre-existing cardiac abnormalities. In patients with certain pre-existing conditions, first dose monitoring is recommended (see below). When reinitiating treatment after an interruption of 7 or more consecutive days, consideration may be given to repeating the baseline ECG and/or monitoring depending on the results of the first evaluation, change in patient characteristics, and duration of interruption. Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays (see sections 4.8 and 5.1). Caution should be applied when etrasimod is initiated in patients receiving treatment with a beta-blocker because of the potential additive effects on lowering heart rate. Similar caution should be applied if patients receive calcium channel blockers, QT prolonging medicinal products, Class Ia and Class III anti-arrhythmic substances (see section 4.5), since co-administration of these substances with etrasimod may lead to additive effects. Temporary interruption of beta-blocker treatment may be needed prior to initiation of etrasimod, depending on the resting HR before initiation of etrasimod (see also section below and section 4.5). If interruption is deemed necessary, treatment with a beta-blocker can be reinitiated depending on the time of reaching the baseline heart rate. Beta-blocker treatment can be initiated in patients receiving stable doses of etrasimod. Cardiologist advice should be obtained before initiation of etrasimod to determine overall benefit risk and the most appropriate monitoring strategy in patients with the following conditions: • Significant QT prolongation (QTcF ≥ 450 msec in males, ≥ 470 msec in females). • Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic medicinal products. • Unstable ischaemic heart disease, history of cardiac arrest, cerebrovascular disease (occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension. • History of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnoea. First dose monitoring in patients with certain pre-existing cardiac conditions Due to the risk of transient decreases in heart rate with the initiation of etrasimod 4-hour monitoring for signs

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