VELSIPITY 2mg tablets medication leaflet

Velsipity 2 mg film-coated tablets

Each film-coated tablet contains etrasimod arginine equivalent to 2 mg etrasimod.

Each film-coated tablet contains 0.0156 mg of the colouring agent tartrazine (E102).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Green, round, film-coated tablet of approximately 6 mm diameter, debossed with “ETR” on one sideand “2” on the other side.

Velsipity is indicated for the treatment of patients 16 years of age and older with moderately toseverely active ulcerative colitis (UC) who have had an inadequate response, lost response, or wereintolerant to either conventional therapy, or a biological agent.

Treatment should be initiated under the supervision of a physician experienced in the management ofulcerative colitis.

The recommended dose is 2 mg etrasimod taken once daily.

If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next doseshould not be doubled.

If treatment is interrupted for 7 or more consecutive days, it is recommended to resume treatment withfood for the first 3 doses.

No dose adjustment is needed in patients over 65 years of age (see section 5.2).

Etrasimod should be used with caution in elderly patients over 65 years of age, given the limited dataavailable and potential for an increased risk of adverse reactions in this population.

No dose adjustment is needed for patients with renal impairment (see section 5.2).

No dose adjustment is needed for patients with mild or moderate hepatic impairment. Etrasimodshould not be used in patients with severe hepatic impairment (see sections 4.3 and 5.2).

The safety and efficacy of etrasimod in children and adolescents less than 16 years of age have not yetbeen established. No data are available.

Given the limited data in adolescents aged 16 and over, etrasimod should be used with cautionespecially when body weight is less than 40 kg due to the potential for increase in exposure (seesection 5.2).

Oral use.

It is recommended that etrasimod be administered with food for the first 3 days to attenuate potentialtransient heart rate lowering effects related to initiation of treatment (see section 4.4). Etrasimod canthen be taken with or without food (see section 5.2).

Tablets should be swallowed whole with water and not be split, crushed or chewed because thesemethods have not been studied in clinical trials.

- 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-degreeatrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless patient has afunctioning pacemaker.

- Severe active infections, active chronic infections such as hepatitis or tuberculosis (see section4.4).

- Active malignancies.

- Severe hepatic impairment.

- During pregnancy and in women of childbearing potential not using effective contraception (seesections 4.4 and 4.6).

Bradyarrhythmia and atrioventricular conduction delays

Treatment initiation with etrasimod

Prior to treatment initiation with etrasimod, an electrocardiogram (ECG) should be obtained in allpatients to assess for pre-existing cardiac abnormalities. In patients with certain pre-existingconditions, first dose monitoring is recommended (see below). When reinitiating treatment after aninterruption of 7 or more consecutive days, consideration may be given to repeating the baseline ECGand/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 (seesections 4.8 and 5.1).

Caution should be applied when etrasimod is initiated in patients receiving treatment with abeta-blocker because of the potential additive effects on lowering heart rate. Similar caution should beapplied 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 withetrasimod 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 thetime of reaching the baseline heart rate. Beta-blocker treatment can be initiated in patients receivingstable doses of etrasimod.

Cardiologist advice should be obtained before initiation of etrasimod to determine overall benefit riskand 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 (occurringmore than 6 months prior to treatment initiation), or uncontrolled hypertension.

- History of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleepapnoea.

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 monitoringfor signs and symptoms of symptomatic bradycardia after the first dose is recommended in patientswith resting heart rate < 50 bpm, second-degree [Mobitz type I] AV block, or a history of myocardialinfarction or heart failure (see section 4.3).

Patients should be monitored with hourly pulse and blood pressure measurement during this 4-hourperiod. An ECG prior to and at the end of this 4-hour period is recommended.

Additional monitoring is recommended in patients, if at the end of 4-hour period:

- Heart rate is < 45 bpm.

- Heart rate is the lowest value post dose, suggesting that the maximum decrease in heart rate maynot have occurred yet.

- ECG shows evidence of a new onset second-degree or higher AV block.

- QTc interval is ≥ 500 msec.

In these cases, appropriate management should be initiated, and observation should continue until thesymptoms/findings have resolved. If medical treatment is required, monitoring should be continuedovernight, and a 4-hour monitoring period should be repeated after the second dose of etrasimod.

Risk of infections

Etrasimod causes a mean reduction in peripheral blood lymphocyte count ranging from 43 to 55% ofbaseline values over 52 weeks because of reversible sequestration of lymphocytes in lymphoid tissues(see section 5.1). Etrasimod may, therefore, increase the susceptibility to infections (see section 4.8).

Before initiating treatment, a recent complete blood count (CBC), including lymphocyte count (i.e.,within the last 6 months or after discontinuation of prior UC therapy), should be obtained.

Assessments of CBC are also recommended periodically during treatment. Absolute lymphocytecounts < 0.2 x 109/L, if confirmed, should lead to interruption of etrasimod therapy until the levelreaches > 0.5 x 109/L when re-initiation of etrasimod can be considered (see section 4.2).

The initiation of etrasimod in patients with any active infection should be delayed until the infection isresolved (see section 4.3).

Patients should be instructed to promptly report symptoms of infection to their physician. Effectivediagnostic and therapeutic strategies should be employed in patients with symptoms of infection whileon therapy.

If a patient develops a serious infection, interruption of etrasimod should be considered.

As residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, maypersist up to 2 weeks after discontinuation of etrasimod, vigilance for infection should be continuedthroughout this period (see section 5.1).

PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) thattypically occurs in patients who are immunocompromised, and that may lead to death or severedisability. Typical symptoms associated with PML are diverse, progress over days to weeks, andinclude progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision,and changes in thinking, memory, and orientation leading to confusion and personality changes.

PML has been reported in multiple sclerosis patients treated with sphingosine-1-phosphate (S1P)receptor modulators and has been associated with some risk factors (e.g., immunocompromisedpatients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptomsor unexplained neurologic findings that may be suggestive of PML. If PML is suspected, treatmentwith etrasimod should be suspended until PML has been excluded by an appropriate diagnosticevaluation.

If PML is confirmed, treatment with etrasimod should be discontinued.

Prior and concomitant treatment with anti-neoplastic, immune-modulating, or non-corticosteroidimmunosuppressive therapies

In clinical studies, patients who received etrasimod were not to receive concomitant treatmentwith anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapiesused for the treatment of UC. In clinical studies, concomitant use of corticosteroids was allowed;however, long-term data on concomitant use of etrasimod and corticosteroids are limited (seesection 5.1).

Caution should be used when co-administering etrasimod and anti-neoplastic, immune-modulating, orimmunosuppressive (including corticosteroid) therapies to patients, because of the risk of additiveimmune system effects during such therapy (see section 4.5).

When switching to etrasimod from immunosuppressive therapies, the duration of effects andmechanism of action should be considered to avoid unintended additive immune system effects. Anappropriate washout period may need to be applied.

No clinical data are available on the safety and efficacy of vaccinations in patients taking etrasimod.

Vaccinations may be less effective if administered during etrasimod treatment. If live attenuatedvaccine immunisations are required, these should be administered at least 4 weeks prior to initiation ofetrasimod. The use of live attenuated vaccines during and for at least 2 weeks after treatment withetrasimod should be avoided (see section 5.1).

It is recommended to update immunisations in agreement with current immunisation guidelines priorto initiating etrasimod therapy.

Liver injury

Elevations of aminotransferases may occur in patients receiving etrasimod (see section 4.8). Recenttransaminase and bilirubin levels (i.e., within last 6 months) should be available before initiation oftreatment with etrasimod.

In the absence of clinical symptoms, liver transaminases and bilirubin levels should be monitored atmonths 1, 3, 6, 9, and 12 on therapy and periodically thereafter.

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea,vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepaticenzymes checked. Etrasimod should be discontinued if significant liver injury is confirmed(for example, alanine aminotransferase (ALT) exceeds 3-fold the upper limit of normal (ULN) andtotal bilirubin exceeds 2-fold the ULN).

Resumption of therapy will be dependent on whether another cause of liver injury is determined andon the benefits to patient of resuming etrasimod therapy versus the risks of recurrence of liverdysfunction. Although there are no data to establish that patients with pre-existing liver disease are atincreased risk of developing elevated liver function test values when taking etrasimod, caution shouldbe exercised in patients with a history of significant liver disease.

In clinical studies, hypertension was more frequently reported in patients treated with etrasimod thanin patients treated with placebo (see section 4.8). Blood pressure should be monitored during treatmentwith etrasimod and managed appropriately.

Based on animal studies, etrasimod may cause foetal harm (see sections 4.6 and 5.3). Due to the risk tothe foetus, etrasimod is contraindicated during pregnancy and in women of childbearing potential notusing effective contraception (see sections 4.3 and 4.6). Before initiation of treatment, women ofchildbearing potential must be informed about this risk to the foetus, must have a negative pregnancytest, and must use effective contraception during treatment and for at least 14 days after treatmentdiscontinuation (see section 4.6).

Macular oedema

S1P receptor modulators, including etrasimod, have been associated with an increased risk of macularoedema. Macular oedema with or without visual symptoms has been reported in 0.3% of patientstreated with Velsipity.

Patients with a history of diabetes mellitus, uveitis, and/or underlying/co-existing retinal disease, are atincreased risk of macular oedema during etrasimod therapy (see section 4.8). It is recommended thatthese patients undergo an ophthalmic evaluation prior to treatment initiation with etrasimod and havefollow-up evaluations while receiving therapy.

In patients without the risk factors above, an ophthalmic evaluation of the fundus, including themacula, is recommended within 3-4 months after starting etrasimod treatment (cases reported withetrasimod occurred within this timeframe) and at any time if there is a change in vision while takingetrasimod.

Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed,treatment with etrasimod should be discontinued. A decision on whether etrasimod should bere-initiated after resolution needs to take into account the potential benefits and risks for the individualpatient.

Cases of malignancies (including cutaneous malignancies) have been reported in patients treated with

S1P receptor modulators. If a suspicious skin lesion is observed, it should be promptly evaluated.

Since there is a potential risk of malignant skin growths, patients treated with etrasimod should becautioned against exposure to sunlight without protection. These patients should not receiveconcomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Posterior reversible encephalopathy syndrome (PRES)

Rare cases of PRES have been reported in patients receiving S1P receptor modulators. Should anetrasimod-treated patient develop any neurological or psychiatric symptoms/signs (e.g., cognitivedeficits, behavioural changes, cortical visual disturbances, or any other neurological corticalsymptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or acceleratedneurological deterioration, the physician should promptly schedule a complete physical andneurological examination and should consider an MRI. Symptoms of PRES are usually reversible butmay evolve into ischaemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment may leadto permanent neurological sequelae. If PRES is suspected, treatment with etrasimod should bediscontinued.

Interaction with other medicinal products, CYP2C9 polymorphism

Etrasimod should not be co-administered with a therapeutic agent or a combination of agents that aremoderate to strong inhibitors of two or more of the following CYP enzymes (CYP2C8, CYP2C9, and

CYP3A4) due to the risk of increased exposure to etrasimod (see section 4.5).

The use of etrasimod is not recommended when co-administered with a therapeutic agent or acombination of agents that are moderate to strong inducers of two or more of the following CYPenzymes (CYP2C8, CYP2C9, and CYP3A4) due to the risk of decreased exposure to etrasimod (seesection 4.5).

The use of etrasimod is not recommended in patients who are known or suspected to be CYP2C9 poormetabolisers (< 5% of the population) and who take medicinal products that are moderate or stronginhibitors of CYP2C8 and/or CYP3A4 due to the risk of increased exposure of etrasimod (seesection 4.5).

Respiratory effects

Reductions in absolute forced expiratory volume over 1 second (FEV1) and forced vital capacity(FVC) were observed in patients treated with S1P receptor modulators, including etrasimod.

Etrasimod should be used with caution in patients with severe respiratory disease (e.g., pulmonaryfibrosis, asthma, and chronic obstructive pulmonary disease).

Tartrazine

This medicinal product contains tartrazine (E102) which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Effect of inhibitors of CYP2C8, CYP2C9, and CYP3A4 on etrasimod

The co-administration of etrasimod with steady state fluconazole (moderate CYP2C9 and CYP3A4inhibitor) increased exposure (AUC) of etrasimod by 84%. Co-administration of etrasimod with atherapeutic agent or a combination of agents that are moderate to strong inhibitors of two or more ofthe following CYP enzymes (CYP2C8, CYP2C9, and CYP3A4) (e.g., fluconazole) increases theexposure 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 etrasimodwith a therapeutic agent or a combination of agents that are moderate to strong inducers of two ormore 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 patientswho are known or suspected to be CYP2C9 poor metabolisers (< 5% of the population) and who takemedicinal products that are moderate or strong inhibitors of CYP2C8 and/or CYP3A4 is notrecommended (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 oratrioventricular conduction because of the potential additive effects on lowering heart rate (seesection 4.4).

Anti-arrhythmic medicinal products, QT prolonging medicinal products, medicinal products that maydecrease 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-arrhythmicmedicinal products have been associated with cases of Torsades de Pointes in patients withbradycardia. If treatment with etrasimod is considered in patients on Class Ia or Class IIIanti-arrhythmic medicinal products, advice from a cardiologist should be sought (see section 4.4).

Due to the potential additive effects on heart rate, if treatment initiation with etrasimod is consideredin patients on QT prolonging medicinal products, advice from a cardiologist should be sought(see section 4.4).

Anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies

Etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, ornon-corticosteroid immunosuppressive therapies. Caution should be used during concomitantadministration because of the risk of additive immune system effects during such therapy and in theweeks following administration (see section 4.4).

Vaccinations may be less effective if administered during and for up to 2 weeks after discontinuationof treatment with etrasimod. The use of live attenuated vaccine may carry the risk of infection andshould therefore be avoided during etrasimod treatment and for at least 2 weeks after discontinuationof treatment with etrasimod (see section 4.4).

No clinically significant differences in the pharmacokinetics and pharmacodynamics of an oralcontraceptive containing 30 mcg ethinyl oestradiol and 150 mcg levonorgestrel were observed whenco-administered with etrasimod. Co-administration of etrasimod with an oral contraceptive containingethinyl oestradiol and levonorgestrel increases AUC values of the ethinyl oestradiol and levonorgestrelby approximately 24% and 32%, respectively.

Interaction studies have only been performed in adults.

Velsipity is contraindicated in women of childbearing potential not using effective contraception (seesection 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negativepregnancy test result must be available and counselling should be provided regarding the serious riskto the foetus. Due to the time it takes to eliminate etrasimod from the body after stoppingtreatment, the potential risk to the foetus may persist and women of childbearing potential must useeffective contraception during etrasimod treatment and for at least 14 days after treatmentdiscontinuation (see section 4.4).

Specific measures are also included in the Healthcare Professional checklist. These measures must beimplemented before etrasimod is prescribed to female patients and during treatment.

There is a limited amount of data from the use of etrasimod in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). Clinical experience with anothersphingosine-1-phosphate receptor modulator indicated a 2-fold higher risk of major congenitalmalformations when administered during pregnancy compared with the rate observed in the generalpopulation. Based on human experience etrasimod may cause congenital malformations whenadministered during the first trimester of pregnancy. The limited human data available for etrasimodalso suggest an increased risk of abnormal pregnancy outcomes. Consequently, Velsipity iscontraindicated during pregnancy (see section 4.3).

Etrasimod should be stopped at least 14 days before a pregnancy is planned (see section 4.4). If awoman becomes pregnant during treatment, etrasimod must be immediately discontinued. Medicaladvice should be given regarding the risk of harmful effects to the foetus associated with treatment andfollow-up examinations should be performed.

It is unknown whether etrasimod is excreted in human milk. A study in lactating rats has indicatedexcretion of etrasimod in milk (see section 5.3). A risk to newborns/infants cannot be excluded.

Etrasimod should not be used during breast-feeding.

The effect of etrasimod on human fertility has not been evaluated. In animal studies, no adverse effectson fertility were observed (see section 5.3).

Etrasimod has no or negligible influence on the ability to drive and use machines.

However, patients who experience dizziness after taking etrasimod should refrain from driving orusing machines until the dizziness resolves (see section 4.8).

The most common adverse reactions are lymphopenia (11%) and headache (7%).

The adverse reactions observed in patients treated with etrasimod are listed below by system organclass (SOC) and frequency category. Within each SOC and frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000to < 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 tractinfectionb

Blood and lymphatic Lymphopeniac Neutropeniasystem disorders

Metabolism and Hypercholesterolaemiadnutrition disorders

Nervous system Headache, dizzinessdisorders

Eye disorders Visual impairment Macular oedema

Cardiac disorders Bradycardiae Atrioventricular blockf

Vascular disorders Hypertension

Hepatobiliary Hepatic enzyme increaseddisordersa 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 adversereactions” below.

Bradyarrhythmia

In ELEVATE UC 52 and ELEVATE UC 12, bradycardia was reported as an AE on the day oftreatment initiation in 1.5% of patients treated with etrasimod. On Day 2, bradycardia was reported asan AE in 0.4% of patients treated with etrasimod. Bradycardia was recorded more frequently on ECGmonitoring (see section 5.1).

In ELEVATE UC 52 and ELEVATE UC 12, on the day of treatment initiation, events of first- orsecond-degree Mobitz type I AV blocks were reported as an AE in 0.6% of patients treated withetrasimod. Events of AV block were mostly transient and asymptomatic. PR interval prolongation wasrecorded more frequently on ECG monitoring (see section 5.1).

In ELEVATE UC 52 and ELEVATE UC 12, the overall rate of infections and rate of seriousinfections in patients treated with etrasimod was comparable to that in patients who received placebo(18.8% vs 17.7% and 0.6% vs 1.9%, respectively). Etrasimod increased the risk of urinary tractinfections and lower respiratory tract infections (see Table 1).

Blood lymphocyte count and neutrophil count reduction

Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs,reducing the number of lymphocytes in peripheral blood (see section 5.1). The proportion of patientstreated with etrasimod who experienced lymphocyte counts less than 0.2 x 109/L was 3.5% in

ELEVATE UC 52 and ELEVATE UC 12. These events did not lead to treatment discontinuation.

Etrasimod caused a reversible decrease in neutrophil count; the proportion of patients treated withetrasimod who experienced neutrophil counts less than 0.5 x 109/L was 0.2% in ELEVATE UC 52 and

ELEVATE UC 12. These events did not lead to treatment discontinuation.

Elevated hepatic enzymes

In ELEVATE UC 52 and ELEVATE UC 12, elevations of ALT to 5-fold and 3-fold the ULN orgreater occurred in 0.9% and 4.0% of patients treated with etrasimod, respectively.

The majority (75%) of patients with ALT greater than 3-fold the ULN continued treatment withetrasimod with values returning to less than 3-fold the ULN while on treatment.

Overall, the percentage of discontinuation because of elevations in hepatic enzymes was 0.4% inpatients treated with etrasimod.

Hepatic enzyme increased includes events of gamma glutamyl transferase increased, alanineaminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepaticfunction abnormal, liver disorder, liver function test abnormal, and transaminases increased (see

Table 1).

In ELEVATE UC 52 and ELEVATE UC 12, patients treated with etrasimod had an average increaseof approximately 1 to 4 mm Hg in systolic blood pressure and approximately 1 to 2 mm Hg indiastolic blood pressure. The increase was first detected after 2 weeks of treatment and remainedwithin the specified average range in blood pressure increases throughout treatment. Hypertension wasreported as an adverse reaction in 2.1% of patients treated with etrasimod. All the events were mild tomoderate in severity.

Macular oedema

In ELEVATE UC 52 and ELEVATE UC 12, macular oedema was reported in 0.4% of patients treatedwith etrasimod.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In patients with overdose of etrasimod, signs and symptoms of bradycardia should be monitored,which may include overnight monitoring. Regular measurements of heart rate, blood pressure, and

ECGs should be performed. There is no specific antidote to etrasimod available. The decrease in heartrate induced by etrasimod can be reversed by parenteral atropine.

Pharmacotherapeutic group: Immunosuppressants, sphingosine 1-phosphate (S1P) receptormodulators, etrasimod ATC code: L04AE05

Etrasimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds to S1P receptors 1, 4 and5 (S1P1,4,5) and is a balanced G-protein and beta-arrestin agonist at S1P1. Etrasimod has minimalactivity on S1P3 and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity oflymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral bloodthereby lowering the number of activated lymphocytes in the tissue.

The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve thereduction of lymphocyte migration into sites of inflammation. The etrasimod-induced reduction oflymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, withgreater decreases in cells involved in the adaptive immune response known to be involved in driving

UC pathology. Etrasimod has minimal impact on cells involved in innate immune response, whichcontribute to immunosurveillance.

Heart rate and rhythm

Etrasimod may result in a transient decrease in heart rate and AV conduction upon treatment initiation(see sections 4.4 and 4.8). On Day 1, in UC patients from ELEVATE UC 52 and ELEVATE UC 12,33% of subjects had bradycardia (nadir HR below 60 bpm within the first 4 hours), or significantbradycardia in 2.5% (HR nadir below 50 bpm). No patients had HR < 40 bpm following the first dose.

The greatest mean decrease in heart rate was observed at Hour 2 or 3 post dose. On Day 1, the mean(SD) change in PR interval from predose to 4 hours post dose with etrasimod was 5.5 msec (18.84).

PR interval prolongation > 200 msec was recorded on ECG in 5.1% and higher degree prolongation(> 230 msec) in 1.8% of subjects.

Reduction in blood lymphocyte and neutrophil counts

In controlled clinical studies, mean lymphocyte counts decreased to approximately 50% of baseline at2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) consistent with the mechanism ofaction, and lowered lymphocyte counts were maintained during once daily treatment with etrasimod.

A reduction in neutrophil counts was observed in controlled clinical studies with etrasimod, meanneutrophil counts were generally in the normal range during etrasimod treatment. Lowered neutrophilcounts were maintained on etrasimod treatment and were reversible upon treatment discontinuation.

Peripheral blood B cells [CD19+] and T cells [CD3+], T-helper [CD3+CD4+], and T-cytotoxic[CD3+CD8+] cell subsets were all reduced, while natural killer cells and monocytes were not. T-helpercells were more sensitive to the effects of etrasimod than T-cytotoxic cells.

Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of patients within1 to 2 weeks of stopping therapy based on a population pharmacokinetic/pharmacodynamic model.

The efficacy of etrasimod were evaluated in 2 randomised, double-blind, placebo-controlledclinical studies (ELEVATE UC 52 and ELEVATE UC 12) in patients 16 to 80 years of age withmoderately to severely active ulcerative colitis.

Both studies included patients who had an inadequate response, loss of response, or intolerance toone or more of the following treatment options: oral aminosalicylates, corticosteroids, thiopurines,

Janus kinase (JAK) inhibitors, or a biologic (e.g., TNF blocker, anti-integrin, anti-IL12/23).

Enrolled patients had UC confirmed by endoscopy and histopathology with the extent of diseasebeing ≥ 10 cm from the anal verge. Patients with isolated proctitis were also included in the studyprovided they met all other inclusion criteria.

Enrolled patients had a modified Mayo score (mMS) of 4 to 9 with an endoscopy score (ES) ≥ 2and rectal bleeding (RB) subscore ≥ 1. The primary evaluation was based on the population with amMS of 5 to 9. Patients enrolled across the two studies had a mean age of 40 years with 3 (0.4%)patients less than 18 years of age and 45 (6%) patients 65 years of age or higher; 57% were male,82% were White, and 13% were Asian.

Patients in these studies may have received the following concomitant UC therapies: stable dailydoses of oral aminosalicylates and/or oral corticosteroids (≤ 20 mg prednisone, ≤ 9 mg budesonide,or equivalent steroid). Concomitant treatment with immunomodulators, biologic therapies, rectal5-ASA, or rectal corticosteroids was not permitted.

ELEVATE UC 52

ELEVATE UC 52 was a “treat-through” study, with a total of 433 patients randomised to receiveetrasimod 2 mg or placebo at a 2:1 ratio administered orally once daily. Patients remained on theirassigned treatment for the duration of the study.

At baseline, enrolled patients had a median mMS of 7, 8% of enrolled patients presented withisolated proctitis. A total of 30% of patients had prior exposure to biologic/JAK inhibitors; a totalof 14% of patients had exposure to > 1 biologic/JAK inhibitor and 11% of patients had priorexposure to anti-integrins. At baseline, 77% of patients were receiving oral aminosalicylates and31% of patients were receiving oral corticosteroids.

The co-primary endpoints were the proportion of patients achieving clinical remission at Week 12and at Week 52, with clinical remission defined as stool frequency (SF) subscore of 0 (or 1 with a≥ 1-point decrease from baseline), RB subscore of 0, and ES ≤ 1 (excluding friability). Thesecondary endpoints included the proportion of patients achieving endoscopic improvement,symptomatic remission, mucosal healing, clinical response, corticosteroid-free clinical remission,and sustained clinical remission. The primary analysis was conducted at Week 12 and at Week 52in patients with moderately to severely active disease, defined as mMS 5 to 9 (see Table 2).

Of the 433 patients randomised, 91.7% and 86.1% of the patients completed Week 12 in theetrasimod and placebo group, respectively. Beginning with Week 12, patients with noimprovement from baseline or who met disease worsening criteria could discontinue per thediscretion of the investigator and could continue in the open label extension study. In this treat-through study 55.7% and 31.9% completed Week 52 treatment in the etrasimod and placebo group,respectively.

A significantly greater proportion of patients treated with etrasimod achieved clinical remission,endoscopic improvement, symptomatic remission, and mucosal healing at Week 12 and at

Week 52, corticosteroid-free clinical remission and sustained clinical remission at Week 52,compared to placebo (see Table 2).

Table 2: Proportion of patients meeting efficacy endpoints at Week 12 and at Week 52 in

ELEVATE UC 52

Placebo Etrasimod 2 mg Treatment

N = 135 N = 274 differencen % n % (95% CI)a

Week 12 endpoints20%

Clinical remissionb 10 7% 74 27%(13%, 27%)l

No prior biologic/9/93 10% 60/194 31%

JAK inhibitor exposure

Prior biologic/1/42 2% 14/80 18%

JAK inhibitor exposure21%

Endoscopic improvementc 19 14% 96 35%(13%, 29%)l

No prior biologic/17/93 18% 76/194 39%

JAK inhibitor exposure

Prior biologic/2/42 5% 20/80 25%

JAK inhibitor exposured 25%

Symptomatic remission 29 22% 126 46%(15%, 34%)l

No prior biologic/22/93 24% 101/194 52%

JAK inhibitor exposure

Prior biologic/7/42 17% 25/80 31%

JAK inhibitor exposure

Mucosal healinge 17%6 4% 58 21%(11%, 23%)l

Placebo Etrasimod 2 mg Treatment

N = 135 N = 274 differencean % n % (95% CI)

No prior biologic/6/93 7% 47/194 24%

JAK inhibitor exposure

Prior biologic/0/42 0% 11/80 14%

JAK inhibitor exposure28%

Clinical responsef 46 34% 171 62%(19%, 38%)l

No prior biologic/35/93 38% 132/194 68%

JAK inhibitor exposure

Prior biologic/11/42 26% 39/80 49%

JAK inhibitor exposure

Week 52 endpoints25%

Clinical remissionb 9 7% 88 32%(18%, 32%)l

No prior biologic/7/93 8% 71/194 37%

JAK inhibitor exposure

Prior biologic/2/42 5% 17/80 21%

JAK inhibitor exposure27%

Endoscopic improvementc 14 10% 102 37%(19%, 34%)l

No prior biologic/12/93 13% 78/194 40%

JAK inhibitor exposure

Prior biologic/2/42 5% 24/80 30%

JAK inhibitor exposure25%

Symptomatic remissiond 25 19% 119 43%(16%, 34%)l

No prior biologic/19/93 20% 97/194 50%

JAK inhibitor exposure

Prior biologic/6/42 14% 22/80 28%

JAK inhibitor exposure18%

Mucosal healinge 11 8% 73 27%(11%, 25%)l

No prior biologic/10/93 11% 55/194 28%

JAK inhibitor exposure

Prior biologic/1/42 2% 18/80 23%

JAK inhibitor exposuref 25%

Clinical response 31 23% 132 48%(16%, 34%)l

No prior biologic/25/93 27% 103/194 53%

JAK inhibitor exposure

Prior biologic/6/42 14% 29/80 36%

JAK inhibitor exposure

Sustained clinical 16%g 3 2% 49 18%remission (11%, 21%)l

No prior biologic/2/93 2% 41/194 21%

JAK inhibitor exposure

Placebo Etrasimod 2 mg Treatment

N = 135 N = 274 differencen % n % (95% CI)a

Prior biologic/1/42 2% 8/80 10%

JAK inhibitor exposure

Corticosteroid-free clinical 25%9 7% 88 32%remissionh (18%, 32%)l

No prior biologic/7/93 8% 71/194 37%

JAK inhibitor exposure

Prior biologic/2/42 5% 17/80 21%

JAK inhibitor exposure

Corticosteroid-free clinicalremission among patients 23%3/40 8% 27/87 31%treated with (10%, 36%)lcorticosteroids at baselinei

No prior biologic/2/26 8% 22/59 37%

JAK inhibitor exposure

Prior biologic/1/14 7% 5/28 18%

JAK inhibitor exposure

Corticosteroid-free 25%j 25 19% 119 43%symptomatic remission (16%, 34%)l

No prior biologic/19/93 20% 97/194 50%

JAK inhibitor exposure

Prior biologic/6/42 14% 22/80 28%

JAK inhibitor exposure

Corticosteroid-free 26%14 10% 101 37%endoscopic improvementk (19%, 34%)l

No prior biologic/12/93 13% 78/194 40%

JAK inhibitor exposure

Prior biologic/2/42 5% 23/80 29%

JAK inhibitor exposurea Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroiduse at baseline, and baseline mMS group).b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline),

RB subscore of 0, and ES ≤ 1 (excluding friability).c Endoscopic improvement was defined as ES ≤ 1 (excluding friability).d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline) and

RB subscore of 0.e Mucosal healing was defined as ES ≤ 1 (excluding friability) with histologic remission (Geboes Index score< 2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no cryptdestruction, erosions, ulcerations, or granulation tissue).f Clinical response was defined as a ≥ 2-point and ≥ 30% decrease from baseline in mMS, and a ≥ 1-pointdecrease from baseline in RB subscore or an absolute RB subscore ≤ 1.g Sustained clinical remission was defined as clinical remission at both Week 12 and Week 52.h Corticosteroid-free clinical remission was defined as clinical remission at Week 52 without receivingcorticosteroids for at least 12 weeks immediately prior to Week 52.i Corticosteroid-free clinical remission among patients treated with corticosteroids at baseline was defined asclinical remission at Week 52 without receiving corticosteroids for at least 12 weeks immediately prior to Week52 among patients treated with corticosteroids at baseline.j Corticosteroid-free symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decreasefrom baseline) and RB subscore of 0 for at least 12 weeks immediately prior to Week 52.k Corticosteroid-free endoscopic improvement was defined as ES ≤ 1 (excluding friability) for at least 12 weeksimmediately prior to Week 52.

l p < 0.001.

Supplementary analysis of mMS 4

The efficacy results in patients with mMS of 4 (including ES ≥ 2 and RB subscore ≥ 1) wereconsistent with those of the primary analysis.

Isolated proctitis

A greater proportion of patients with isolated proctitis at baseline treated with etrasimod compared toplacebo achieved clinical remission at Week 12 (46% vs 29%) and Week 52 (42% vs 14%).

Early onset of symptomatic improvement

At Week 2 (first study visit), a greater proportion of patients treated with etrasimod compared toplacebo achieved symptomatic remission (16% vs 11%). At Week 4, a greater proportion of patientstreated with etrasimod compared to placebo achieved complete symptomatic remission (11% vs 4%)defined as a SF subscore of 0 and RB subscore of 0.

Endoscopic and histologic assessment

Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ESof 0. A greater proportion of patients treated with etrasimod compared to placebo achieved endoscopicremission by Week 12 (15% vs 4%), Week 52 (26% vs 6%), and both Week 12 and Week 52(11% vs 2%).

Endoscopic remission and Geboes histologic score < 2.0 (indicating no neutrophils in crypts or laminapropria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulationtissue) were achieved by a greater proportion of patients treated with etrasimod compared to placeboat Week 12 (11% vs 2%) and at Week 52 (18% vs 5%).

Abdominal pain and bowel urgency

At Week 12, a greater proportion of patients treated with etrasimod compared to placebo had absenceof abdominal pain (27% vs 13%) and absence of bowel urgency (19% vs 7%). At Week 52, a greaterproportion of patients treated with etrasimod compared to placebo had absence of abdominal pain(22% vs 7%) and absence of bowel urgency (19% vs 8%).

Inflammatory bowel disease questionnaire (IBDQ)

Patients treated with etrasimod compared to placebo demonstrated greater improvement from baselinein the total IBDQ score. Changes in IBDQ total score at Week 12 from baseline with etrasimodcompared to placebo were 42.8 and 27.4, respectively and changes in IBDQ total score at Week 52from baseline with etrasimod compared to placebo were 55.8 and 38.1, respectively.

ELEVATE UC 12

In ELEVATE UC 12, a total of 354 patients were randomised to receive etrasimod 2 mg or placebo ata 2:1 ratio administered orally once daily.

At baseline, enrolled patients had a median mMS of 7, with 5.6% of patients having mMS of 4, and67% having mMS 5 to 7 (moderately active disease), and 27.4% having mMS > 7 (severely activedisease). 8% of enrolled patients presented with isolated proctitis. A total of 33% of patients had priorexposure to biologic/JAK inhibitors; a total of 18% of patients had exposure to > 1 biologic/JAKinhibitor and 12% of patients had prior exposure to anti-integrins. At baseline, 83% of patients werereceiving oral aminosalicylates and 28% of patients were receiving oral corticosteroids.

Of the 354 patients randomised, 89.5% and 88.8% of the patients completed Week 12 in the etrasimodand placebo group, respectively.

The primary endpoint was the proportion of patients achieving clinical remission at Week 12. Thesecondary endpoints included the proportion of patients achieving endoscopic improvement,symptomatic remission, mucosal healing, and clinical response at Week 12. The primary analysis wasconducted at Week 12 in patients with moderately to severely active disease, defined as mMS 5 to 9(see Table 3).

A significantly greater proportion of patients treated with etrasimod achieved clinical remission,endoscopic improvement, symptomatic remission, and mucosal healing at Week 12, compared toplacebo (see Table 3).

Table 3: Proportion of patients meeting efficacy endpoints at Week 12 in ELEVATE UC 12

Endpoints Placebo Etrasimod 2 mg Treatment

N = 112 N = 222 differencen % n % (95% CI)a10%

Clinical remissionb 17 15% 55 25%(1%, 18%)g

No prior biologic/JAK12/74 16% 41/148 28%inhibitor exposure

Prior biologic/JAK5/38 13% 14/74 19%inhibitor exposure12%

Endoscopic improvementc 21 19% 68 31%(3%, 21%)g

No prior biologic/JAK14/74 19% 51/148 35%inhibitor exposure

Prior biologic/JAK7/38 18% 17/74 23%inhibitor exposure17%

Symptomatic remissiond 33 30% 104 47%(7%, 28%)g

No prior biologic/JAK23/74 31% 73/148 49%inhibitor exposure

Prior biologic/JAK10/38 26% 31/74 42%inhibitor exposure7%

Mucosal healinge 10 9% 36 16%(1%, 14%)g

No prior biologic/JAK8/74 11% 28/148 19%inhibitor exposure

Prior biologic/JAK2/38 5% 8/74 11%inhibitor exposure21%

Clinical responsef 46 41% 138 62%(10%, 32%)h

No prior biologic/JAK32/74 43% 97/148 66%inhibitor exposure

Prior biologic/JAK14/38 37% 41/74 55%inhibitor exposurea Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroiduse at baseline, and baseline mMS group).b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscoreof 0, and ES ≤ 1 (excluding friability).c Endoscopic improvement was defined as ES ≤ 1 (excluding friability).d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline) and RBsubscore of 0.e Mucosal healing was defined as ES ≤ 1 (excluding friability) with histologic remission (Geboes Index score< 2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no cryptdestruction, erosions, ulcerations, or granulation tissue).f Clinical response was defined as a ≥ 2-point and ≥ 30% decrease from baseline in mMS, and a ≥ 1-pointdecrease from baseline in RB subscore or an absolute RB subscore ≤ 1.g p < 0.05.h p < 0.001.

Supplementary analysis of mMS 4

The efficacy results in patients with mMS of 4 (including ES ≥ 2 and RB subscore ≥ 1) wereconsistent with those of the primary analysis.

Isolated proctitis

A greater proportion of patients with isolated proctitis at baseline treated with etrasimod compared toplacebo achieved clinical remission at Week 12 (39% vs 8%).

Early onset of symptomatic improvement

At Week 4, a greater proportion of patients treated with etrasimod compared to placebo achievedsymptomatic remission (28% vs 16%) and complete symptomatic remission (12% vs 4%) defined as a

SF subscore of 0 and RB subscore of 0.

Endoscopic and histologic assessment

Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as

ES of 0. A greater proportion of patients treated with etrasimod compared to placebo achievedendoscopic remission by Week 12 (17% vs 8%).

Endoscopic remission and Geboes histologic score < 2.0 (indicating no neutrophils in crypts or laminapropria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulationtissue) were achieved by a greater proportion of patients treated with etrasimod compared to placeboat Week 12 (10% vs 5%).

Abdominal pain and bowel urgency

At Week 12, a greater proportion of patients treated with etrasimod compared to placebo had absenceof abdominal pain (32% vs 18%) and absence of bowel urgency (21% vs 12%).

Inflammatory bowel disease questionnaire (IBDQ)

Patients treated with etrasimod compared to placebo demonstrated greater improvement from baselinein the total IBDQ score. Changes in IBDQ total score at Week 12 from baseline with etrasimodcompared to placebo were 47.5 and 30.2, respectively.

The European Medicines Agency has deferred the obligation to submit the results of studies withetrasimod in one or more subsets of the paediatric population in UC (see section 4.2 for information onpaediatric use).

Following etrasimod single oral dosing, Cmax and AUC increased approximately dose-proportionally inthe dose-range studied (0.1 mg to 5 mg). Following multiple dosing, mean Cmax and AUC increasedslightly more than dose proportional from 0.7 mg to 2 mg. Steady state plasma concentrations arereached within 7 days following 2 mg once daily dosing, with a mean Cmax of 113 ng/mL and

AUCtau of 2163 h*ng/mL. Estimated steady state etrasimod accumulation ratio ranges from about 2- to3-fold. The pharmacokinetics of etrasimod is similar in healthy subjects and subjects with UC.

The time (Tmax) to reach maximum plasma concentrations (Cmax) after oral administration ofimmediate release oral pharmaceutical forms of etrasimod is approximately 4 hours (range 2-8 hours).

Etrasimod absorption is extensive, based on high permeability and observation of relatively little intactetrasimod eliminated in the faeces (11.2% of administered radioactive dose).

Food intake can result in slightly delayed absorption (the median Tmax increased by 2 hours). Fooddoes not have an effect on etrasimod exposure measures (Cmax and AUC); therefore, etrasimod can beadministered without regard to meals.

Etrasimod distributes to body tissues with a mean oral volume of distribution (Vz/F) of 66 L.

Etrasimod is highly bound to human plasma proteins (97.9%), primarily albumin and mainlydistributed in the plasma fraction of whole blood with blood-to-plasma ratio of 0.7.

Etrasimod is extensively metabolised via CYP2C8 (38%), CYP2C9 (37%), and CYP3A4 (22%), andwith minor contributions via CYP2C19 and CYP2J2. The major circulating component in plasma isunchanged etrasimod and main metabolites M3 and M6. Etrasimod contributes to the majority of S1Ppharmacology (> 90%). Etrasimod is extensively metabolised by oxidation, dehydrogenation, andconjugation by UGTs and sulfotransferases.

Etrasimod is not a substrate of P-gp, BCRP, OATP1B1/3, OAT1/3, or OCT1/2 transporters. Medicinalproducts that are inhibitors of these transporters are unlikely to impact the pharmacokinetics ofetrasimod.

After oral administration, the apparent steady state oral clearance (CL/F) was approximately 1 L/h.

The mean plasma effective elimination half-life (t1/2) of etrasimod is approximately 30 hours.

Excretion

Etrasimod is primarily eliminated hepatically with 82% recovery of a total radioactive dose in thefaeces and 4.89% in the urine. Unchanged etrasimod was only detected in faeces, but not in urine.

Effect of etrasimod on other medicinal products

In vitro studies indicate that, at the recommended dose of 2 mg once daily, etrasimod is unlikely toshow any clinically relevant interaction potential for CYP or membrane transporters.

Pharmacokinetics in specific groups of patients

No dose adjustments are needed in patients with renal impairment as Cmax and AUC were comparablebetween subjects with severe renal impairment and subjects with normal renal function (see section4.2). The severe renal impairment cohort included 2 subjects with eGFR ≤ 29 mL/min (not onhaemodialysis), and 6 subjects with ESRD who received haemodialysis prior to administration ofetrasimod. The impact of haemodialysis performed after etrasimod administration has not beenevaluated.

Etrasimod is contraindicated in patients with severe hepatic impairment. No dose adjustments areneeded in patients with mild or moderate hepatic impairment (see section 4.2). The total etrasimod

AUC parameters are 13%, 29%, and 57% higher in subjects with mild, moderate, and severe hepaticimpairment, respectively, compared with subjects with normal liver function for the 2 mg single dosestudied.

Population pharmacokinetic analyses showed that age did not have an effect on the pharmacokineticsof etrasimod in patients over 65 years of age (n=40 (3.7%) of patients were aged ≥ 65). There is nomeaningful difference in the pharmacokinetics in elderly patients compared to younger patients.

The systemic exposure of etrasimod 2 mg is not altered by body weight differences to a clinicallymeaningful extent in patients with body weight ≥ 40 kg. In patients with body weight below 40 kg, anapproximately 1.5-fold increase in exposure is predicted (see section 4.2).

Sex, race, and ethnicity

Population pharmacokinetics analysis showed that sex, race, or ethnicity has no clinicially significanteffect on etrasimod pharmacokinetics.

Paediatric

A population pharmacokinetics analysis predicted similar etrasimod exposures in adult and olderadolescent (16 to < 18 years old) patients with UC.

No data are available on administration of etrasimod to paediatric or adolescent patients below the ageof 16 years.

Nonclinical data reveal no special hazard for etrasimod in humans with the following exception:changes in the left ventricular arteries (hypertrophy/hyperplasia of the tunica media) were observed in3- and 9- month repeat-dose toxicity studies in dogs at exposures ≥ 24 times the recommended humandose (RHD) exposure based on AUC. The relevance of this finding for humans is uncertain.

Furthermore, the exposure to the most abundant human metabolites (M3 and M6) was investigated inrats only. The relevance for humans is uncertain.

Fertility and reproductive toxicity

Etrasimod did not affect male and female fertility in rats up to the highest dose tested, representing anapproximate 467-fold exposure margin based on human systemic exposures at the RHD for males and21-fold for females.

Etrasimod administration to pregnant rats and rabbits daily during organogenesis resulted inpost-implantation loss with a corresponding lower number of viable foetuses and foetal external,visceral, and/or skeletal malformations and variations in the absence of maternal toxicity.

Malformations were observed at the lowest dose tested in rats with maternal plasma AUCapproximately 5 times that in humans at the RHD. The exposure at the no-adverse-effect dose(2 mg/kg/day) in the rabbit was approximately 0.8 times, that in humans at the RHD of 2 mg/day.

Following daily oral administration of etrasimod through pregnancy and lactation in rats, decreasedmean pup weights, lower pup viability, and reduced fertility and reproductive performance (reductionin implantations and increased preimplantation loss) in F1 pups were observed. Plasma exposure(AUC) in dams at the lowest dose tested was equivalent (1.1 times) to those in humans at the RHD.

Etrasimod was detected in the plasma of F1 pups, indicating exposure from the milk of the lactatingdam.

Magnesium stearate (E470b)

Mannitol (E421)

Microcrystalline cellulose (E460i)

Sodium starch glycolate (Type A)

Brilliant blue FCF aluminium lake (E133)

Indigo carmine aluminium lake (E132)

Tartrazine aluminium lake (E102)

Macrogol 4000 (E1521)

Poly(vinyl alcohol) (E1203)

Talc (E553b)

Titanium dioxide (E171)

Not applicable.

3 years

This medicinal product does not require any special temperature storage conditions. Store in theoriginal package in order to protect from moisture.

High-density polyethylene (HDPE) bottle closed with a polypropylene cap, desiccant integrateddirectly into the cap. Pack size of 30 film-coated tablets.

Aluminium blister strip laminated to an oriented polyamine (oPA) film and integrated desiccant layer(HDPE/LDPE), with a paper/aluminium/LDPE backing. Pack size of 28 or 98 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Brussels

Belgium

EU/1/23/1790/001

EU/1/23/1790/002

EU/1/23/1790/003

Date of first authorisation: 16 February 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.