ZEPOSIA 0.92mg capsules medication leaflet

Zeposia 0.23 mg hard capsules

Zeposia 0.46 mg hard capsules

Zeposia 0.92 mg hard capsules

Zeposia 0.23 mg hard capsules

Each hard capsule contains ozanimod hydrochloride equivalent to 0.23 mg ozanimod.

Zeposia 0.46 mg hard capsules

Each hard capsule contains ozanimod hydrochloride equivalent to 0.46 mg ozanimod.

Zeposia 0.92 mg hard capsules

Each hard capsule contains ozanimod hydrochloride equivalent to 0.92 mg ozanimod.

For the full list of excipients, see section 6.1.

Hard capsule

Zeposia 0.23 mg hard capsules

Light grey opaque hard capsule, 14.3 mm, imprinted in black ink with “OZA” on the cap and“0.23 mg” on the body.

Zeposia 0.46 mg hard capsules

Light grey opaque body and orange opaque cap hard capsule, 14.3 mm, imprinted in black ink with“OZA” on the cap and “0.46 mg” on the body.

Zeposia 0.92 mg hard capsules

Orange opaque hard capsule, 14.3 mm, imprinted in black ink with “OZA” on the cap and “0.92 mg”on the body.

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.

Zeposia is indicated for the treatment of adult patients with moderately to severely active ulcerativecolitis (UC) who have had an inadequate response, lost response, or were intolerant to eitherconventional therapy or a biologic agent.

Treatment should be initiated under the supervision of a physician experienced in the management ofmultiple sclerosis (MS) or ulcerative colitis (UC).

The initial dose escalation regimen of ozanimod from Day 1 to Day 7 is required and shown below in

Table 1. Following the 7-day dose escalation, the recommended dose is 0.92 mg ozanimod once daily,starting on Day 8.

Table 1: Dose escalation regimen

Days 1 - 4 0.23 mg once daily

Days 5 - 7 0.46 mg once daily

Days 8 and thereafter 0.92 mg once daily

Re-initiation of therapy following treatment interruption

The same dose escalation regimen described in Table 1 is recommended when treatment is interruptedfor:

* 1 day or more during the first 14 days of treatment.

* more than 7 consecutive days between Day 15 and Day 28 of treatment.

* more than 14 consecutive days after Day 28 of treatment.

If the treatment interruption is of shorter duration than the above, the treatment should be continuedwith the next dose as planned.

Adults over 55 years old and elderly population

There are limited data available on RRMS patients > 55 years of age and on UC patients ≥ 65 years ofage. No dose adjustment is needed in patients over 55 years of age. Caution should be used in MSpatients over 55 years and in UC patients over 65 years of age, given the limited data available andpotential for an increased risk of adverse reactions in this population, especially with long-termtreatment (see sections 5.1 and 5.2).

No dose adjustment is necessary for patients with renal impairment.

Patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B) arerecommended to complete the 7-day dose escalation regimen, and then take 0.92 mg once every otherday (see section 5.2).

Ozanimod was not evaluated in patients with severe hepatic impairment. Therefore, patients withsevere hepatic impairment (Child-Pugh class C) must not be treated with ozanimod (see sections 4.3and 5.2).

The safety and efficacy of Zeposia in children and adolescents aged below 18 years have not yet beenestablished. No data are available.

Oral use.

The capsules can be taken with or without food.

* 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 hospitalisationor 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 (seesection 4.4).

* Active malignancies.

* Severe hepatic impairment (Child-Pugh class C).

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

Bradyarrhythmia

Initiation of treatment with ozanimod

Prior to treatment initiation with ozanimod, an electrocardiogram (ECG) in all patients should beobtained to determine whether any pre-existing cardiac abnormalities are present. In patients withcertain 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 8should 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 meanreduction at Hour 5, returning towards baseline at Hour 6. With continued dose escalation, there wereno clinically relevant HR decreases. Heart rates below 40 beats per minute were not observed. Ifnecessary, the decrease in HR induced by ozanimod can be reversed by parenteral doses of atropine orisoprenaline.

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 foradditive effects on lowering HR. Beta-blockers and calcium-channel blockers treatment can beinitiated in patients receiving stable doses of ozanimod.

The co-administration of ozanimod in patients on a beta-blocker in combination with a calciumchannel 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-hourmonitoring for signs and symptoms of symptomatic bradycardia is recommended in patients withresting HR < 55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction orheart failure (see section 4.3).

Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hourperiod. 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

* heart rate is the lowest value post-dose, suggesting that the maximum decrease in HR may nothave 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 cases, appropriate management should be initiated and observation continued until thesymptoms/findings have resolved. If medical treatment is required, monitoring should be continuedovernight, and a 6-hour monitoring period should be repeated after the second dose of ozanimod.

Cardiologist advice should be obtained before initiation of ozanimod in the following patients todecide if ozanimod can safely be initiated and to determine the most appropriate monitoring strategy

* history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreatedsleep apnoea, history of recurrent syncope or symptomatic bradycardia;

* pre-existing significant QT interval prolongation (QTc greater than 500 msec) or other risks for

QT prolongation, and patients on medicinal products other than beta-blockers and calcium-channel blockers that may potentiate bradycardia;

* Patients on class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol)antiarrhythmic medicinal products, which have been associated with cases of torsades depointes in patients with bradycardia have not been studied with ozanimod.

Liver injury

Elevations of aminotransferases, gamma-glutamyl transferase (GGT) and bilirubin have been reportedin patients treated with ozanimod (see section 4.8).

Clinically significant liver injury has occurred in patients treated with ozanimod in the post marketingsetting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin,have occurred as early as ten days after the first dose. Severe liver injury may result in the need for aliver transplant (see section 4.8).

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available beforeinitiation of treatment with ozanimod. In the absence of clinical symptoms, liver transaminases andbilirubin levels should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter.

If liver transaminases rise above 5 times the ULN, more frequent monitoring including serum bilirubinand alkaline phosphatase (ALP) should be instituted. If liver transaminases above 5 times the ULN areconfirmed, or at least 3 times the ULN associated with increase of serum bilirubin more than 2 timesthe ULN, treatment with ozanimod should be interrupted and only re-commenced once livertransaminase values have normalised (including if an alternative cause of the hepatic dysfunction isdiscovered).

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 and ozanimod should be discontinued if significant liver injury is confirmed.

Resumption of therapy will be dependent on whether another cause of liver injury is determined andon the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction.

Patients with pre-existing liver disease may be at increased risk of developing elevated hepaticenzymes when taking ozanimod (see section 4.2).

Ozanimod has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C)and must not be used in these patients (see section 4.3).

Immunosuppressive effects

Ozanimod has an immunosuppressive effect that predisposes patients to a risk of infection, includingopportunistic infections, and may increase the risk of developing malignancies, including those of theskin. Physicians should carefully monitor patients, especially those with concurrent conditions orknown factors, such as previous immunosuppressive therapy. If this risk is suspected, discontinuationof treatment should be considered by the physician on a case-by-case basis (see section 4.3).

Ozanimod causes a mean reduction in peripheral blood lymphocyte count to approximately 45% ofbaseline values because of reversible retention of lymphocytes in the lymphoid tissues. Ozanimodmay, therefore, increase the susceptibility to infections (see section 4.8).

A recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood cellcount (CBC) should be obtained, including lymphocyte count, before initiation of ozanimod.

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

The initiation of ozanimod administration in patients with any active infection should be delayed untilthe infection is resolved.

Patients should be instructed to report promptly 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, treatment interruption with ozanimod should beconsidered.

Because the elimination of ozanimod after discontinuation may take up to 3 months, monitoring forinfections should be continued throughout this period.

Prior and concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, orimmune-modulating therapies

In MS and UC clinical studies, patients who received ozanimod were not to receive concomitantantineoplastic, non-corticosteroid immunosuppressive (e.g. azathioprine and 6-mercaptopurine in UC),or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ozanimodwith any of these therapies would be expected to increase the risk of immunosuppression and shouldbe avoided.

In UC clinical studies, concomitant use of corticosteroids was allowed and did not appear to influencethe safety or efficacy of ozanimod, however, long-term data on concomitant use of ozanimod andcorticosteroids are still limited. When switching to ozanimod from immunosuppressive medicinalproducts, the half-life and mode of action must be considered to avoid an additive immune effectwhilst at the same time minimizing the risk of disease reactivation.

Ozanimod can generally be started immediately after discontinuation of interferon (IFN) or glatiramer.

PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) thattypically occurs in patients who are immunocompromised and may lead to death or severe disability.

PML has been reported in patients treated with ozanimod (see section 4.8). JCV infection resulting in

PML has been associated with some risk factors (e.g., polytherapy with immunosuppressants, severelyimmunocompromised patients). Typical symptoms associated with PML are diverse, progress overdays to weeks, and include 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 andpersonality changes.

Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML.

MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment withozanimod should be suspended until PML has been excluded. If confirmed, treatment with ozanimodshould be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with

S1P receptors modulators, who developed PML and subsequently discontinued treatment. IRISpresents as a clinical decline in the patient’s condition that may be rapid, can lead to seriousneurological complications or death, and is often associated with characteristic changes on MRI. Thetime to onset of IRIS in patients with PML was usually from weeks to months after S1P receptormodulator discontinuation. Monitoring for development of IRIS and appropriate treatment of theassociated inflammation should be undertaken.

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

The use of live attenuated vaccines should be avoided during and for 3 months after treatment withozanimod.

If live attenuated vaccine immunisations are required, these should be administered at least 1 monthprior to initiation of ozanimod. Varicella Zoster Virus (VZV) vaccination of patients withoutdocumented immunity to VZV is recommended prior to initiating treatment with ozanimod.

Cutaneous neoplasms

Half of the neoplasms reported with ozanimod in the MS controlled Phase 3 studies consisted ofnon-melanoma skin malignancies, with basal cell carcinoma presenting as the most common skinneoplasm and reported with similar incidence rates in the combined ozanimod (0.2%, 3 patients) and

IFN ß-1a (0.1%, 1 patient) groups.

In patients treated with ozanimod in UC controlled clinical studies one patient (0.2%) had squamouscell carcinoma of the skin, in the induction period, and one patient (0.4%) had basal cell carcinoma, inthe maintenance period. There were no cases in patients who received placebo.

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

Macular oedema

Macular oedema with or without visual symptoms was observed with ozanimod (see section 4.8) inpatients with pre-existing risk factors or comorbid conditions.

Patients with a history of uveitis or diabetes mellitus or underlying/co-existing retinal disease are atincreased risk of macular oedema (see section 4.8). It is recommended that patients with diabetesmellitus, uveitis or a history of retinal disease undergo an ophthalmological evaluation prior totreatment initiation with ozanimod and have follow up evaluations while receiving therapy.

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

Posterior reversible encephalopathy syndrome (PRES)

PRES is a syndrome characterised by sudden onset of severe headache, confusion, seizures and visualloss. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebralhaemorrhage. In MS controlled clinical trials with ozanimod, one case of PRES was reported in apatient with Guillain-Barré syndrome. If PRES is suspected, treatment with ozanimod should bediscontinued.

In MS and UC controlled clinical studies, hypertension was more frequently reported in patientstreated with ozanimod than in patients treated with IFN β-1a intra-muscular (IM) (MS) or placebo(UC) and in patients receiving concomitant ozanimod and SSRIs or SNRIs (see section 4.8). Bloodpressure should be regularly monitored during treatment with ozanimod.

Respiratory effects

Ozanimod should be used with caution in patients with severe respiratory disease, pulmonary fibrosisand chronic obstructive pulmonary disease.

The coadministration with inhibitors of monoamine oxidase (MAO), or CYP2C8 inducer (rifampicin)with ozanimod is not recommended (see section 4.5).

Due to risk to the foetus, ozanimod is contraindicated during pregnancy and in women of childbearingpotential not using effective contraception. Before initiation of treatment, women of childbearingpotential must be informed of this risk to the foetus, must have a negative pregnancy test and must useeffective contraception during treatment, and for 3 months after treatment discontinuation (seesections 4.3 and 4.6 and the information contained in the Healthcare Professional checklist).

Return of MS disease activity after ozanimod discontinuation

Severe exacerbation of disease, including disease rebound, has been rarely reported afterdiscontinuation of another S1P receptor modulator. In the ozanimod long-term extension study,following permanent discontinuation of ozanimod, clinical relapses were reported in 3.3% of patients,none with severe exacerbation of disease or severe increase in disability. Patients should be observedfor return of disease activity upon ozanimod discontinuation and appropriate treatment should beinstituted as required.

After stopping ozanimod in the setting of PML, it is recommended to monitor patients fordevelopment of immune reconstitution inflammatory syndrome (PML-IRIS) (see “Progressivemultifocal leukoencephalopathy” above).

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

Potassium content

This medicinal product contains less than 1 mmol potassium (39 mg) per capsule, that is to sayessentially ‘potassium-free’.

Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies

Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies should not becoadministered due to the risk of additive immune system effects (see sections 4.3 and 4.4).

During and for up to 3 months after treatment with ozanimod, vaccination may be less effective. Theuse of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided duringand 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, thecoadministration with Monoamine oxidase B (MAO-B) inhibitors may decrease exposure of the majoractive metabolites and may result in reduced clinical response. The coadministration of MAOinhibitors (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 inreduced clinical response. The coadministration of CYP2C8 inducers (i.e. rifampicin) with ozanimodis 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 acting80 mg once daily or diltiazem 240 mg once daily did not result in any additional clinically meaningfulchanges in HR and PR interval compared to either propranolol or diltiazem alone. Caution should beapplied 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 onantiarrhythmic medicinal products (which have been associated with cases of torsades de pointes inpatients 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 stateand a single dose of ozanimod 0.46 mg increased exposure (AUC) of the major active metabolites byapproximately 47% to 69%. Caution should be exercised for concomitant use of ozanimod with strong

CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel).

Effect of inhibitors of the breast cancer resistance protein (BCRP) on ozanimod

Coadministration of ozanimod with ciclosporin, a strong BCRP inhibitor, had no effect on theexposure of ozanimod and its major active metabolites (CC112273 and CC1084037).

Zeposia 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 confirmed and repeated at suitable intervals. Counselling should beprovided regarding the risk to the foetus. Women of childbearing potential must use effectivecontraception during ozanimod treatment and for 3 months after treatment discontinuation (seesection 4.4).

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

When stopping ozanimod therapy for planning a pregnancy the possible return of disease activityshould be considered (see section 4.4).

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, notablymalformations of blood vessels, generalised oedema (anasarca), and malpositioned testes andvertebrae (see section 5.3). Sphingosine 1-phosphate is known to be involved in vascular formationduring embryogenesis (see section 5.3).

Consequently, Zeposia is contraindicated during pregnancy (see section 4.3). Zeposia should bestopped 3 months before planning a pregnancy (see section 4.4). If a woman becomes pregnant duringtreatment, Zeposia must be discontinued. Medical advice should be given regarding the risk of harmfuleffects to the foetus associated with treatment and ultrasonography examinations should be performed.

Ozanimod/metabolites are excreted in milk of treated animals during lactation (see section 5.3). Due tothe potential for serious adverse reactions to ozanimod/metabolites in nursing infants, womenreceiving ozanimod should not breastfeed.

No fertility data are available in humans. In animal studies, no adverse effects on fertility wereobserved (see section 5.3).

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

The most commonly reported adverse reactions are nasopharyngitis (12.3%), alanine aminotransferase(ALT) increased (5%), and gamma-glutamyl transferase (GGT) increased (5.4%). Initiation ofozanimod may result in transient bradycardia that usually resolves by the end of the first week. Otherserious adverse reactions include serious opportunistic infections (PML has been reported in patientstreated with ozanimod), macular oedema (see section 4.4), hypertension, and rare cases of clinicallysignificant liver injury (see section 4.4).

The most common adverse reactions leading to discontinuation were related to liver enzymeelevations (1.1%) in the MS clinical studies. Liver enzyme elevations leading to discontinuationoccurred in 0.4% of patients, in UC controlled clinical studies.

The overall safety profile was similar for patients with multiple sclerosis and ulcerative colitis.

The adverse reactions observed in patients treated with ozanimod in MS and UC clinical studies andfrom post-marketing experience including spontaneous case reports are listed below by system organclass (SOC) and frequency for all adverse reactions. 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 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 systemdisorders Very common Lymphopenia*****

Immune system disorders Uncommon Hypersensitivity (including rash and urticaria*)

Nervous system disorders Common Headache

Eye disorders Uncommon Macular oedema**

Cardiac disorders Common Bradycardia*,*****

Hypertension*†,*****

Vascular disorders Common

Alanine aminotransferase increased*****

Common Gamma-glutamyl transferase increased*****

Blood bilirubin increased*****

Rare Liver injury****

General disorders andadministration site conditions Common Peripheral oedema

Investigations Common Pulmonary function test abnormal***,*****

* At least one of these adverse reactions was reported as serious† Includes hypertension, essential hypertension, and blood pressure increased (see section 4.4).

** for patients with pre-existing factors (see section 4.4)

*** including pulmonary function test decreased, spirometry abnormal, forced vital capacity decreased, carbon monoxidediffusing capacity decreased, forced expiratory volume decreased

**** Adverse reactions from post-marketing reports

***** see Description of selected adverse reactions

Elevated hepatic enzymes

In MS clinical studies, elevations of ALT to 5-fold the upper limit of normal (ULN) or greateroccurred in 1.6% of patients treated with ozanimod 0.92 mg and 1.3% of patients on IFN β-1a IM.

Elevations of 3-fold the ULN or greater occurred in 5.5% of patients on ozanimod and 3.1% ofpatients on IFN β-1a IM. The median time to elevation 3-fold the ULN was 6 months. The majority(79%) continued treatment with ozanimod with values returning to < 3-fold the ULN withinapproximately 2-4 weeks. Ozanimod was discontinued for a confirmed elevation greater than 5-foldthe ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was 1.1% of MSpatients on ozanimod 0.92 mg and 0.8% of patients on IFN beta-1a IM.

In UC clinical studies, during the induction period, elevations of ALT to 5-fold the ULN or greateroccurred in 0.9% of patients treated with ozanimod 0.92 mg and 0.5% of patients who receivedplacebo, and in the maintenance period elevations occurred in 0.9% and no patients, respectively. Inthe induction period, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patientstreated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenanceperiod elevations occurred in 2.3% and no patients, respectively. In controlled and uncontrolled UCclinical studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continuedtreatment with ozanimod with values returning to less than 3-fold the ULN within approximately 2 to4 weeks.

Overall, the discontinuation rate due to elevations in hepatic enzymes was 0.4% of patients treatedwith ozanimod 0.92 mg, and none in patients who received placebo in the controlled UC clinicalstudies.

Severe liver injury has been reported in a post-marketing setting (see section 4.4).

Bradyarrhythmia

After the initial dose of ozanimod 0.23 mg, the greatest mean reduction from baseline in sitting/supine

HR occurred at Hour 5 on day 1 (decrease of 1.2 bpm in MS clinical studies and 0.7 bpm in the UCclinical studies), returning towards baseline at Hour 6. With continued dose escalation, there were noclinically relevant HR decreases.

In MS clinical studies, bradycardia was reported in 0.5% of patients treated with ozanimod versus 0%of patients treated with IFN β-1a IM on the day of treatment initiation (Day 1). After Day 1, theincidence of bradycardia was 0.8% on ozanimod versus 0.7% on IFN β-1a IM. (see section 5.1).

Patients who experienced bradycardia were generally asymptomatic. Heart rates below 40 beats perminute were not observed.

In MS clinical studies, first-degree atrioventricular block was reported in 0.6% (5/882) of patientstreated with ozanimod versus 0.2% (2/885) treated with IFN β-1a IM. Of the cases reported withozanimod, 0.2% were reported on Day 1 and 0.3% were reported after Day 1.

In UC clinical studies, during the induction period, bradycardia was reported on the day of treatmentinitiation (Day 1), in 0.2% of patients treated with ozanimod and none in patients treated with placebo.

After Day 1 bradycardia was reported in 0.2% of patients treated with ozanimod. During themaintenance period, bradycardia was not reported.

In MS clinical studies, patients treated with ozanimod had an average increase of approximately1-2 mm Hg in systolic pressure over IFN β-1a IM, and approximately 1 mm Hg in diastolic pressureover IFN β-1a IM. The increase in systolic pressure was first detected after approximately 3 months oftreatment initiation and remained stable throughout treatment.

Hypertension-related events (hypertension, essential hypertension, and blood pressure increased) werereported as an adverse reaction in 4.5% of patients treated with ozanimod 0.92 mg and in 2.3% ofpatients treated with IFN β-1a IM.

In UC clinical studies, during the induction period, patients treated with ozanimod had an averageincrease of 1.4 mm Hg in systolic pressure over placebo (3.7 vs 2.3 mm Hg) and 1.7 mm Hg indiastolic pressure over placebo (2.3 vs 0.6 mm Hg). During the maintenance period, patients treatedwith ozanimod had an average increase of 3.6 mm Hg in systolic pressure over placebo (5.1 vs1.5 mm Hg) and 1.4 mm Hg in diastolic pressure over placebo (2.2 vs 0.8 mm Hg).

Hypertension was reported as an adverse reaction in 1.2% of patients treated with ozanimod 0.92 mgand none in patients treated with placebo in the induction period. In the maintenance period,hypertension was reported in 2.2% of patients in each treatment arm. Hypertensive crisis was reportedin two patients receiving ozanimod, who recovered without treatment interruption, and one patientreceiving placebo.

Blood lymphocyte count reduction

In MS clinical studies, 3.3% of patients and in UC controlled clinical studies, 3% of patientsexperienced lymphocyte counts less than 0.2 x 109/L with values generally resolving to greater than0.2 x 109/L while remaining on treatment with ozanimod.

In MS clinical studies, the overall rate of infections (35%) with ozanimod 0.92 mg was similar to

IFN β-1a IM. The overall rate of serious infections was similar between ozanimod (1%) and IFN β-1a

IM (0.8%) in MS clinical studies.

In UC clinical studies, during the induction period, the overall rate of infections and rate of seriousinfections in patients treated with ozanimod or placebo were similar (9.9% vs. 10.7% and 0.8% vs.0.4%, respectively). During the maintenance period, the overall rate of infections in patients treatedwith ozanimod was higher than in patients treated with placebo (23% vs. 12%) and the rate of seriousinfections was similar (0.9% vs. 1.8%).

Ozanimod increased the risk of herpes infections, upper respiratory tract infections and urinary tractinfections.

Herpetic infections

In MS clinical studies, herpes zoster was reported as an adverse reaction in 0.6% of patients treatedwith ozanimod 0.92 mg and in 0.2% of patients on IFN β-1a IM.

In UC clinical studies, herpes zoster was reported in 0.4% of patients who received ozanimod 0.92 mgand none in patients who received placebo in the induction period. In the maintenance period, herpeszoster was reported in 2.2% of patients who received ozanimod 0.92 mg and in 0.4% of patients whoreceived placebo. None were serious or disseminated.

Minor dose-dependent reductions in forced expiratory volume in 1 second (FEV1) and forced vitalcapacity (FVC) were observed with ozanimod treatment. At months 3 and 12 of treatment in MSclinical studies, median changes from baseline in FEV1 (FVC) in the ozanimod 0.92 mg groupwere -0.07 L and -0.1 L (-0.05 L and - 0.065 L), respectively, with smaller changes from baseline inthe IFN ß-1a group (FEV1: -0.01 L and -0.04 L, FVC: 0.00 L and -0.02 L).

Similar to MS clinical studies, small mean reductions in pulmonary function tests were observed withozanimod relative to placebo (FEV1 and FVC) during UC clinical studies, in the induction period.

There were no further reductions with longer term treatment with ozanimod in the maintenance periodand these small changes in pulmonary function tests were reversible in patients re-randomised toplacebo.

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 ozanimod, monitor for signs and symptoms of bradycardia, which mayinclude overnight monitoring. Regular measurements of HR and blood pressure are required, and

ECGs should be performed (see sections 4.4 and 5.1). The decrease in HR induced by ozanimod canbe reversed by parenteral atropine or isoprenaline.

Pharmacotherapeutic group: Immunosuppressants, Sphingosine-1-phosphate (S1P) receptormodulators, ATC code: L04AE02

Ozanimod is a potent sphingosine 1-phosphate (S1P) receptor modulator, which binds with highaffinity to sphingosine 1-phosphate receptors 1 and 5. Ozanimod has minimal or no activity on S1P2,

S1P3, and S1P4. In vitro, ozanimod and its major active metabolites demonstrated similar activity andselectivity for S1P1 and S1P5. The mechanism by which ozanimod exerts therapeutic effects in MSand UC is unknown, but may involve the reduction of lymphocyte migration into the central nervoussystem (CNS) and intestine.

The ozanimod-induced reduction of lymphocytes in the peripheral circulation has differential effectson leucocyte subpopulations, with greater decreases in cells involved in the adaptive immuneresponse. Ozanimod has minimal impact on cells involved in innate immune response, whichcontribute to immunosurveillance.

Ozanimod is extensively metabolised in humans to form a number of circulating active metabolitesincluding two major metabolites (see section 5.2). In humans, approximately 94% of circulating totalactive substances exposure are represented by ozanimod (6%) and the two major metabolites

CC112273 (73%), and CC1084037 (15%) (see section 5.2).

Reduction of peripheral blood lymphocytes

In active-controlled MS and placebo-controlled UC clinical studies, mean lymphocyte countsdecreased to approximately 45% of baseline by 3 months (approximate mean blood lymphocyte count0.8 x 109/L) and remained stable during treatment with ozanimod. After discontinuing ozanimod0.92 mg, the median time to recovery of peripheral blood lymphocytes to the normal range wasapproximately 30 days, with approximately 80% to 90% of patients recovering to normal within3 months (see sections 4.4 and 4.8).

Reduction in faecal calprotectin (FCP)

In patients with UC, treatment with ozanimod resulted in a decrease in the inflammatory marker,faecal calprotectin (FCP) during the induction period, which was then maintained throughout themaintenance period.

Heart rate and rhythm

Ozanimod may cause a transient reduction in HR on initiation of dosing (see sections 4.4 and 4.8).

This negative chronotropic effect is mechanistically related to the activation of G-protein-coupledinwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation by ozanimod and itsactive metabolites leading to cellular hyperpolarisation and reduced excitability with a maximal effecton HR seen within 5 hours post dose. Due to its functional antagonism at S1P1 receptors, a doseescalation schedule with ozanimod 0.23 mg followed by 0.46 mg, and 0.92 mg successivelydesensitises GIRK channels until the maintenance dose is reached. After the dose escalation period,with continued administration of ozanimod, HR returns to baseline.

Potential to prolong the QT interval

In a randomised, positive - and placebo-controlled thorough QT study using a 14-day dose-escalationregimen of 0.23 mg daily for 4 days, 0.46 mg daily for 3 days, 0.92 mg daily for 3 days, and 1.84 mgdaily for 4 days in healthy subjects, no evidence of QTc prolongation was observed as demonstratedby the upper boundary of the 95% one-sided confidence interval (CI) that was below the 10 ms.

Concentration-QTc analysis for ozanimod and the major active metabolites CC112273 and

CC1084037, using data from another Phase 1 study showed the upper boundary of the 95% CI formodel derived QTc (corrected for placebo and baseline) below 10 ms at maximum concentrationsachieved with ozanimod doses ≥ 0.92 mg once daily.

Multiple sclerosis

Ozanimod was evaluated in two Phase 3 randomised, double-blind, double-dummy, parallel-group,active controlled clinical trials of similar design and endpoints, in patients with relapsing remitting MS(RRMS). Study 1 - SUNBEAM, was a 1-year study with patients continuing assigned treatmentbeyond month 12 until the last enrolled patient completed the study. Study 2 -RADIANCE was a2-year study.

The dose of ozanimod was 0.92 mg and 0.46 mg given orally once daily, with a starting dose of0.23 mg on days 1-4, followed by an escalation to 0.46 mg on days 5-7, and followed by the assigneddose on day 8 and thereafter. The dose of IFN β-1a, the active comparator, was 30 mcg givenintramuscularly once weekly.

Both studies included patients with active disease as defined by having at least one relapse within theprior year, or one relapse within the prior two years with evidence of at least a gadolinium-enhancing(GdE) lesion in the prior year and had an Expanded Disability Status Scale (EDSS) score from 0 to5.0.

Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspectedrelapse. MRIs were performed at baseline (Studies 1 and 2), 6 months (SUNBEAM), 1 year (Studies 1and 2), and 2 years (RADIANCE).

The primary outcome of both SUNBEAM and RADIANCE was the annualised relapse rate (ARR)over the treatment period (minimum of 12 months) for SUNBEAM and 24 months for RADIANCE.

The key secondary outcome measures included 1) the number of new or enlarging MRI T2hyperintense lesions over 12 and 24 months; 2) the number of MRI T1 GdE lesions at 12 and24 months; and 3) the time to confirmed disability progression, defined as at least a 1-point increasefrom baseline EDSS sustained for 12 weeks. Confirmed disability progression was prospectivelyevaluated in a pooled analysis of Studies 1 and 2.

In SUNBEAM, 1346 patients were randomised to receive ozanimod 0.92 mg (n = 447), ozanimod0.46 mg (n = 451), or IFN β-1a IM (n = 448); 94% of ozanimod treated 0.92 mg, 94% of ozanimodtreated 0.46 mg, and 92% of IFN β-1a IM treated patients completed the study. In RADIANCE,1313 patients were randomised to receive ozanimod 0.92 mg (n = 433), ozanimod 0.46 mg (n = 439),or IFN β-1a IM (n = 441); 90% of ozanimod treated 0.92 mg, 85% of ozanimod treated 0.46 mg, and85% of IFN β-1a IM treated patients completed the study. Patients enrolled across the 2 studies had amean age of 35.5 years (range 18-55), 67% were female, mean time since MS symptom onset was6.7 years. The median EDSS score at baseline was 2.5; approximately one-third of the patients hadbeen treated with a disease-modifying therapy (DMT), predominately interferon or glatiramer acetate.

At baseline, the mean number of relapses in the prior year was 1.3 and 45% of patients had one ormore T1 Gd-enhancing lesions (mean 1.7).

The results for SUNBEAM and RADIANCE are shown in Table 3. The efficacy has beendemonstrated for ozanimod 0.92 mg with a dose effect observed for study endpoints shown in Table 3.

Demonstration of efficacy for 0.46 mg was less robust since this dose did not show a significant effectfor the primary endpoint in RADIANCE when considering the preferred negative binomial modelstrategy.

Table 3: Key clinical and MRI endpoints in RMS patients from Study 1 - SUNBEAM and

Study 2 - RADIANCE

Endpoints SUNBEAM RADIANCE(≥ 1 year)* (2 year)

Ozanimod IFN β-1a IM Ozanimod IFN β-1a IM0.92 mg 30 mcg 0.92 mg 30 mcg(n = 447) (n = 448) (n = 433) (n = 441)% % % %

Clinical endpoints

Annualised relapse rate 0.181 0.350 0.172 0.276(Primary endpoint)

Relative reduction 48% (p < 0.0001) 38% (p < 0.0001)

Proportion relapse-free** 78% 76%(p = 0.0002)1 66% (p = 0.0012)1 64%

Proportion with 3-monthconfirmed disability 7.6% Ozanimod vs. 7.8% IFN β-1a IM

Progression (CDP)†2 0.95 (0.679, 1.330)

Hazard ratio (95% CI)

Proportion with 6-month 5.8% Ozanimod vs. 4.0% IFN β-1a IM

CDP†2# 1.413 (0.922, 2.165)

Hazard ratio (95% CI)

MRI endpoints

Mean number of new or 1.465 2.836 1.835 3.183enlarging T2 hyperintenselesions per MRI3 48% (p < 0.0001) 42% (p < 0.0001)

Relative reduction

Mean number of T1 Gd 0.160 0.433 0.176 0.373enhancing lesions4

Relative reduction 63% (p < 0.0001) 53% (p = 0.0006)

* Mean duration was 13.6 months

** Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for multiplicity† Disability progression defined as 1-point increase in EDSS confirmed 3 months or 6 months later# In a post hoc analysis of 6-month CDP which included data from the open-label extension (Study 3), the HR (95% CI) wasfound to be 1.040 (0.730, 1.482).)1 Log rank test2 Prospectively planned pooled analysis of Studies 1 and 23 Over 12 months for Study 1 and over 24 months for Study 24 At 12 months for Study 1 and at 24 months for Study 2

In SUNBEAM and RADIANCE, treatment with ozanimod 0.92 mg resulted in reductions in meanpercent change from baseline in normalised brain volume compared to IFN beta-1a IM (-0.41% versus

- 0.61%, and -0.71% versus -0.94%, respectively, nominal p-value < 0.0001 for both studies).

The studies enrolled DMT naive and previously treated patients with active disease, as defined byclinical or imaging features. Post-hoc analyses of patient populations with differing baseline levels ofdisease activity, including active and highly active disease, showed that the efficacy of ozanimod onclinical and imaging endpoints was consistent with the overall population.

Patients with RRMS who completed the SUNBEAM, RADIANCE, Phase 2 extension or Phase 1

PK/PD studies could enter an open-label extension (Study 3 - DAYBREAK) and received ozanimod0.92 mg once daily to assess the long-term safety and efficacy of ozanimod. In total, 2494 subjectswere treated in DAYBREAK with ozanimod 0.92 mg once daily (736 patients switched frominterferon beta-1a IM 30 mcg once weekly, 877 switched from ozanimod 0.46 mg once daily, and 881continued with ozanimod 0.92 mg once daily) with a median duration of treatment of 68 months up toa maximum of 81 months. The adjusted ARR for all subjects over the treatment period was 0.098(95% CI: 0.082, 0.117) with 69.1% of patients remaining relapse free. Subjects who continued onozanimod 0.92 mg into DAYBREAK had an ARR of 0.090 (95% CI: 0.073, 0.111). A total of 379(15.2%) of subjects experienced 6-month confirmed disability progression over the study.

The efficacy and safety of ozanimod were evaluated in two multicentre, randomised, double-blind,placebo-controlled clinical studies [TRUENORTH-I (induction period) and TRUENORTH-M(maintenance period)] in adult patients, aged less than 75 years, with moderately to severely activeulcerative colitis. TRUENORTH-I included patients who were randomised 2:1 to ozanimod 0.92 mgor placebo. The 10-week induction period (TRUENORTH-I) was followed by a 42-week, randomised,withdrawal maintenance period (TRUENORTH-M) for a total of 52 weeks of therapy. Ozanimod wasadministered as monotherapy (i.e., without concomitant use of biologics and non-corticosteroidimmunosuppressants) for UC. There are limited data available on UC patients ≥ 65 years of age

The study included patients with moderately to severely active ulcerative colitis defined at baseline(week 0) as a Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥ 2.

TRUENORTH-I (induction study)

In TRUENORTH-I, patients were randomised to either ozanimod 0.92 mg given, orally once daily(n = 429) or placebo (n = 216) beginning with a dose titration (see section 4.2). Patients receivedconcomitant aminosalicylates (e.g., mesalazine 71%; sulfasalazine 13%) and/or oral corticosteroids(33%) at a stable dose prior to and during the induction period.

There were 30% of patients who had an inadequate response, loss of response or intolerant to tumournecrosis factor (TNF) blockers. Of these patients with prior biologic therapy, 63% received at leasttwo or more biologics including TNF blockers; 36% failed to ever respond to at least one TNFblocker; 65% lost response to a TNF blocker; 47% received an integrin receptor blocker (e.g.,vedolizumab). There were 41% of patients who failed and/or were intolerant to immunomodulators.

At baseline, patients had a median Mayo score of 9, with 65% of patients less than or equal to 9 and35% having greater than 9.

The primary endpoint was clinical remission at week 10, and the key secondary endpoints at week 10were clinical response, endoscopic improvement, and mucosal healing.

A significantly greater proportion of patients treated with ozanimod achieved clinical remission,clinical response, endoscopic improvement, and mucosal healing compared to placebo at week 10 asshown in Table 4.

Table 4: Proportion of patients meeting efficacy endpoints in the induction period from

TRUENORTH-I (at week 10)

Ozanimod 0.92 mg Placebo Treatment(N = 429) (N = 216) Difference %an % n % (95% CI)

Clinical remissionb 79 18% 13 6% 12%(7.5, 17.2)f

Without prior TNF blockerexposure 66/299 22% 10/151 7%

Prior TNF blocker exposure 13/130 10% 3/65 5%

Clinical responsec 205 48% 56 26% 22%(14.4, 29.3)f

Without prior TNF blockerexposure 157/299 53% 44/151 29%

Prior TNF blocker exposure 48/130 37% 12/65 19%

Ozanimod 0.92 mg Placebo Treatment(N = 429) (N = 216) Difference %an % n % (95% CI)

Endoscopic improvementd 117 27% 25 12% 16%(9.7, 21.7)f

Without prior TNF blockerexposure 97/299 32% 18/151 12%

Prior TNF blocker exposure 20/130 15% 7/65 11%

Mucosal healinge 54 13% 8 4% 9%(4.9, 12.9)g

Without prior TNF blockerexposure 47/299 16% 6/151 4%

Prior TNF blocker exposure 7/130 5% 2/65 3%

CI = confidence interval; TNF = tumour necrosis factor.a Treatment difference (adjusted for stratification factors of prior TNF blocker exposure and corticosteroid use at baseline).b Clinical remission is defined as: RBS = 0, SFS ≤ 1 (and a decrease of ≥ 1 point from the baseline SFS), and endoscopysubscore ≤ 1 without friability.c Clinical response is defined as a reduction from baseline in the 9-point Mayo score of ≥ 2 points and ≥ 35%, and a reductionfrom baseline in the RBS of ≥ 1 or an absolute RBS of ≤ 1 point.d Endoscopic improvement is defined as a Mayo endoscopic score ≤ 1 without friability.e Mucosal healing defined as both Mayo endoscopic score ≤ 1 point without friability and histological remission (Geboesscore < 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 p < 0.0001.g p < 0.001.

Rectal bleeding (RBS) and stool frequency (SFS) subscores

Decreases in rectal bleeding and stool frequency subscores were observed as early as week 2 (i.e.,1 week after completing the required 7-day dose titration) in patients treated with ozanimod. Anominally significantly greater proportion of subjects achieved symptomatic remission, defined as

RBS = 0, SFS ≤ 1 and a decrease from baseline of ≥ 1, with ozanimod 0.92 mg than with placebo at

Week 5 (27% vs 15%) and at Week 10 of the Induction Period (37.5% versus 18.5%).

Patients who had a decrease from baseline in SFS and/or RBS of at least 1 point but did not achieveclinical response or clinical remission at week 10 of TRUENORTH-I, had an increased rate ofsymptomatic remission after an additional 5 weeks of ozanimod treatment, 21% (26/126). The rate ofsymptomatic remission in these patients continued to increase through an additional 46 weeks oftreatment, 50% (41/82).

TRUENORTH-M (maintenance study)

In order to be randomised to treatment in the maintenance study (TRUENORTH-M), patients had tohave received ozanimod 0.92 mg and be in clinical response at week 10 of the induction period.

Patients could have come from either TRUENORTH-I or from a group who received ozanimod0.92 mg open-label. Patients were (re)-randomised in a double-blinded fashion (1:1) to receive eitherozanimod 0.92 mg (n = 230) or placebo (n = 227) for 42 weeks. The total study duration was52 weeks, including both the induction and maintenance periods. Efficacy assessments were atweek 52. Concomitant aminosalicylates were required to remain stable through week 52. Patients onconcomitant corticosteroids were to taper their dose upon entering the maintenance period.

At study entry, 35% of patients were in clinical remission, 29% of patients were on corticosteroids and31% of patients who were previously treated with TNF blockers.

As shown in the Table 5, the primary endpoint was the proportion of patients in clinical remission atweek 52. Key secondary endpoints at week 52 were the proportion of patients with clinical response,endoscopic improvement, maintenance of clinical remission at week 52 in the subset of patients inremission at week 10, corticosteroid-free clinical remission, mucosal healing and durable clinicalremission.

Table 5: Proportion of patients meeting efficacy endpoints in the maintenance period in

TRUENORTH-M (at week 52)

Ozanimod 0.92 mg Placebo Treatment(N = 230) (N = 227) difference %a(95% CI)n % n %

Clinical remissionb 85 37% 42 19% 19%(10.8, 26.4)i

Without prior TNF blocker exposure 63/154 41% 35/158 22%

Prior TNF blocker exposure 22/76 29% 7/69 10%

Clinical responsec 138 60% 93 41% 19%(10.4, 28.0)i

Without prior TNF blocker exposure 96/154 62% 76/158 48%

Prior TNF blocker exposure 42/76 55% 17/69 25%

Endoscopic improvementd 105 46% 60 26% 19%(11.0, 27.7)j

Without prior TNF blocker exposure 77/154 50% 48/158 30%

Prior TNF blocker exposure 28/76 37% 12/69 17%

Maintenance of clinical remission atweek 52 in the subset of patients in 41/79 52% 22/75 29% 24%kremission at week 10e (9.1, 38.6)

Without prior TNF blocker exposure 37/64 58% 19/58 33%

Prior TNF blocker exposure 4/15 27% 3/17 18%

Corticosteroid-free clinical remissionf 73 32% 38 17% 15%(7.8, 22.6)j

Without prior TNF blocker exposure 55/154 36% 31/158 20%

Prior TNF blocker exposure 18/76 24% 7/69 10%

Mucosal healingg 68 30% 32 14% 16%(8.2, 22.9)j

Without prior TNF blocker exposure 51/154 33% 28/158 18%

Prior TNF blocker exposure 17/76 22% 4/69 6%

Durable clinical remissionh 41 18% 22 10% 8%(2.8, 13.6)l

Without prior TNF blocker exposure 37/154 24% 19/158 12%

Prior TNF blocker exposure 4/76 5% 3/69 4%

CI = confidence interval; TNF = tumour necrosis factor.a Treatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at week 10).b Clinical remission is defined as: RBS = 0 point and SFS ≤ 1 point (and a decrease of ≥ 1 point from the baseline SFS) andendoscopy subscore ≤ 1 point without friability.c Clinical response is defined as: A reduction from baseline in the 9-point Mayo score of ≥ 2 points and ≥ 35%, and areduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point.d Endoscopic improvement is defined as: Endoscopy subscore of ≤ 1 point without friability.e Maintenance of remission defined as clinical remission at week 52 in the subset of patients in clinical remission at week 10.f Corticosteroid-free remission is defined as clinical remission at week 52 while off corticosteroids for ≥ 12 weeks.g Mucosal healing is defined as both Mayo endoscopic score ≤ 1 without friability and histological remission (Geboes score< 2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction,erosions, ulcerations, or granulation tissue)h Durable clinical remission is defined as clinical remission at week 10 and at week 52 in all subjects who entered themaintenance period.i p < 0.0001.j p < 0.001.k p = 0.0025.l p = 0.0030

Steroid free mucosal healing and steroid-free (2-component) symptomatic remission

A significantly greater proportion of patients continuously treated with ozanimod 0.92 mg vs re-randomised to placebo achieved corticosteroid-free (at least 12 weeks) symptomatic remission (42.2%ozanimod versus 30.4% placebo) and corticosteroid-free (at least 12 weeks) endoscopic improvement(40.0% ozanimod versus 23.3% placebo) at week 52.

Histologic remission at week 10 and 52

Histologic remission (defined as Geboes index score < 2.0 points), was assessed at week 10 of

TRUENORTH-I and at week 52 of TRUENORTH-M. At week 10, a significantly greater proportionof patients treated with ozanimod 0.92 mg achieved histologic remission (18%) compared to patientstreated with placebo (7%). At week 52, maintenance of this effect was observed with a significantlygreater proportion of patients in histologic remission in patients treated with ozanimod 0.92 mg (34%)compared to patients treated with placebo (16%).

Patients who did not achieve clinical response at the end of the induction period, lost response in themaintenance period or completed the TRUENORTH study were eligible to enter an open labelextension study (OLE) and received ozanimod 0.92 mg. Among patients who entered the OLE,clinical remission, clinical response, endoscopic improvement, and symptomatic remission weregenerally maintained through week 142. No new safety concerns were identified in this studyextension in patients with ulcerative colitis (with a mean treatment duration of 22 months).

The European Medicines Agency has deferred the obligation to submit the results of studies withozanimod in one or more subsets of the paediatric population in MS and UC (see section 4.2).

Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites,including two major active metabolites, CC112273 and CC1084037, with similar activity andselectivity for S1P1 and S1P5 to the parent. The maximum plasma concentration (Cmax) and area underthe curve (AUC) for ozanimod, CC112273, and CC1084037 increased proportionally over the doserange of ozanimod 0.46 mg to 0.92 mg (0.5 to 1 times the recommended dose). Following multipledosing, approximately 94% of circulating total active substances are represented by ozanimod (6%),

CC112273 (73%), and CC1084037 (15%). At a dose of 0.92 mg orally once daily in RRMS, thegeometric mean [coefficient of variation (CV%)] Cmax and AUC0-24h at steady state were 231.6 pg/mL(37.2%) and 4223 pg*h/mL (37.7%), respectively, for ozanimod and 6378 pg/mL (48.4%) and132861 pg*h/mL (45.6%), respectively, for CC112273. Cmax and AUC0-24h for CC1084037 areapproximately 20% of that for CC112273. Factors affecting CC112273 are applicable for CC1084037as they are interconverting metabolites. Population pharmacokinetic analysis indicated that there wereno meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.

The tmax of ozanimod is approximately 6-8 hours. The tmax of CC112273 is approximately 10 hours.

Administration of ozanimod with a high-fat, high-calorie meal had no effect on ozanimod exposure(Cmax and AUC). Therefore, ozanimod may be taken without regard to meals.

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) was 5590 L (27%), indicatingextensive tissue distribution. Binding of ozanimod to human plasma proteins is approximately 98.2%.

Binding of CC112273 and CC1084037 to human plasma proteins is approximately 99.8% and 99.3%,respectively.

Ozanimod is widely metabolised by multiple biotransformation pathways including aldehydedehydrogenase and alcohol dehydrogenase (ALDH/ADH), cytochrome P450 (CYP) isoforms 3A4 and1A1, and gut microflora and no single enzyme system predominates the overall metabolism.

Following repeated dosing, the AUCs of the two major active metabolites CC112273 and CC1084037exceed the AUC of ozanimod by 13-fold and 2.5-fold, respectively. In vitro studies indicated that

MAO-B is responsible for the formation of CC112273 (via an intermediate minor active metabolite

RP101075) while CYP2C8 and oxido-reductases are involved in the metabolism of CC112273.

CC1084037 is formed directly from CC112273 and undergoes reversible metabolism to CC112273.

The interconversion between these 2 active metabolites is mediated by carbonyl reductases (CBR),aldo-keto reductase (AKR) 1C1/1C2, and/or 3β- and 11β- hydroxysteroid dehydrogenase (HSD).

The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%). The mean(CV%) plasma half-life (t1/2) of ozanimod was approximately 21 hours (15%). Steady state forozanimod was achieved within 7 days, with the estimated accumulation ratio following repeated oraladministration of 0.92 mg once daily of approximately 2.

The model-based mean (CV%) effective half-life (t1/2) of CC112273 was approximately11 days (104%) in RMS patients, with mean (CV%) time to steady state of approximately45 days (45%) and accumulation ratio of approximately 16 (101%) indicating the predominance of

CC112273 over ozanimod. Plasma levels of CC112273 and its direct, interconverting metabolite

CC1084037 declined in parallel in the terminal phase, yielding similar t1/2 for both metabolites. Steadystate attainment and accumulation ratio for CC1084037 are expected to be similar to CC112273.

Following a single oral 0.92 mg dose of [14C]-ozanimod, approximately 26% and 37% of theradioactivity was recovered from urine and faeces, respectively, primarily composed of inactivemetabolites. Ozanimod, CC112273, and CC1084037 concentrations in urine were negligible,indicating that renal clearance is not an important excretion pathway for ozanimod, CC112273, and

CC1084037.

Pharmacokinetics in specific groups of patients

In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ozanimod, exposures(AUClast) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively,in patients with end stage renal disease (N = 8) compared to patients with normal renal function(n = 8). Based on this trial, renal impairment had no clinically important effects on pharmacokineticsof ozanimod or CC112273. No dose adjustment is needed in patients with renal impairment.

In single dose and multiple dose studies in subjects with chronic liver disease, there was nomeaningful impact of mild or moderate chronic hepatic impairment (Child-Pugh class A or B) on thepharmacokinetics of ozanimod or the major metabolite CC112273 on Day 1, Day 5, or Day 8 ofdosing. After dose escalation in the second trial, administration of 0.92 mg ozanimod resulted inincreased CC112273 and CC1084037 mean unbound AUC0-last (measured up to 64 days post-dose) insubjects with mild or moderate chronic hepatic impairment of 99.64% to 129.74% relative to healthycontrol subjects. Patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B)are recommended to complete the 7-day dose escalation regimen, and then take 0.92 mg once everyother day (see section 4.2).

The pharmacokinetics of ozanimod were not evaluated in patients with severe hepatic impairment. Usein patients with severe hepatic impairment is contraindicated (Child-Pugh class C) (see section 4.3).

Population pharmacokinetic analysis showed that steady state exposure (AUC) of CC112273 inpatients over 65 years of age were approximately 3 - 4% greater than patients 45 - 65 years of age and27% greater than adult patients under 45 years of age. There is not a meaningful difference in thepharmacokinetics in elderly patients.

No data are available on administration of ozanimod to paediatric or adolescent patients (< 18 years ofage).

In repeated dose toxicology studies in mice (up to 4 weeks), rats (up to 26 weeks) and monkeys (up to39 weeks), ozanimod markedly affected the lymphoid system (lymphopenia, lymphoid atrophy andreduced antibody response) and increased lung weights and the incidence of mononuclear alveolarinfiltrates, which is consistent with its primary activity at S1P1 receptors (see section 5.1). At the noobserved adverse effect levels in chronic toxicity studies, systemic exposures to the disproportionatemain active and persistent human metabolites CC112273 and CC1084037 (see section 5.2), and evento the total human active substances (ozanimod combined with the mentioned metabolites), werelower than those expected in patients at the maximum human dose of 0.92 mg ozanimod.

Ozanimod and its main active human metabolites did not reveal a genotoxic potential in vitro and invivo.

Ozanimod was evaluated for carcinogenicity in the 6-month Tg.rasH2 mouse bioassay and thetwo-year rat bioassay. In the two-year rat bioassay, no treatment-related tumours were present at anyozanimod dose. However, metabolite exposure at the highest dose tested, was 62% of the humanexposure for CC112273 and 18% of the human exposure for CC1084037 at the maximum clinicaldose of 0.92 mg ozanimod.

In the 6-month Tg.rasH2 mouse study, haemangiosarcomas increased in a statistically-significant anddose-related manner. At the low dose (8 mg/kg/day), the haemangiosarcoma incidence was increasedstatistically significant in males and in both males and females at the mid and high dose levels(25 mg/kg/day and 80 mg/kg/day) compared to concurrent controls. In contrast to rats and humans,mouse S1P1 receptor agonism results in sustained production of placental growth factor 2 (PLGF2)and subsequently, persistent vascular endothelial cell mitoses, potentially leading to species specifichaemangiosarcomas with S1P1 agonists. Therefore, S1P1 receptor agonism related haemangiosarcomasin mice may be species specific and not predictive of a risk in humans.

No other treatment-related tumours were present at any dose in the Tg.rasH2 mouse study. At thelowest dose tested, exposure in Tg.rasH2 mice to the disproportionate two main active humanmetabolites was for CC112273 2.95 fold and for CC1084037 1.4 fold above the human exposure at themaximum clinical dose of 0.92 mg ozanimod.

Ozanimod had no effect on male and female fertility up to approximately 150-fold the systemicexposure to total active substances (combined ozanimod and the metabolites CC112273 and

CC1084037) at the maximum human dose of 0.92 mg ozanimod.

Embryofoetal development was adversely affected by maternal treatment with ozanimod, with low(rats) or no (rabbits) safety margins based on comparison of systemic exposures to total activesubstances, resulting in embryolethality and teratogenicity (generalised oedema/anasarca andmalpositioned testes in rats, malpositioned caudal vertebrae and malformations of the great vessels inrabbits). The vascular findings in rats and rabbits are consistent with the expected S1P1 pharmacology.

Pre- and post-natal development was not affected by ozanimod administration up to the 5.6-fold thesystemic exposure to total active substances at the maximum human dose of 0.92 mg ozanimod.

Ozanimod and metabolites were present in rat milk.

Microcrystalline cellulose

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Magnesium stearate

Zeposia 0.23 mg and 0.46 mg

Gelatin

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Yellow iron oxide (E172)

Black iron oxide (E172)

Red iron oxide (E172).

Zeposia 0.92 mg

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172).

Shellac (E904)

Iron oxide black (E172)

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Concentrated ammonia solution(E527)

Potassium hydroxide (E525)

Not applicable.

3 years

Do not store above 25°C.

Polyvinyl chloride (pVC)/polychlorotrifluoroethylene (PCTFE)/aluminium foil blisters.

Treatment initiation pack: Zeposia 0.23 mg and 0.46 mg

Pack size of 7 hard capsules (4 x 0.23 mg, 3 x 0.46 mg).

Maintenance pack: Zeposia 0.92 mg

Pack size of 28 or 98 hard capsules.

Not all pack sizes may be marketed.

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

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

Treatment initiation pack - Zeposia 0.23 mg/0.46 mg hard capsules

EU/1/20/1442/001 (Pack size of 7 hard capsules)

Maintenance pack - Zeposia 0.92 mg hard capsules

EU/1/20/1442/002 (Pack size of 28 hard capsules)

EU/1/20/1442/003 (Pack size of 98 hard capsules)

Date of first authorisation: 20 May 2020

Date of latest renewal:

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

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