ZEPOSIA 0.23 MG / 0.46 MG HARD CAPSULES - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Zeposia 0.23 mg hard capsules

Zeposia 0.46 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

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.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

Ulcerative colitis

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

4.2 Posology and method of administration

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

Posology

The recommended dose is 0.92 mg ozanimod once daily. The capsules can be taken with or without food.

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 once daily dose is 0.92 mg, starting on Day 8.

Table 1: Dose escalation regimen

Re-initiation of therapy following treatment interruption

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

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 continued with the next dose as planned.

Special populations

Elderly population

No dose adjustment is needed in patients over 65 years of age. Caution should be used in patients over 65 years of age, given the limited data available and potential for an increased risk of adverse

reactions in this population, especially with long-term treatment (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment.

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh class A and B).

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

Paediatric population

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

Method of administration

Oral use.

4.3 Contraindications

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 (MI), unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation or New York Heart Association (NYHA) Class III/IV heart failure.

Patients with history or presence of second-degree atrioventricular (AV) block Type II or third-degree AV block or sick sinus syndrome unless the patient has a functioning pacemaker.

Severe active infections, active chronic infections such as hepatitis and tuberculosis (see section 4.4).

Active malignancies.

Severe hepatic impairment (Child-Pugh class C).

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

4.4 Special warnings and precautions for use

Bradyarrhythmia

Initiation of treatment with ozanimod

Prior to treatment initiation with ozanimod, an ECG in all patients should be obtained to determine whether any pre-existing cardiac abnormalities are present. In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below).

Initiation of ozanimod may result in transient reductions in heart rate (HR) (see sections 4.8 and 5.1), and, therefore the initial dose escalation regimen to reach the maintenance dose (0.92 mg) on day 8 should be followed (see section 4.2).

After the initial dose of ozanimod 0.23 mg, the HR decrease started at Hour 4, with the greatest mean reduction at Hour 5, returning to near baseline at Hour 6. With continued dose escalation, there were no clinically relevant HR decreases. Heart rates below 40 beats per minute were not observed. If necessary, the decrease in HR induced by ozanimod can be reversed by parenteral doses of atropine or isoprenaline.

Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta- blocker or a calcium-channel blocker (e.g. diltiazem and verapamil) because of the potential for additive effects on lowering HR. Beta-blockers and calcium-channel blockers treatment can be initiated in patients receiving stable doses of ozanimod.

The co-administration of ozanimod in patients on a beta-blocker in combination with a calcium channel blocker has not been studied (see section 4.5).

First dose monitoring in patients with certain pre-existing cardiac conditions

Due to the risk of transient decreases in HR with the initiation of ozanimod, first-dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure (see section 4.3).

Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended.

Additional monitoring is recommended in patients if at hour 6 post-dose:

heart rate less than 45 bpm

heart rate is the lowest value post-dose, suggesting that the maximum decrease in HR may not have occurred yet

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 the symptoms/findings have resolved. If medical treatment is required, monitoring should be continued overnight, 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 to decide if ozanimod can safely be initiated and to determine the most appropriate monitoring strategy

history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep 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 betablockers 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 de pointes in patients with bradycardia have not been studied with ozanimod.

Liver function

Elevations of aminotransferases may occur in patients receiving ozanimod (see section 4.8). Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with ozanimod. In the absence of clinical symptoms, liver transaminases and bilirubin 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 should be instituted. If liver transaminases above 5 times the ULN are confirmed, treatment with ozanimod should be interrupted and only re-commenced once liver transaminase values have normalised.

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 hepatic enzymes 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 and on 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 hepatic enzymes 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, including opportunistic infections, and may increase the risk of developing malignancies, including those of the skin. Physicians should carefully monitor patients, especially those with concurrent conditions or known factors, such as previous immunosuppressive therapy. If this risk is suspected, discontinuation of treatment should be considered by the physician on a case-by-case basis (see section 4.3).

Infections

Ozanimod causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible retention of lymphocytes in the lymphoid tissues. Ozanimod may, 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 cell count (CBC) should be obtained, including lymphocyte count, before initiation of ozanimod. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 × 109/L, if confirmed, should lead to interruption of ozanimod therapy until the level reaches > 0.5 × 109/L when re-initiation of ozanimod can be considered.

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

Patients should be instructed to report promptly symptoms of infection to their physician. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. If a patient develops a serious infection, treatment interruption with ozanimod should be considered.

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

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

In MS and UC clinical studies, patients who received ozanimod were not to receive concomitant antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ozanimod with any of these therapies would be expected to increase the risk of immunosuppression. In UC clinical studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ozanimod. When switching to ozanimod from immunosuppressive medicinal products, the half-life and mode of action must be considered to avoid an additive immune effect whilst at the same time minimizing the risk of disease reactivation.

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

Progressive multifocal leukoencephalopathy (PML)

PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that typically occurs in patients who are immunocompromised and may lead to death or severe disability. JCV infection resulting in PML has been observed in patients treated with MS and UC therapies and has been associated with some risk factors (e.g., polytherapy with immunosuppressants, severely immunocompromised patients). Typical symptoms associated with PML are diverse, progress over days 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 and personality 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 with ozanimod should be suspended until PML has been excluded. If confirmed, treatment with ozanimod should be discontinued.

Vaccinations

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 with ozanimod.

If live attenuated vaccine immunizations are required, these should be administered at least 1 month prior to initiation of ozanimod. Varicella Zoster Virus (VZV) vaccination of patients without documented 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 of non-melanoma skin malignancies, with basal cell carcinoma presenting as the most common skin

neoplasm and reported with similar incidence rates in the combined ozanimod (0.2%, 3 patients) and IFN B-1a (0.1 %, 1 patient) groups.

In patients treated with ozanimod in UC controlled clinical studies one patient (0.2%) had squamous cell carcinoma of the skin, in the induction period, and one patient (0.4%) had basal cell carcinoma, in the 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 be cautioned against exposure to sunlight without protection. These patients should not receive concomitant 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) in patients with pre-existing risk factors or comorbid conditions.

Patients with a history of uveitis or diabetes mellitus or underlying/co existing retinal disease are at increased risk of macular oedema (see section 4.8). It is recommended that patients with diabetes mellitus, uveitis or a history of retinal disease undergo an ophthalmological evaluation prior to treatment 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 be re- initiated after resolution needs to take into account the potential benefits and risks for the individual patient.

Posterior reversible encephalopathy syndrome (PRES)

PRES is a syndrome characterised by sudden onset of severe headache, confusion, seizures and visual loss. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral haemorrhage. In MS controlled clinical trials with ozanimod, one case of PRES was reported in a patient with Guillain-Barre syndrome. If PRES is suspected, treatment with ozanimod should be discontinued.

Blood pressure effects

In MS and UC controlled clinical studies, hypertension was more frequently reported in patients treated with ozanimod than in patients treated with IFN [Ma IM (MS) or placebo (UC) and in patients receiving concomitant ozanimod and SSRIs or SNRIs (see section 4.8). Blood pressure should be regularly monitored during treatment with ozanimod.

Respiratory effects

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

Concomitant medicinal products

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

Women of childbearing potential

Due to risk to the foetus, ozanimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment, and for 3 months after treatment discontinuati­on (see

sections 4.3 and 4.6 and the information contained in the Healthcare Professional

checklist). Return of MS disease activity (rebound) after ozanimod discontinuation

Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of another S1P receptor modulator. The possibility of severe exacerbation of disease after stopping ozanimod treatment should be considered. Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon ozanimod discontinuation and appropriate treatment should be instituted as required.

4.5 Interaction with other medicinal products and other forms of interaction

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

An inhibitor of the BCRP (ciclosporin) doubled the exposure (AUC) of the minor active metabolites which may subsequently lead to a similar increase in the major active metabolites and increase the risk of adverse reactions. The coadministration of BCRP inhibitors (e.g. ciclosporin and eltrombopag) with ozanimod is not recommended (see section 4.4).

Effect of inhibitors of CYP2C8 on ozanimod

The coadministration of gemfibrozil (a strong inhibitor of CYP2C8) 600 mg twice daily at steady state and a single dose of ozanimod 0.46 mg increased exposure (AUC) of the major active metabolites by approximately 47% to 69%. Caution should be exercised for concomitant use of ozanimod with strong CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel).

Effect of inducers of CYP2C8 on ozanimod

The coadministration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ozanimod 0.92 mg reduced exposure (AUC) of major active metabolites by approximately 60% via CYP2C8 induction which may result in reduced clinical response. The coadministration of CYP2C8 inducers (i.e., rifampin) with ozanimod is not recommended (see section 4.4).

Effect of inhibitors of monoamine oxidase (MAO) on ozanimod

The potential for clinical interaction with MAO inhibitors has not been studied.

However, the coadministration with MAO-B inhibitors may decrease exposure of the major active metabolites and may result in reduced clinical response. The coadministration of MAO inhibitors (e.g., selegiline, phenelzine) with ozanimod is not recommended (see section 4.4).

Effects of ozanimod on medicinal products that slow heart rate or atrioventricular conduction (e.g., beta blockers or calcium channel blockers)

In healthy subjects, a single dose of ozanimod 0.23 mg with steady state propranolol long acting 80 mg once daily or diltiazem 240 mg once daily did not result in any additional clinically meaningful changes in HR and PR interval compared to either propranolol or diltiazem alone. Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta-blocker or a calcium-channel blocker (see section 4.4). Patients on other bradycardic medicinal products and on antiarrhythmic medicinal products (which have been associated with cases of torsades de pointes in patients with bradycardia) have not been studied with ozanimod.

Vaccination

During and for up to 3 months after treatment with ozanimod, vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided during and for up to 3 months after treatment with ozanimod (see section 4.4).

Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies

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

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in females

Zeposia is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the risk to the foetus. Women of childbearing potential must use effective contraception during ozanimod treatment and for 3 months after treatment discontinuation (see section 4.4).

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

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

Pregnancy

There are no or limited amount of data from the use of ozanimod in pregnant women. Studies in animals have shown reproductive toxicity including foetal loss and anomalies, notably malformations of blood vessels, generalised oedema (anasarca), and malpositioned testes and vertebrae (see section 5.3). Sphingosine 1-phosphate is known to be involved in vascular formation during embryogenesis (see section 5.3).

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions (> 5%) in controlled periods of the adult multiple sclerosis and ulcerative colitis clinical studies are nasopharyngitis , alanine aminotransferase (ALT) increased , and gamma-glutamyl transferase (GGT) increased. The most common adverse reactions leading to discontinuation were related to liver enzyme elevations (1.1%) in the MS clinical studies. Liver enzyme elevations leading to discontinuation occurred in 0.4% of patients, in UC controlled clinical studies.

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

colitis. Tabulated list of adverse reactions

The adverse reactions observed in patients treated with ozanimod are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. 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: Summary of adverse reactions reported in MS and UC clinical studies

*At least one of these adverse reactions was reported as serious

f 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 monoxide diffusing capacity decreased, forced expiratory volume decreased

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 greater occurred in 1.6% of patients treated with ozanimod 0.92 mg and 1.3% of patients on IFN P- 1a IM. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients on ozanimod and 3.1% of

patients on IFN P-ia 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 within approximately 2–4 weeks. Ozanimod was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was i.i% of MS patients on ozanimod 0.92 mg and 0.8% of patients on IFN beta-ia IM.

In UC clinical studies, during the induction period, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 0.9% and no patients, respectively. In the induction period, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 2.3% and no patients, respectively. In controlled and uncontrolled UC clinical studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ozanimod with values returning to less than 3 fold the ULN within approximately 2 to 4 weeks.

Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% of patients treated with ozanimod 0.92 mg, and none in patients who received placebo in the controlled UC clinical studies.

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 i (decrease of i.2 bpm in MS clinical studies and 0.7 bpm in the UC clinical studies), returning to near baseline at Hour 6. With continued dose escalation, there were no clinically 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 P—ia IM on the day of treatment initiation (Day 1). After Day 1, the incidence of bradycardia was 0.8% on ozanimod versus 0.7% on IFN P-1a IM. (see section 5.i).

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

In MS clinical studies, first-degree atrioventricular block was reported in 0.6% (5/882) of patients treated with ozanimod versus 0.2% (2/885) treated with IFN p-1a IM. Of the cases reported with ozanimod, 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 treatment initiation (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 the maintenance period, bradycardia was not reported

Increased blood pressure

In MS clinical studies, patients treated with ozanimod had an average increase of approximately

1–2 mm Hg in systolic pressure over IFN P-1a IM, and approximately 1 mm Hg in diastolic pressure over IFN p-1a IM. The increase in systolic pressure was first detected after approximately 3 months of treatment initiation and remained stable throughout treatment.

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

The mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated with ozanimod is similar to patients with MS. In UC clinical studies, during the induction period, the average increase from baseline in SBP was 3.7 mm Hg in patients treated with ozanimod and 2.3 mm Hg in patients treated with placebo. During the maintenance period, the average increase from baseline in SBP was 5.1 mm Hg in patients treated with ozanimod and 1.5 mm Hg in patients treated with placebo. There was no effect on DBP.

Hypertension was reported as an adverse reaction in 1.2% of patients treated with ozanimod 0.92 mg and none in patients treated with placebo in the induction period, and in 2.2% and 2.2% of patients in the maintenance period, respectively. Hypertensive crisis was reported in two patients receiving ozanimod and one patient receiving placebo.

Blood lymphocyte count reduction

In MS clinical studies, 3.3% of patients and in UC controlled clinical studies , <3% of patients experienced lymphocyte counts less than 0.2 × 109/L with values generally resolving to greater than

0.2 × 109/L while remaining on treatment with ozanimod.

Infections

In MS clinical studies, the overall rate of infections (35%) with ozanimod 0.92 mg was similar to IFN P-ia IM. The overall rate of serious infections was similar between ozanimod (1%) and IFN P-ia IM (0.8%) in MS clinical studies.

In UC clinical studies, during the induction period, the overall rate of infections and rate of serious infections in patients treated with ozanimod were similar to that in patients who received placebo. (9.9% vs. i0.7% and 0.8% vs. 0.4%, respectively). During the maintenance period, the overall rate of infections in patients treated with ozanimod was higher than in patients treated with placebo (23% vs. i2%) and the rate of serious infections was similar (0.9% vs. i.8%).

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

Herpetic infections

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

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

Respiratory system

Minor dose-dependent reductions in forced expiratory volume in i second (FEVi) and forced vital capacity (FVC) were observed with ozanimod treatment. At months 3 and i2 of treatment in MS clinical studies, median changes from baseline in FEVi (FVC) in the ozanimod 0.92 mg group were –

0.07 L and – 0.1 L (- 0.05 L and — 0.065 L), respectively, with smaller changes from baseline in the IFN B-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 observed with ozanimod 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 period and these small changes in pulmonary function tests were reversible in patients re-randomised to placebo.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: at www.mhra. gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

In patients with overdosage of ozanimod, monitor for signs and symptoms of bradycardia, which may include 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 can be reversed by parenteral atropine or isoprenaline.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA38

Mechanism of action

Ozanimod is a potent sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity 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 and selectivity for S1P1 and S1P5. The mechanism by which ozanimod exerts therapeutic effects in MS and UC is unknown, but may involve the reduction of lymphocyte migration into the central nervous system (CNS) and intestine.

The ozanimod-induced reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response. Ozanimod has minimal impact on cells involved in innate immune response, which are key components of immunosurveillance.

Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites including two major metabolites (see section 5.2). In humans, approximately 94% of circulating total active drug exposure are represented by ozanimod (6%) and the two major metabolites CC112273 (73%), and CC1084037 (15%) (see section 5.2).

Pharmacodynamic effects

Reduction of peripheral blood lymphocytes

In active-controlled MS and UC clinical studies, mean lymphocyte counts decreased to approximately 45% of baseline by 3 months (approximate mean blood lymphocyte count 0.8 × 109/L) and remained stable during treatment with ozanimod. After discontinuing ozanimod 0.92 mg, the median time to recovery of peripheral blood lymphocytes to the normal range was approximately 30 days, with approximately 80% to 90% of patients recovering to normal within 3 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 the maintenance 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-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation by ozanimod and its active metabolites leading to cellular hyperpolarisation and reduced excitability with a maximal effect on HR seen within 5 hours post dose. Due to its functional antagonism at S1P1 receptors, a dose escalation schedule with ozanimod 0.23 mg followed by 0.46 mg, and 0.92 mg successively desensitizes 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 doseescalation regimen 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 mg daily for 4 days in healthy subjects, no evidence of QTc prolongation was observed as demonstrated by 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 for model derived QTc (corrected for placebo and baseline) below 10 ms at maximum concentrations achieved with ozanimod doses >0.92 mg once daily.

Clinical efficacy and safety

Multiple sclerosis

Ozanimod was evaluated in two 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 treatment beyond month 12 until the last enrolled patient completed the study. Study 2 -RADIANCE was a 2-year study.

The dose of ozanimod was 0.92 mg and 0.46 mg given orally once daily, with a starting dose of

0.23 mg on days 1–4, followed by an escalation to 0.46 mg on days 5–7, and followed by the assigned dose on day 8 and thereafter. The dose of IFN P-1a, the active comparator, was 30 mcg given intramuscularly once weekly.

Both studies included patients with active disease as defined by having at least one relapse within the prior 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 to 5.0.

Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. MRIs were performed at baseline (Studies i and 2), 6 months (SUNBEAM), i year (Studies i and 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 i2 months) for SUNBEAM and 24 months for RADIANCE. The key secondary outcome measures included i) the number of new or enlarging MRI T2 hyperintense lesions over i2 and 24 months; 2) the number of MRI Ti GdE lesions at i2 and 24 months; and 3) the time to confirmed disability progression, defined as at least a i-point increase from baseline EDSS sustained for i2 weeks. Confirmed disability progression was prospectively evaluated in a pooled analysis of Studies i and 2. In SUNBEAM, i346 patients were randomised to receive ozanimod 0.92 mg (n = 447), ozanimod

0.46 mg (n= 451), or IFN P-1a IM (n = 448); 94% of ozanimod treated 0.92 mg, 94% of ozanimod treated 0.46 mg, and 92% of IFN P-ia 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 P-1a IM (n = 441); 90% of ozanimod treated 0.92 mg, 85% of ozanimod treated 0.46 mg, and 85% of IFN P-1a IM treated patients completed the study. Patients enrolled across the 2 studies had a mean age of 35.5 years (range 18–55), 67% were female, mean time since MS symptom onset was 6.7 years. The median EDSS score at baseline was 2.5; approximately one-third of the patients had been 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 or more T1 Gd-enhancing lesions (mean 1.7).

The results for SUNBEAM and RADIANCE are shown in Table 3. The efficacy has been demonstrated 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

effect for the primary endpoint in RADIANCE when considering the preferred negative binomial model strategy.

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

SUNBEAM and Study 2 – RADIANCE

* Mean duration was 13.6 months

Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for multiplicity f 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) was found to be 1.040 (0.730, 1.482).)

1 Log rank test

2 Prospectively planned pooled analysis of Studies 1 and 2

3 Over 12 months for Study 1 and over 24 months for Study 2

4 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 mean percent 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 by clinical or imaging features. Post-hoc analyses of patient populations with differing baseline levels of disease activity, including active and highly active disease, showed that the efficacy of ozanimod on clinical and imaging endpoints was consistent with the overall population.

Long-term Data

Patients who completed the Phase 3 SUNBEAM and RADIANCE studies could enter an open label extension study (Study 3 – DAYBREAK). Of the 751 patients initially randomised to ozanimod 0.92 mg and treated for up to 3 years, the (adjusted) ARR was 0.124 after the 2nd year of treatment.

Ulcerative colitis

The efficacy and safety of ozanimod were evaluated in two multicenter, randomised, double-blind, placebo-controlled clinical studies [TRUENORTH-I (induction period) and TRUENORTH-M (maintenance period)] in adult patients with moderately to severely active ulcerative colitis.

TRUENORTH-I included patients who were randomised 2:1 to ozanimod 0.92 mg or 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. Patients could have had an inadequate response, loss of response, or intolerance to a biologic (e.g., TNF blocker and/or vedolizumab), corticosteroids, and/or immunomodulators (e.g. 6-mercaptopurine and azathioprine) therapy. Patients were to be receiving treatment with oral aminosalicylates and/or corticosteroids.

Disease assessment was based on the Mayo score, which ranges from 0 to 12 and has four subscores from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (week 0) as a Mayo score of 6 to 12, including a Mayo endoscopy subscore > 2. An endoscopy score of 2 was defined by marked erythema, lack of vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration.

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 received concomitant 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 TNF blockers. Of these patients, 63% received at least two or more biologics including TNF blockers; 47% received an integrin receptor blocker (e.g. vedolizumab); 36% failed to ever respond to at least one TNF blocker; 65% lost response to a TNF blocker. 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 and 35% having greater than 9.

The primary endpoint was clinical remission at week 10, defined as a Three-component Mayo: rectal bleeding subscore = 0 and stool frequency subscore < 1 (and a decrease of > 1 point from the Baseline Stool Frequency subscore) and endoscopy subscore < 1.

Key secondary endpoints at week 10 were clinical response, endoscopic improvement, and mucosal healing. Clinical response with a definition of (Three-component Mayo: A reduction from Baseline in the 9-point Mayo score of > 2 points and > 35%, and a reduction from Baseline in the Rectal Bleeding subscore of > 1 point or an absolute Rectal Bleeding subscore of < 1 point), endoscopic improvement with a definition of Endoscopy subscore of < 1 point), and mucosal healing defined as Endoscopy subscore of < 1 point and a Geboes index score < .0.

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 as shown in Table 4.

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

TRUENORTH-I (at week 10)

CI = confidence interval; TNF = tumor necrosis factor.

a Treatment difference (adjusted for stratification factors of prior TNF blocker exposure and corticosteroid use at baseline).

bClinical remission is defined as: RBS = 0, SFS < 1 (and a decrease of > 1 point from the baseline SFS), and endoscopy subscore < 1 without friability.

'Clinical response is defined as a reduction from baseline in the 9-point Mayo score of > 2 and > 35%, and a reduction from baseline in the RBS of > 1 or an absolute RBS of < 1.

dEndoscopic improvement is defined as a Mayo endoscopic score < 1 without friability.

eEndoscopic improvement with histologic remission defined as both Mayo endoscopic score < 1 without friability and histological remission (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation Geboes index score < 2.0).

fp=<0.0001.

gp=<0.001.

Rectal bleeding and stool frequency subscores

Decreases in rectal bleeding and stool frequency subscores were observed as early as week 2 (ie, 1 week after completing the required 7-day dose titration) in patients treated with ozanimod.

TRUENORTH-M (maintenance study)

In order to be randomised to treatment in the maintenance study (TRUENORTH-M), patients had to have 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 ozanimod 0.92 mg open-label. Patients were re-randomised in a double-blinded fashion (1:1) to receive either ozanimod 0.92 mg (n=230) or placebo (n=227) for 42 weeks. The total study duration was 52 weeks, including both the induction and maintenance periods. Efficacy assessments were at week 52.

Concomitant aminosalicylates were required to remain stable through week 52. Patients on concomitant 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 and 31% 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 at week 52. Key secondary endpoints at week 52 were the proportion of patients with clinical response, endoscopic improvement, the proportion of patients maintaining clinical remission at week 52, corticosteroid-free clinical remission, mucosal healing and durable clinical remission among patients who achieved clinical remission at 10 weeks of the induction period.

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

TRUENORTH-M (at week 52)

CI = confidence interval; TNF = tumor necrosis factor.

a Treatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at week 10).

bClinical remission is defined as: RBS = 0 point and SFS < 1 point (and a decrease of > 1 point from the baseline SFS) and endoscopy 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 a reduction 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 (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation Geboes index score < 2.0)

h Durable clinical remission is defined as clinical remission at week 10 and at week 52 in all subjects who entered the maintenance period. ip=<0.0001.

j p=<0.001. k

p=0.0025. l

p=0.0030

The proportion of patients treated with ozanimod 0.92 mg who did not experience a disease relapse was higher relative to placebo during the maintenance period, as shown in figure 1.

Figure 1: Time to disease relapse in maintenance study TRUENORTH-M (Kaplan-Meier

Curves)

Time (Weeks)

Disease relapse is defined as an increase in partial Mayo score of > 2 points compared to the week 10 partial Mayo score with an absolute partial Mayo score > 4 points AND an endoscopic subscore of > 2 points

Histologic remission at week 10 and 52

Histologic remission (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation Geboes index score < 2.0) was assessed at week 10 of TRUENORTH-I and at week 52 of TRUENORTH-M. At week 10, a significantly greater proportion of patients treated with ozanimod 0.92 mg achieved histologic remission (18%) compared to patients treated with placebo (7 %). At week 52, maintenance of this effect was observed with a significantly greater proportion of patients in histologic remission in patients treated with ozanimod 0.92 mg (34%) compared to patients treated with placebo (16%).

Endoscopic Normalisation

Endoscopic normalisation was defined as a Mayo endoscopic subscore of 0. At week 10 of TRUENORTH-I endoscopic normalisation was achieved in 6% of patients treated with ozanimod 0.92 mg compared to 3% of patients treated with placebo. At week 52 of TRUENORTH-M endoscopic normalisation was achieved in 24% of patients treated with ozanimod 0.92 mg compared to 12% of patients treated with placebo.

Health-related quality of life

General health status was assessed using the Short Form health survey (SF-36) and the EuroQol Visual Analogue Scale (EQ-5D VAS). At week 10 of TRUENORTH-I, patients receiving ozanimod showed significantly greater and clinically meaningful improvements compared to placebo on the SF-36 Physical Component Summary Score. These improvements were maintained in ozanimod treated patients in TRUENORTH-M at week 52. Significant improvements were also observed in the EQ-5D VAS for ozanimod compared to placebo at both week 10 and week 52.

Long-term data

Patients who did not achieve clinical response at the end of the induction period, lost response in the maintenance period or completed the TRUENORTH study were eligible to enter an open label extension study (OLE) and received ozanimod 0.92 mg. A total of 821 of the 1012 eligible patients entered the OLE. In this open-label extension study, the benefits of ozanimod as assessed by clinical remission, clinical response, endoscopic improvement, corticosteroid-free remission were observed in patients for up to 142 weeks.

Additional clinical data

TOUCHSTONE, a 33 week placebo controlled phase 2 study in patients with moderate to severe ulcerative colitis demonstrated a significant treatment difference for ozanimod 0.92 mg (n=67) relative to placebo (n=65) in clinical remission (using the pre-specified 4-component Total Mayo

Score) of 11% (p=0.0482) at week 9 and 15% (p=0.0108) at week 33. Corresponding values for the 3– component modified Mayo Score (post-hoc analysis using phase 3 definitions) for clinical remission were 14% (p=0.0263) and 18% (p=0.0053) at week 9 and 33, respectively.

Paediatric population

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

5.2 Pharmacokinetic properties

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 and selectivity for S1P1 and S1P5 to the parent. The maximum plasma concentration (Cmax) and area under the curve (AUC) for ozanimod, CC112273, and CC1084037 increased proportionally over the dose range of ozanimod 0.46 mg to 0.92 mg (0.5 to 1 times the recommended dose). Following multiple dosing, approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). At a dose of 0.92 mg orally once daily in RRMS, the geometric 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%) and 132861 pg*h/mL (45.6%), respectively, for CC112273. Cmax and AUC0–24h for CC1084037 are approximately 20% of that for CC112273. Factors affecting CC112273 are applicable for CC1084037 as they are interconverting metabolites. Population pharmacokinetic analysis indicated that there were no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.

Absorption

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.

Distribution

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) was 5590 L (27%), indicating extensive 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.

Biotransformation

Ozanimod is widely metabolised by multiple biotransformation pathways including aldehyde dehydrogenase and alcohol dehydrogenase (ALDH/ADH), cytochrome P450 (CYP) isoforms 3A4 and 1A1, 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 CC1084037 exceed the AUC of ozanimod by 13-fold and 2.5-fold, respectively. In vitro studies indicated that monoamine oxidase B (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 30– and 110– hydroxysteroid dehydrogenase (HSD).

Elimination

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 for ozanimod was achieved within 7 days, with the estimated accumulation ratio following repeated oral administration of 0.92 mg once daily of approximately 2.

The model-based mean (CV%) effective half-life (t1/2) of CC112273 was approximately 11 days (104%) in RMS patients, with mean (CV%) time to steady state of approximately 45 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. Steady state 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 the radioactivity was recovered from urine and faeces, respectively, primarily composed of inactive metabolites. 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

Renal impairment

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 pharmacokinetics of ozanimod or CC112273. No dose adjustment is needed in patients with renal impairment.

Hepatic impairment

In a dedicated hepatic impairment trial, following a single oral dose of 0.23 mg ozanimod, exposures (AUClast) for ozanimod and CC112273 were approximately 11% lower and 31% lower, respectively, in patients with mild hepatic impairment (Child-Pugh A; n = 8) when compared to patients with normal hepatic function (n = 7). Exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 33% lower, respectively, in patients with moderate hepatic impairment (Child-Pugh B; N=8) when compared to patients with normal hepatic function (n = 8). These differences were not considered clinically meaningful. The pharmacokinetics of ozanimod were not evaluated in patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Use in patients with severe hepatic impairment is contraindicated (Child-Pugh class C) (see section 4.3).

Elderly

Population pharmacokinetic analysis showed that steady state exposure (AUC) of CC112273 in patients over 65 years of age were approximately 3 – 4% greater than patients 45 – 65 years of age and 27% greater than adult patients under 45 years of age. There is not a meaningful difference in the pharmacokinetics in elderly patients.

Paediatric population

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

5.3 Preclinical safety data

In repeated dose toxicology studies in mice (up to 4 weeks), rats (up to 26 weeks) and monkeys (up to 39 weeks), ozanimod markedly affected the lymphoid system (lymphopenia, lymphoid atrophy and reduced antibody response) and increased lung weights and the incidence of mononuclear alveolar infiltrates, which is consistent with its primary activity at S1P1 receptors (see section 5.1). At the no observed adverse effect levels in chronic toxicity studies, systemic exposures to the disproportionate main active and persistent human metabolites CC112273 and CC1084037 (see section 5.2), and even to the total human active drug (ozanimod combined with the mentioned metabolites), were lower than those expected in patients at the maximum human dose of 0.92 mg ozanimod.

Genotoxicity and carcinogenicity

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

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

In the 6-month Tg.rasH2 mouse study, hemangiosarcomas increased in a statistically-significant and dose-related manner. At the low dose (8 mg/kg/day), the hemangiosarcoma incidence was increased statistically 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 specific hemangiosarcomas with S1P1 agonists. Therefore S1P1 receptor agonism related hemangiosarcomas in 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 the lowest dose tested, exposure in Tg.rasH2 mice to the disproportionate two main active human metabolites was for CC112273 2.95 fold and for CC1084037 1.4 fold above the human exposure at the maximum clinical dose of 0.92 mg ozanimod.

Reproductive toxicity

Ozanimod had no effect on male and female fertility up to approximately 150-fold the systemic exposure to total active drug (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 active drug, resulting in embryolethality and teratogenicity (generalised oedema/anasarca and malpositioned testes in rats, malpositioned caudal vertebrae and malformations of the great vessels in rabbits). 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 the systemic exposure to total active drug at the maximum human dose of 0.92 mg ozanimod. Ozanimod and metabolites were present in rat milk.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content

Microcrystalline cellulose Silica, colloidal anhydrous Croscarmellose sodium Magnesium stearate

Capsule shell

Zeposia 0.23 mg and 0.46 mg

Gelatin

Titanium dioxide (E171) 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).

Printing ink

Shellac (E904)

Iron oxide black (E172)

Propylene glycol (E1520)

Ammonia solution, concentrated (E527)

Potassium hydroxide (E525)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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 × 0.23 mg, 3 × 0.46 mg).

Not all pack sizes may be marketed.