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.

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

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 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.

• 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).

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 betablocker
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 beta-blockers and calciumchannel 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 x 109/L, if confirmed, should lead to interruption of ozanimod therapy until the level reaches > 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 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 ß-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 reinitiated 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-Barré 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 β-1a 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.

 

Effect of inhibitors of the breast cancer resistance protein (BCRP) on ozanimod
Coadministration of ozanimod with cyclosporine, a strong BCRP inhibitor, had no effect on the
exposure of ozanimod and its major active metabolites (CC112273 and CC1084037).
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 calciumchannel
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.

 

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).

 

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

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

System Organ Class	Frequency	Adverse reaction
Infections and infestations	Very common	Nasopharyngitis
	Common	Pharyngitis, Respiratory tract infection viral, Urinary tract infection*, Herpes zoster, Herpes simplex
Blood and lymphatic system disorders	Very common	Lymphopenia
Immune system disorders	Uncommon	Hypersensitivity (including rash and urticaria*)
Eye disorders	Uncommon	Macular oedema**
Cardiac disorders	Common	Bradycardia*
Vascular disorders	Common	Hypertension*†, Orthostatic hypotension
Investigations	Common	Alanine aminotransferase increased, Gamma-glutamyl transferase increased, Blood bilirubin increased, 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 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 β-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 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 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 1.1% of MS
patients 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 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 1 (decrease of 1.2 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 β-1a 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 β-1a IM. (see section 5.1).
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 β-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 β-1a IM, and approximately 1 mm Hg in diastolic pressure
over IFN β-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 β-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 x 109/L with values generally resolving to greater than
0.2 x 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
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 serious
infections in patients treated with ozanimod were similar to that in patients who received placebo.
(9.9% vs. 10.7% 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.
12%) and the rate of serious infections was similar (0.9% vs. 1.8%).
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 β-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 1 second (FEV1) and forced vital
capacity (FVC) were observed with ozanimod treatment. At months 3 and 12 of treatment in MS
clinical studies, median changes from baseline in FEV1 (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 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 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 the national reporting system.

− To report any side effect(s):
• Saudi Arabia:

Please report adverse drug events to: The National Pharmacovigilance Centre (NPC): o SFDA Call Center: 19999 o E-mail: npc.drug@sfda.gov.sa o Website: https://ade.sfda.gov.sa

• Other GCC States:

Please contact the relevant competent authority.

 

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.

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 x 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 dose-escalation
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 β-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 1 and 2), 6 months (SUNBEAM), 1 year (Studies
1 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 12 months) for SUNBEAM and 24 months for RADIANCE.

The key secondary outcome measures included 1) the number of new or enlarging MRI T2
hyperintense lesions over 12 and 24 months; 2) the number of MRI T1 GdE lesions at 12 and 24
months; and 3) the time to confirmed disability progression, defined as at least a 1-point increase from
baseline EDSS sustained for 12 weeks. Confirmed disability progression was prospectively evaluated
in a pooled analysis of Studies 1 and 2.
In SUNBEAM, 1346 patients were randomised to receive ozanimod 0.92 mg (n = 447), ozanimod
0.46 mg (n= 451), or IFN β-1a IM (n = 448); 94% of ozanimod treated 0.92 mg, 94% of ozanimod
treated 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, and
85% of IFN β-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

 

Endpoints	SUNBEAM (≥ 1 year)*		RADIANCE (2 year)
	Ozanimod 0.92 mg (n=447) %	IFN β-1a IM 30 mcg (n=448) %	Ozanimod 0.92 mg (n=433) %	IFN β-1a IM 30 mcg (n=441) %
Clinical Endpoints
Annualized Relapse Rate (Primary Endpoint) Relative Reduction	0.181	0.350	0.172	0.276
	48% (p<0.0001)		38% (p<0.0001)
Proportion Relapse-free**	78% (p=0.0002)1	66%	76% (p=0.0012)1	64%
Proportion with 3-month Confirmed Disability Progression (CDP)†2 Hazard ratio (95% CI) Proportion with 6-month CDP†2# Hazard Ratio (95% CI)	7.6% Ozanimod vs. 7.8% IFN β-1a IM 0.95 (0.679, 1.330) 5.8% Ozanimod vs. 4.0% IFN β-1a IM 1.413 (0.922, 2.165)
MRI Endpoints
Mean number of new or enlarging T2 hyperintense lesions per MRI3 Relative Reduction	1.465	2.836	1.835	3.183
	48% (p<0.0001)		42% (p<0.0001)
Mean number of T1 Gd enhancing lesions4 Relative Reduction	0.160	0.433	0.176	0.373
	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) 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 < 2.0.
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)

	Ozanimod 0.92 mg (N=429)		Placebo (N=216)		Treatment Difference %a (95% CI)
	n	%	n	%
Clinical remissionb	79	18%	13	6%	12% (7.5, 17.2)f
Without prior TNF blocker exposure	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 blocker exposure	157/299	53%	44/151	29%
Prior TNF blocker exposure	48/130	37%	12/65	19%
Endoscopic improvementd	117	27%	25	12%	16% (9.7, 21.7)f
Without prior TNF blocker exposure	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 blocker exposure	47/299	16%	6/151	4%
Prior TNF blocker exposure	7/130	5%	2/65	3%

CI = confidence interval; TNF = tumor 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 endoscopy subscore ≤ 1
without friability.
c 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.
d Endoscopic improvement is defined as a Mayo endoscopic score ≤ 1 without friability.

e Endoscopic 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).
f p=<0.0001.
g p=<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)

	Ozanimod 0.92 mg (N=230)		Placebo (N=227)		Treatment 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 at week 52 in the subset of patients in remission at week 10e	41/79	52%	22/75	29%	24% (9.1, 38.6)k
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 = tumor 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) 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.
i p=<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)

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 16% (p=0.0482) at week 9 and 21% (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 22% (p=0.0263) and 25% (p=0.0046) 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).

 

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 3β- and 11β- 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).

 

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 twoyear
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.

 

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)

Not applicable.

3 years

Do not store above 30 °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 local
requirements.