The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC ,please click here: https://www.medicines.org.uk/emc/product/11908/smpc

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and 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 (similar activity and selectivity shown in vitro). Ozanimod has minimal or no activity on S1P2, S1P3, and S1P4. The mechanism by which ozanimod exerts therapeutic effects in UC is unknown, but may involve the reduction of lymphocyte migration into the 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 contribute to immunosurveillance.

Therapeutic indications

Ozanimod 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.

Dosing, administration

Ozanimod is administered orally, once daily, with or without food.

The initial dose escalation regimen from Day 1 to Day 7 is required and shown below in Table 1.
Following the 7-day dose escalation, the recommended dose is 0.92 mg ozanimod once daily, starting on Day 8.

Table 1: Dose escalation regimen

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

- Adults over 65 years old and elderly population: There are limited data available on UC patients ≥ 65 years of age. Caution should be used in UC 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.

- Renal impairment: No dose adjustment is necessary.

- Hepatic impairment: Patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B) are recommended to complete the 7-day dose escalation regimen, and then take 0.92 mg once every other day. Ozanimod was not evaluated in patients with severe hepatic impairment. Therefore, patients with Child-Pugh class C must not be treated with ozanimod.

- Paediatric population: The safety and efficacy of ozanimod in children and adolescents aged below 18 years have not yet been established. No data are available.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients.

• Immunodeficient state predisposing to systemic opportunistic infections (see section 4.4 of the SmPC for more details).

• 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.

• Active malignancies.

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

• During pregnancy and in women of childbearing potential not using effective contraception: 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. S1P is known to be involved in vascular formation during embryogenesis. Prior to treatment initiatiation, patients must have a negative pregnancy test and must use effective contraception during treatment, and for 3 months after treatment discontinuation

• During Breastfeeding: ozanimod metabolites are excreted in milk of treated animals during lactation. Due to the potential for serious adverse reactions to ozanimod/metabolites in nursing infants, women receiving ozanimod should not breastfeed.

Adverse effects

The most commonly reported adverse reactions are nasopharyngitis (12.3%), alanine aminotransferase (ALT) increased (5%), and gamma-glutamyl transferase (GGT) increased (5.4%).

Initiation of ozanimod may result in transient bradycardia that usually resolves by the end of the first week.

Other serious adverse reactions include serious opportunistic infections (PML has been reported in patients treated with ozanimod), macular oedema, hypertension, and rare cases of clinically significant liver injury.

Liver enzyme elevations leading to discontinuation occurred in 0.4% of patients, in UC controlled clinical studies.

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with ozanimod in multiple sclerosis and UC clinical studies and from post-marketing experience including spontaneous case reports 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: Adverse reactions

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

^† Includes hypertension, essential hypertension, and blood pressure increased.

** for patients with pre-existing factors (see section 4.4 of the SmPC for more details)

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

**** Adverse reactions from post-marketing reports

***** see Description of selected adverse reactions

Interactions with other Drugs

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 Monoamine oxidase B (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.

Effect of inducers of CYP2C8 on ozanimod

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

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. 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.

Effect of inhibitors of CYP2C8

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).

Special warnings and precautions

Bradyarrhythmia

1) Initiation of treatment with ozanimod

Prior to treatment initiation, an electrocardiogram (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) and therefore the initial dose escalation regimen to reach the maintenance dose (0.92 mg) on day 8 should be followed.

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 towards 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 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.

2) 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 is less than 45 bpm

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

• there is evidence of a new onset second-degree or higher AV block at the 6-hour post-dose ECG

• QTc interval ≥ 500 mse

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 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 injury

Elevations of aminotransferases, gamma-glutamyl transferase and bilirubin have been reported in patients treated with ozanimod.

Clinically significant liver injury has occurred in patients treated with ozanimod in the post marketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. Severe liver injury may result in the need for a liver transplant.

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 including serum bilirubin and alkaline phosphatase (ALP) should be instituted. If liver transaminases above 5 times the ULN are confirmed, or at least 3 times the ULN associated with increase of serum bilirubin more than 2 times the ULN, treatment with ozanimod should be interrupted and only re-commenced once liver transaminase values have normalised (including if an alternative cause of the hepatic dysfunction is discovered).

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.

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.

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. A recent (i.e., within 6 months or after discontinuation of prior 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.

If a patient develops a serious infection, treatment interruption with ozanimod should be considered.

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

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

In UC clinical studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ozanimod, however, long-term data on concomitant use of ozanimod and corticosteroids are still limited. 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) or glatiramer.

Progressive multifocal leukoencephalopathy (PML)

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 (e.g., 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), 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 immunisations 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

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 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. 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 multiple sclerosis 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 UC controlled clinical studies, hypertension was more frequently reported in patients treated with ozanimod than in patients treated with placebo (UC) and in patients receiving concomitant ozanimod and SSRIs or SNRIs. 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.