Adult: In patients with relapsing forms of multiple sclerosis (including clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease): Initially, 0.23 mg once daily on Days 1-4, then titrate to 0.46 mg once daily on Days 5-7. Maintenance dose: 0.92 mg once daily starting from Day 8 onwards. Reinitiate titration schedule if treatment is interrupted for ≥1 day in the first 2 weeks, for >7 consecutive days between weeks 3 and 4, or >14 consecutive days after 4 weeks of treatment. If the interruption is shorter than the previously mentioned conditions, continue treatment with the regular dosing schedule.
Oral Ulcerative colitis
Adult: In patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or are intolerant to either conventional treatment or biologic agent: Initially, 0.23 mg once daily on Days 1-4, then titrate to 0.46 mg once daily on Days 5-7. Maintenance dose: 0.92 mg once daily starting from Day 8 onwards. Reinitiate titration schedule if treatment is interrupted for ≥1 day in the first 2 weeks, for >7 consecutive days between weeks 3 and 4, or >14 consecutive days after 4 weeks of treatment. If the interruption is shorter than the previously mentioned conditions, continue treatment with the regular dosing schedule.
Hepatic Impairment
Mild to moderate (Child-Pugh class A and B): Initially, 0.23 mg once daily on Days 1-4, then titrate to 0.46 mg once daily on Days 5-7. Maintenance dose: 0.92 mg once every other day starting from Day 8 onwards. Severe (Child-Pugh class C): Contraindicated.
Administration
Ozanimod May be taken with or without food.
Contraindications
MI, unstable angina, decompensated heart failure (requiring hospitalisation), NYHA class III or IV heart failure, stroke, or TIA within the last 6 months; history or presence of Mobitz type II 2nd-degree or 3rd-degree AV block, sick sinus syndrome, or sinoatrial block (unless with a functioning pacemaker); severe untreated sleep apnoea; immunodeficiency; active malignancies; severe active infections or active chronic infections (e.g. hepatitis, TB). Severe hepatic impairment (Child-Pugh class C). Pregnancy and women of childbearing potential. Concomitant administration with MAOIs.
Special Precautions
Patient with history of cerebrovascular disease, recurrent syncope or symptomatic bradycardia, uncontrolled hypertension, arrhythmias (requiring treatment with class Ia or III antiarrhythmic drugs), ischaemic heart disease, heart failure, pre-existing significant QT interval prolongation (QT >450 milliseconds in males; >470 milliseconds in females) or other risk factors for QT prolongation; severe respiratory disease, pulmonary fibrosis, COPD; risk factors for macular oedema (including history of diabetes mellitus, uveitis or retinal disease). Patients receiving QT-prolonging or heart rate-lowering agents (e.g. β-blockers, Ca-channel blockers). Avoid use of live attenuated vaccines during therapy and for 3 months after stopping the treatment; if required, vaccination must be at least 1 month prior to treatment initiation. Concomitant administration with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies. Mild to moderate hepatic impairment (Child-Pugh class A or B). Elderly. Lactation.
Adverse Reactions
Significant: Cardiovascular effects (including bradycardia, bradyarrhythmia or transient AV conduction delays; hypertension, orthostatic hypotension, hypertensive crisis); increased serum transaminases (including hyperbilirubinemia, elevated ALT and alkaline phosphatase); immunosuppression (increases risk for infections and malignancies); cutaneous neoplasms or non-melanoma skin cancer; lymphocytopenia; viral infections (e.g. herpes zoster infection, herpes simplex infection), URTI, UTI; posterior reversible encephalopathy syndrome (PRES); reduced forced expiratory volume (FEV1) and forced vital capacity (FVC); macular oedema (with or without visual symptoms). Rarely, severe exacerbation of multiple sclerosis including disease rebound (after treatment discontinuation), reversible posterior leucoencephalopathy syndrome (RPLS). Gastrointestinal disorders: Nausea, upper abdominal pain. General disorders and administration site conditions: Fever, peripheral oedema. Immune system disorders: Hypersensitivity reactions (e.g. rash, urticaria). Infections and infestations: Nasopharyngitis, pharyngitis. Investigations: Increased GGT. Musculoskeletal and connective tissue disorders: Arthralgia, back pain. Nervous system disorders: Headache. Potentially Fatal: Progressive multifocal leucoencephalopathy (PML), cryptococcal meningitis, disseminated cryptococcal infections.
Patient Counseling Information
Women of childbearing potential must use proven birth control methods during therapy and for 3 months after stopping the treatment. Full-course varicella-zoster virus (VZV) vaccination for antibody-negative patients or those without documented immunity to VZV is recommended; wait ≥1 month after a full vaccination course has been completed before initiating treatment. Avoid exposure to sunlight and phototherapy with ultraviolet B (UVB) radiation or psoralen and ultraviolet A (PUVA) photochemotherapy.
Monitoring Parameters
Confirm pregnancy status before treatment initiation in women of reproductive potential. Obtain CBC including lymphocyte count (at baseline [within 6 months], periodically or as clinically indicated, and 3 months post-therapy); bilirubin, transaminase levels (at baseline [within 6 months], months 1, 3, 6, 9, and 12 of treatment then periodically thereafter); ECG (at baseline). Evaluate respiratory function (e.g. spirometry with FEV1 and FVC) as clinically indicated; VZV antibodies prior to treatment initiation (particularly in patients without documented full series vaccination to VZV or no healthcare professional-confirmed history of chickenpox). Screen for latent infection (e.g. hepatitis, TB) in high-risk populations or countries with high TB burden (at baseline). Perform ophthalmologic baseline evaluation of the fundus (including macula), then repeat as clinically indicated (especially if vision changes) during treatment and more frequently in patients with diabetes, history of uveitis or retinal disease; brain MRI for PML signs. Monitor heart rate and blood pressure regularly during treatment; signs and symptoms of bradycardia; respiratory status changes. Assess for signs and symptoms of hepatic dysfunction, immune reconstitution inflammatory syndrome, PRES, and severe increase in disability (after treatment discontinuation). Monitor for signs and symptoms of infection during treatment and at least 4 weeks following discontinuation; promptly evaluate and treat, if necessary, including opportunistic ones (e.g. cryptococcal meningitis, disseminated infections). Perform 1st-dose 6-hour monitoring in patients with pre-existing cardiac conditions (e.g. resting heart rate <55 bpm, 2nd-degree Mobitz type I AV block, or history of MI or heart failure); monitor for symptomatic bradycardia (6 hours after first dose); pulse and heart rate (hourly during the 6-hour period). Additional monitoring may be needed as clinically indicated; if medical treatment is required, continue monitoring overnight. Repeat a 6-hour monitoring period following the 2nd dose of ozanimod.
Overdosage
Symptom: Bradycardia. Management: Symptomatic and supportive treatment. Monitor blood pressure and heart rate. Perform ECG. May administer parenteral atropine or isoprenaline for reversal of decreased heart rate.
Drug Interactions
Increased exposure with strong CYP2C8 inhibitors (e.g. clopidogrel, gemfibrozil). Decreased exposure CYP2C8 inducers (e.g. rifampicin). Enhanced risk for immunosuppression with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies. Increased risk for bradycardia with drugs that are known to slow the heart rate or AV conductions (e.g. β-blockers, Ca-channel blockers, class Ia [e.g. procainamide, quinidine] or class III [e.g. amiodarone, sotalol] antiarrhythmic drugs). Reduce therapeutic effect of vaccines. Potentially Fatal: May reduce exposure of the major active metabolites and may lead to reduced clinical response when coadministered with MAOIs (e.g. linezolid, phenelzine, selegiline).
Food Interaction
Concomitant ingestion of tyramine-rich food or beverages (particularly >150 mg tyramine amount) may cause sudden and severe increase in blood pressure (hypertensive crisis).
Action
Description: Mechanism of Action: Ozanimod is a potent sphingosine 1-phosphate (S1P) receptor modulator with high affinity to S1P receptors 1 and 5. It inhibits the ability of lymphocytes to emerge from lymph nodes, thus leading to a reduction in the quantity of lymphocytes available to the central nervous system (CNS) and intestine. Pharmacokinetics: Absorption: Time to peak plasma concentration: Approx 6-8 hours. Distribution: Extensively distributed into the tissues. Volume of distribution: 5,590 L. Plasma protein binding: Approx 98.2% (ozanimod); approx 99.8% (CC112273); approx 99.3% (CC1084037). Metabolism: Widely metabolised via multiple biotransformation pathways by aldehyde dehydrogenase, alcohol dehydrogenase, CYP3A4 and CYP1A1, and gut microflora into major active metabolites (CC112273 and CC1084037) and minor active metabolites (RP101988, RP101075, and RP112509). Excretion: Via urine (approx 26% as inactive metabolites); faeces (37% as inactive metabolites). Elimination half-life: Approx 21 hours (ozanimod); approx 11 days (CC112273 and CC1084037).
Chemical Structure
Ozanimod Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 52938427, Ozanimod. https://pubchem.ncbi.nlm.nih.gov/compound/Ozanimod. Accessed Apr. 26, 2024.
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