Zeposia (Ozanimod)
ozanimod — sphingosine 1-phosphate (S1P) receptor modulator
Indications
| Indication | Population | Key Details | Status |
|---|---|---|---|
| Relapsing forms of MS | Adults | Includes CIS, RRMS, and active SPMS; no prior biologic failure required | Approved (2020) |
| Moderately-to-severely active UC | Adults | No prior biologic failure required; can be used before biologics | Approved (2021) |
Ozanimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptor subtypes 1 and 5 (S1P1 and S1P5). By causing functional antagonism of S1P1 on lymphocytes, ozanimod sequesters circulating lymphocytes into lymph nodes, reducing their migration to sites of inflammation. This mechanism is shared with fingolimod (Gilenya) and siponimod (Mayzent), but ozanimod is distinguished by its improved receptor selectivity for S1P1 and S1P5 over S1P2, S1P3, and S1P4, which may contribute to a more favorable cardiac and pulmonary profile. Importantly, unlike JAK inhibitors and most biologics for UC, ozanimod does not require prior TNF blocker failure, making it the first oral advanced therapy that can be used before biologics for ulcerative colitis. No pediatric indications are approved.
Dosing
Standard Dosing (MS and UC — Identical Regimen)
| Phase | Days | Dose | Notes |
|---|---|---|---|
| Titration | Days 1–4 | 0.23 mg QD | Mandatory 7-day up-titration to mitigate cardiac effects (bradycardia, AV conduction delays). Use starter pack if available. Do NOT skip titration steps |
| Titration | Days 5–7 | 0.46 mg QD | |
| Maintenance | Day 8 onward | 0.92 mg QD | Swallow capsule whole, with or without food. Same dose for both MS and UC. |
Dose Modifications
| Clinical Scenario | Dose Modification | Notes |
|---|---|---|
| Mild or moderate hepatic impairment (Child-Pugh A or B) | 0.92 mg every other day (after standard 7-day titration) | Effect of HI on active metabolite pharmacokinetics is unknown; use reduced maintenance frequency |
| Severe hepatic impairment (Child-Pugh C) | Not recommended | Insufficient data |
| Renal impairment (any severity including ESRD) | No dose adjustment | No clinically important effects on ozanimod or CC112273 exposure |
| Missed dose within first 2 weeks | Reinitiate with Day 1 titration | Cardiac effects may recur without re-titration |
| Missed dose after first 2 weeks | Continue treatment as planned | No re-titration needed |
Unlike fingolimod (which requires 6-hour first-dose cardiac monitoring), ozanimod does not carry a label requirement for first-dose observation when initiating with the titration protocol. The 7-day up-titration attenuates the heart rate reduction such that the greatest mean decrease was only 1.2 bpm at Hour 5 on Day 1 in MS trials, and 0.7 bpm in UC trials. Heart rates below 40 bpm were not observed. However, patients with certain preexisting cardiac conditions should have cardiology consultation before initiation, and some centers still perform an ECG at baseline as part of routine pre-treatment assessment.
Pharmacology
Mechanism of Action
Ozanimod is a selective agonist of S1P receptor subtypes 1 and 5. By binding to S1P1 on lymphocytes, it causes receptor internalization and functional antagonism, preventing lymphocyte egress from lymph nodes. This results in a dose-dependent reduction in peripheral blood lymphocyte count to approximately 45% of baseline by 3 months, reducing the number of lymphocytes available to migrate to sites of inflammation in the central nervous system (MS) and gastrointestinal tract (UC). S1P5 agonism may contribute to neuroprotective effects on oligodendrocytes and modulation of innate immune cells. After discontinuation, the median time for lymphocytes to return to the normal range is approximately 30 days, with ~80–90% of patients normalizing within 3 months.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~6–8 hours; high oral bioavailability; no clinically relevant food effect | Can take with or without food; slow absorption contributes to gradual onset |
| Distribution | Vz/F ~5590 L; protein binding: ozanimod 98.2%, CC112273 99.8%, CC1084037 99.3% | Very high tissue distribution; extremely high protein binding for all active moieties |
| Metabolism | Extensive via multiple pathways: ALDH/ADH → RP101988; CYP3A4 → RP101075 → MAO-B → CC112273; CC112273 ↔ CC1084037 (interconversion via CYP2C8/AKR). ~94% of total active drug exposure: ozanimod (6%), CC112273 (73%), CC1084037 (15%) | CC112273 is the dominant circulating active species. CYP2C8 is the critical enzyme for metabolite clearance — strong CYP2C8 inhibitors (gemfibrozil) increase metabolite exposure. CYP3A4 inhibitors have no clinically significant effect. |
| Elimination | Ozanimod t½ ~21 hours; CC112273/CC1084037 t½ ~11 days; CL/F ~192 L/h; urine 26%, feces 37% (primarily inactive metabolites) | The long active metabolite half-life (~11 days) means pharmacodynamic effects persist for ~3 months after discontinuation. This drives the 3-month contraception and immunosuppression washout periods. |
Side Effects
| Adverse Effect | Ozanimod 0.92 mg | IFN beta-1a | Clinical Note |
|---|---|---|---|
| Upper respiratory infection | 26% | 23% | Includes nasopharyngitis, pharyngitis, bronchitis, rhinitis |
| Hepatic transaminase elevation | 10% | 5% | ALT ≥5x ULN in 1.6%; most resolved with continued treatment. Acute liver failure reported postmarketing. |
| Orthostatic hypotension | 4% | 3% | Usually at initiation |
| Urinary tract infection | 4% | 3% | Standard management |
| Back pain | 4% | 3% | Non-specific |
| Hypertension | 4% | 2% | Mean SBP increase ~1–2 mm Hg over IFN; monitor BP during treatment |
| Adverse Effect | Induction (ZEPOSIA) | Induction (Placebo) | Maintenance (ZEPOSIA) | Maintenance (Placebo) |
|---|---|---|---|---|
| Liver test increased | 5% | 0% | 11% | 2% |
| Upper respiratory infection | 5% | 4% | — | — |
| Headache | 4% | 3% | 5% | <1% |
| Pyrexia | 3% | 2% | — | — |
| Nausea | 3% | 2% | — | — |
| Arthralgia | 3% | 1% | — | — |
| Adverse Effect | Key Data | Required Action |
|---|---|---|
| Progressive multifocal leukoencephalopathy (PML) | Reported with S1P modulators including ZEPOSIA; risk increases with treatment duration (>18 months) | Withhold at first sign/symptom; MRI for evaluation; discontinue if confirmed. Monitor for IRIS after discontinuation. |
| Bradyarrhythmia / AV conduction delays | Greatest HR decrease 1.2 bpm (MS) / 0.7 bpm (UC) at Hour 5 Day 1 with titration; bradycardia Day 1: 0.6% (MS) | Use 7-day titration. Cardiology consult for preexisting conduction abnormalities, QT prolongation, or heart rate-lowering drugs. |
| Liver injury (including acute liver failure) | ALT ≥5x ULN: 1.6% MS, 0.9% UC. Acute liver failure requiring transplant reported postmarketing (as early as 10 days after first dose). | Obtain baseline LFTs; monitor periodically and for 2 months after discontinuation. Interrupt if DILI suspected. |
| Macular edema | MS: 0.3% (vs 0.3% IFN); UC: 0.2–0.4%. Higher risk with uveitis or diabetes. | Baseline fundus exam required; periodic monitoring; consider discontinuation if macular edema develops. |
| Cutaneous malignancies (BCC, SCC, melanoma) | Increased risk with S1P modulators; BCC and melanoma reported in controlled trials | Skin exam at baseline and periodically; limit sun/UV exposure; no concomitant phototherapy. |
| Respiratory effects (FEV1/FVC decline) | MS: FEV1 decline ~60 mL vs IFN at 12 months. Reversibility after discontinuation unknown. | Spirometry if clinically indicated during treatment. |
| PRES (posterior reversible encephalopathy syndrome) | Rare; 1 case reported in MS controlled trials | Suspect with cognitive deficits, visual disturbances, or seizures; MRI for evaluation; discontinue if confirmed. |
| Infections (herpes zoster, cryptococcal meningitis) | HZ: 0.6% MS, 0.4–2.2% UC. Fatal cryptococcal meningitis reported with S1P modulators. | VZV antibody testing pre-treatment; vaccinate if negative. Monitor for infections during and 3 months after treatment. |
Severe exacerbation of MS disease, including disease rebound, has been rarely reported after discontinuation of S1P receptor modulators. Patients should be observed for severe increase in disability after stopping ozanimod, and appropriate treatment should be instituted as required. The immune system effects of ozanimod persist for approximately 3 months after the last dose due to the long half-life of the active metabolite CC112273.
Drug Interactions
Ozanimod has a complex metabolic pathway involving multiple enzyme systems. The parent drug is metabolized by ALDH/ADH and CYP3A4, but the clinically relevant active metabolite CC112273 is primarily cleared by CYP2C8. This means that CYP2C8 inhibitors (not CYP3A4 inhibitors) are the critical drug interaction concern. Additionally, because the active metabolite CC112273 inhibits MAO-B in vitro, coadministration with MAO inhibitors is contraindicated due to the theoretical risk of hypertensive crisis. Notably, itraconazole (a strong CYP3A4 inhibitor) had no clinically significant effect on ozanimod exposure, making this drug unique among oral immunomodulators in not requiring CYP3A4 dose adjustments.
Monitoring
- ECGBaseline
RoutineAssess for preexisting conduction abnormalities before initiation. Cardiology consultation for patients with QT prolongation, arrhythmia history, or use of heart rate-lowering drugs. - CBC with LymphocytesWithin 6 months before initiation
RoutineObtain recent CBC before starting. Lymphocytes decrease to ~45% of baseline by 3 months. ALC <0.2 × 10&sup9;/L occurred in 2–3.3% of patients; values generally recovered while on treatment. - Liver Function TestsBaseline, periodically during, and 2 months after stopping
RoutineObtain transaminases and bilirubin within 6 months before initiation. Acute liver failure reported postmarketing (as early as 10 days). Continue monitoring for 2 months after discontinuation. - Ophthalmic ExamBaseline (near start of treatment), periodically during
RoutineFundoscopy including macula required. Patients with diabetes or uveitis history at higher risk for macular edema. Re-evaluate with any vision changes. - Skin ExaminationBaseline, periodically during
RoutineIncreased risk of cutaneous malignancies (BCC, SCC, melanoma) with S1P modulators. Promptly evaluate suspicious lesions. Limit sun/UV exposure. - VZV AntibodiesBaseline (if no confirmed varicella history)
RoutineTest for VZV antibodies in patients without confirmed chickenpox history or full VZV vaccination. Vaccinate if antibody-negative; postpone ozanimod initiation 4 weeks after vaccination. - Blood PressureDuring treatment
RoutineMean SBP increase from baseline ~1–2 mm Hg over IFN (MS). UC: mean SBP increase from baseline 3.7 mm Hg (induction) and 5.1 mm Hg (maintenance) vs 2.3 and 1.5 mm Hg placebo, respectively. Manage per standard guidelines. - Pulmonary FunctionIf clinically indicated
Trigger-basedDose-dependent FEV1/FVC reductions observed. Spirometry if respiratory symptoms develop. - MRI Surveillance (MS)Per clinical practice
Trigger-basedMonitor for PML (especially after >18 months of treatment). MRI findings may precede clinical symptoms. Also monitor for disease rebound after stopping.
Contraindications & Cautions
Absolute Contraindications (PI Section 4)
- Recent (<6 months) MI, unstable angina, stroke, TIA, decompensated HF requiring hospitalization, or Class III/IV heart failure
- Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sinoatrial block — unless patient has a functioning pacemaker
- Severe untreated sleep apnea
- Concomitant MAO inhibitor use — at least 14 days must elapse between stopping ozanimod and starting an MAO inhibitor
Relative Contraindications (Specialist Input)
- Active infection — delay initiation until resolved
- Severe hepatic impairment (Child-Pugh C) — not recommended
- History of uveitis or diabetes mellitus — higher risk of macular edema
- Significant QT prolongation (QTcF >450 ms males, >470 ms females) — cardiology input required
- Pregnancy — fetal harm in animals; contraception required during + 3 months after
Unlike the JAK inhibitor class (tofacitinib, upadacitinib), which carry a Boxed Warning for MACE based on postmarketing data, ozanimod has formal contraindications for patients with specific cardiac conduction and structural heart disease. These reflect the S1P receptor modulator class mechanism: initial S1P1 agonism transiently reduces heart rate by activating inward-rectifying potassium channels on atrial myocytes. While the 7-day titration mitigates this effect (greatest mean HR decrease only 1.2 bpm at Day 1), patients with preexisting conduction abnormalities are at risk for clinically significant bradycardia. These contraindications differ from fingolimod in that ozanimod does not require first-dose observation; however, the same underlying cardiac mechanism necessitates the pre-treatment ECG and cardiology evaluation for high-risk patients.
Patient Counselling
Purpose of Therapy
Ozanimod is a once-daily oral capsule that works by keeping certain white blood cells (lymphocytes) in the lymph nodes, reducing their ability to travel to areas of inflammation in the brain (MS) or the intestinal lining (UC). It starts with a 7-day dose increase schedule to protect the heart from temporary slowing, using a starter pack with three different capsule strengths. After the first week, you take the full-strength capsule each day.
How to Take
Swallow the capsule whole, with or without food. Follow the 7-day titration schedule exactly as prescribed. If you miss a dose during the first two weeks of treatment, you must restart the entire titration schedule from Day 1. If you miss a dose after the first two weeks, simply take your next scheduled dose as planned. Do not stop taking ozanimod without consulting your prescriber, as stopping suddenly may cause your MS to worsen significantly.
Sources
- Zeposia (ozanimod) prescribing information. Bristol-Myers Squibb Company. Revised 8/2024. Full Prescribing InformationPrimary source for all dosing, titration, contraindications, adverse reactions, CYP2C8/MAO interactions, and hepatic impairment dosing.
- Zeposia (ozanimod) European Medicines Agency Summary of Product Characteristics. EMA SmPCEuropean regulatory perspective with risk minimization measures for cardiac monitoring and PML.
- Comi G, Kappos L, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009–1020. DOISUNBEAM: pivotal MS trial demonstrating 48% relative ARR reduction vs IFN beta-1a at 12 months.
- Cohen JA, Comi G, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021–1033. DOIRADIANCE: 24-month MS trial demonstrating 38% relative ARR reduction vs IFN beta-1a and MRI superiority.
- Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280–1291. DOITrue North: pivotal UC trial establishing ozanimod 0.92 mg efficacy for induction and maintenance in moderately-to-severely active UC.
- Cree BAC, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944–1962. DOIDAYBREAK OLE: up to 5-year safety and efficacy data confirming stable long-term profile.
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777–788. DOIAAN guideline providing framework for DMT selection in relapsing MS.
- Singh S, Loftus EV Jr, Limketkai BN, et al. AGA living clinical practice guideline on pharmacological management of moderate-to-severe ulcerative colitis. Gastroenterology. 2024;167(7):1307–1343. DOIAGA guideline classifying ozanimod as an intermediate-efficacy UC therapy that can be used before biologics.
- Tran JQ, Hartung JP, Tompkins CA, et al. Single-dose pharmacokinetics of ozanimod and its major active metabolites alone and in combination with gemfibrozil, itraconazole, or rifampin in healthy subjects. Adv Ther. 2020;37(10):4381–4395. DOIPhase 1 DDI study establishing CYP2C8 (gemfibrozil) as the critical metabolite interaction pathway and confirming no clinically significant CYP3A4 effect.
- Tran JQ, Hartung JP, Peach RJ, et al. Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator. J Clin Pharmacol. 2017;57(8):988–996. DOIFirst-in-human PK study characterizing ozanimod absorption, half-life, and lymphocyte pharmacodynamics.
- Surapaneni S, Yerramilli U, Engel K, et al. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor modulator. Drug Metab Dispos. 2021;49(5):405–419. DOIDefinitive ADME study establishing the complex metabolic pathway (ALDH/ADH → CYP3A4 → MAO-B → CYP2C8) and circulating active species distribution (ozanimod 6%, CC112273 73%, CC1084037 15%).
- Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778–1792. DOIDiscovery pharmacology study establishing ozanimod’s S1P1/S1P5 selectivity profile and preclinical efficacy.