ZEPOSIA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZEPOSIA (ZEPOSIA).
Sphingosine 1-phosphate receptor modulator; binds with high affinity to S1P receptors 1 and 5, blocking lymphocyte egress from lymph nodes, reducing circulating lymphocytes.
| Metabolism | Primarily metabolized by CYP3A4 and to a minor extent by CYP2C8; also undergoes hydroxylation via non-CYP enzymes. |
| Excretion | Primarily fecal (approximately 78% of dose) via biliary excretion of unchanged drug and oxidative metabolites; renal excretion accounts for approximately 15% of dose, with <1% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is approximately 21 hours (range 14–30 hours) in healthy subjects, supporting once-daily dosing without need for loading dose. |
| Protein binding | >99% bound to plasma proteins, primarily to albumin and lipoproteins. |
| Volume of Distribution | Volume of distribution is approximately 22 L (0.3 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Absolute oral bioavailability is approximately 73% (90% CI 68–79%) under fasted conditions; no significant food effect observed. |
| Onset of Action | Reduction in peripheral lymphocyte count occurs within 4–6 hours after a single oral dose, with maximal effect observed by 24 hours. |
| Duration of Action | Lymphocyte counts begin to recover within 3–4 days after discontinuation and return to normal range within 4–6 weeks in most patients. |
| Molecular Weight | 404.5 |
0.92 mg orally once daily with or without food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to severe renal impairment (CrCl ≥15 mL/min). Not recommended in end-stage renal disease (CrCl <15 mL/min) or on dialysis. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). No dose adjustment needed for mild to moderate hepatic impairment (Child-Pugh class A or B). |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment for elderly. Use with caution due to age-related decrease in organ function and comorbidities. |
| 1st trimester | Based on animal studies and its mechanism of action (sphingosine 1-phosphate receptor modulator), there is potential for fetal harm. Human data are limited; use only if benefit clearly outweighs risk. |
| 2nd trimester | Same as first trimester. Avoid unless essential. |
| 3rd trimester | Same as first and second trimesters. May cause neonatal effects; avoid near term. |
Clinical note
Comprehensive clinical and safety monograph for ZEPOSIA (ZEPOSIA).
| Placental transfer | Ozanimod and its active metabolites cross the placenta in animal studies; human data not available. Based on molecular weight and lipophilicity, placental transfer is expected. |
| Breastfeeding | ZEPOSIA (ozanimod) is excreted in animal milk; no human data. Because of potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 3 months after the last dose. |
■ FDA Black Box Warning
WARNING: INFECTIONS; BRADYARRHYTHMIA AND AV CONDUCTION DELAYS; MACULAR EDEMA; RESPIRATORY EFFECTS; HEPATIC INJURY; FETAL RISK; INCREASED BLOOD PRESSURE; MALIGNANCIES; SEVERE EXACERBATION OF MULTIPLE SCLEROSIS AFTER DISCONTINUATION; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME.
| Serious Effects |
Concurrent use of monoamine oxidase inhibitors (MAOIs)In patients with recent (within 6 months) myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or New York Heart Association (NYHA) class III/IV heart failureIn patients with a history of second-degree Mobitz type II or third-degree atrioventricular (AV) block, sick sinus syndrome, or sinoatrial block unless pacemaker is in placeSevere untreated sleep apneaHypersensitivity to ozanimod or any of its excipients
| Precautions | Increased risk of infections (including PML and herpes); bradyarrhythmia and AV block; macular edema (monitor ophthalmologic exams); respiratory effects (decline in FEV1 and DLCO); hepatic injury (monitor LFTs); fetal risk based on animal studies; increased blood pressure; malignancies (skin cancers); severe exacerbation of MS after discontinuation; PML; PRES; immune system effects after switching from other MS therapies. |
Loading safety data…
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | ZEPOSIA (ozanimod) is a sphingosine 1-phosphate receptor modulator. Based on animal studies, there is a risk of fetal harm, including structural malformations and embryolethality, when administered to pregnant women. In rats, oral administration during organogenesis resulted in increased post-implantation loss, reduced fetal body weight, and increased fetal skeletal and visceral malformations at maternal exposures similar to the clinical dose. In rabbits, embryofetal mortality and malformations were observed at maternal exposures similar to the clinical dose. Because there are no adequate and well-controlled studies in pregnant women, ZEPOSIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose. |
| Fetal Monitoring | Monitor fetal growth and development via ultrasound as clinically indicated. No specific maternal or fetal monitoring for ZEPOSIA is mandated, but given the potential for bradycardia and AV conduction delays, consider fetal heart rate monitoring if maternal bradycardia occurs. After delivery, monitor the infant for signs of bradycardia, infection, and respiratory depression. |
| Fertility Effects | Based on animal studies, ZEPOSIA may impair male and female fertility. In male rats, reduced sperm count and motility and increased abnormal sperm were observed at exposures similar to the clinical dose. In female rats, prolonged estrous cycles and reduced fertility indices were noted. The clinical relevance of these findings is unknown. Advise patients about potential effects on fertility. |
| Food/Dietary | Grapefruit and grapefruit juice may increase ozanimod exposure and should be avoided. ZEPOSIA can be taken with or without food. No other significant food interactions are reported. Avoid consumption of grapefruit products during treatment. |
| Clinical Pearls | ZEPOSIA (ozanimod) is a sphingosine 1-phosphate receptor modulator indicated for relapsing forms of multiple sclerosis and moderately to severely active ulcerative colitis. Due to its mechanism, it can cause bradycardia and AV conduction delays at treatment initiation; obtain baseline ECG and monitor for 6 hours after first dose. Avoid use in patients with recent MI, unstable angina, stroke, TIA, or certain arrhythmias. Assess for prior varicella zoster virus (VZV) exposure; vaccinate if no history of chickenpox or VZV vaccination. Monitor liver function tests and blood pressure regularly. Can cause macular edema, especially in patients with a history of uveitis or diabetes; perform ophthalmologic evaluation before and during treatment. Transition from other MS therapies requires washout periods; especially careful with immunosuppressants. |
| Patient Advice | Take ZEPOSIA exactly as prescribed, usually once daily with or without food. · You will need to have an ECG before starting and for at least 6 hours after the first dose to monitor your heart rate. · Report any symptoms of slow heart rate (dizziness, fainting, chest pain) or irregular heartbeat immediately. · Inform your doctor if you have ever had chickenpox or received the vaccine; a vaccine may be needed before starting treatment. · Contact your doctor if you experience vision changes, as this may be a sign of macular edema. · Avoid grapefruit and grapefruit juice while taking ZEPOSIA, as they can increase the drug levels in your blood. · Do not stop or change your dose without consulting your doctor; abrupt discontinuation may lead to worsening of disease. · Tell your doctor if you have liver problems, high blood pressure, or a history of uveitis or diabetes. · Use effective contraception during treatment and for 3 months after stopping, as ZEPOSIA can harm an unborn baby. · Keep all appointments for blood tests and monitoring required by your healthcare provider. |