ozanimod

General

Pronunciation:
oh-zan-i-mod

Trade Name(s)

Zeposia

Ther. Class.

anti-multiple sclerosis agents

Pharm. Class.

receptor modulators

Indications

Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Moderately to severely active ulcerative colitis.

Action

Acts as a sphingosine 1-phosphate (S1P) receptor modulator that binds to SIP receptors 1 and 5, resulting in ↓ migration of lymphocytes from lymph nodes into peripheral blood, the CNS, and the intestine.

Therapeutic Effect(s):

↓ frequency of relapses/delayed accumulation of disability in MS.
Achievement of clinical remission in ulcerative colitis.

Pharmacokinetics

Absorption: Unknown.

Distribution: Extensively distributed to tissues.

Protein Binding: Ozanimod: 98%; CC112273: 99.8%; CC1084037: 99%.

Metabolism and Excretion: Metabolized by several enzymes into 2 major active metabolites (CC112273 and CC1084037) and 3 minor active metabolites. These metabolites are further converted by multiple enzymes systems. Excreted in feces (37%) and urine (26%), primarily as inactive metabolites.

Half-life: Ozanimod: 21 hr; CC112273 and CC1084037: 11 days.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	6–8 hr	24 hr

Contraindication/Precautions

Contraindicated in:

MI, unstable angina, stroke, TIA, decompensated HF requiring hospitalization, or class III or IV HF within previous 6 mo;
2nd- or 3rd-degree heart block, sick sinus syndrome, or sinoatrial block (in the absence of a pacemaker);
Severe untreated sleep apnea;
Use of MAO inhibitor concurrently or within 14 days of last dose of ozanimod;
Active acute/chronic untreated infection;
Severe hepatic impairment;
OB: Pregnancy.

Use Cautiously in:

QT interval prolongation (>450 msec in males, >470 msec females), hypokalemia, hypomagnesemia, congenital long QT syndrome, or concurrent use of QT interval prolonging medications;
Heart rate <55 bpm;
Cardiac arrhythmias requiring use of class Ia or III antiarrhythmics;
Ischemic heart disease, MI, HF, cardiac arrest, cerebrovascular disease, or uncontrolled hypertension;
Uveitis or diabetes mellitus (↑ risk of macular edema);
Immunocompromised or taking other immunosuppressant medications (↑ risk of progressive multifocal leukoencephalopathy [PML]);
Mild or moderate hepatic impairment (↓ dose);
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children;
Geri: Risk of adverse reactions may be ↑ in older adults; consider age-related ↓ in cardiac/renal/hepatic function, chronic illnesses, and concurrent drug therapy.

Adverse Reactions/Side Effects

CV: bradycardia, heart block, hypertension, orthostatic hypotension

Derm: BASAL/SQUAMOUS CELL CARCINOMA, MELANOMA

EENT: macular edema

GI: abdominal pain, ↑ liver enzymes

Hemat: lymphopenia

Neuro: PML, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES)

Resp: ↓ pulmonary function

Misc: IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS), INFECTION (including bacterial, viral and fungal), hypersensitivity reactions, MALIGNANCY

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

MAO inhibitors, including phenelzine, selegiline, and linezolid, may ↑ risk of hypertensive crises; concurrent use or use within 14 days of last dose of ozanimod contraindicated.
↑ risk of immunosuppression with antineoplastics, immunosuppressants, or immune-modulating therapies ; avoid initiating therapy with ozanimod after alemtuzumab therapy is discontinued.
Concurrent use of QT-interval prolonging medications may ↑ risk of QT interval prolongation and torsades de pointes; avoid concurrent use.
Class Ia antiarrhythmics and class III antiarrhythmics may ↑ risk of torsades de pointes in presence of bradycardia; use concurrently with caution.
Strong CYP2C8 inhibitors, including gemfibrozil, may ↑ levels of active metabolite and risk of toxicity.
Opioids, SSRIs, SNRIs, TCAs or sympathomimetic drugs may ↑ risk of hypertensive crises.
Live-attenuated vaccines ↑ risk of infection; avoid concurrent use and for 3 mo following last dose.

Drug-Food:

Foods containing high amounts of tyramine (>150 mg) may lead to severe hypertension; avoid concurrent use.

Route/Dosage

PO (Adults): 0.23 mg once daily on Days 1–4, then 0.46 mg once daily on Days 5–7, then 0.92 mg once daily thereafter starting on Day 8.

Hepatic Impairment
PO (Adults): Mild or moderate hepatic impairment: 0.23 mg once daily on Days 1–4, then 0.46 mg once daily on Days 5–7, then 0.92 mg every other day thereafter starting on Day 8.

Availability

Capsules: 0.23 mg, 0.46 mg, 0.92 mg

Assessment

Assess ECG for pre-existing conduction abnormalities before starting therapy. May cause transient ↓ in HR and atrioventricular conduction delays.
Monitor BP during therapy. May cause hypertension requiring treatment.
Monitor for signs of infection during and for 3 mo after discontinuation of therapy. Consider suspending therapy if serious infection develops. If clinical signs of PML (progressive unilateral body weakness; changes in vision, memory, orientation, personality) or MRI changes occur, immediately withhold therapy and perform appropriate diagnostics. If PML is confirmed, permanently discontinue ozanimod and monitor for IRIS (rapid neurologic clinical decline, characteristic MRI changes). The time to onset of IRIS in patients with PML was generally within a few mo after receptor modulator discontinuation. If IRIS occurs, initiate appropriate medical treatment.
Perform ophthalmologic exam of the fundus, including the macula, at start of therapy, periodically during therapy, and if any visual changes occur. If macular edema occurs consider discontinuing ozanimod based on benefits and risks for the individual patient.
Monitor for signs and symptoms of liver injury. If symptoms of liver injury occur, check liver enzymes and discontinue ozanimod if significant injury confirmed.
Monitor for symptoms of PRES (sudden onset headache, altered mental status, visual changes and seizures). If symptoms occur, discontinue ozanimod.
Evaluate pulmonary function with spirometry periodically during therapy when indicated clinically.
Perform baseline skin exam and periodically thereafter. Evaluate suspicious skin lesions promptly.
Monitor for severe ↑ in disability on discontinuation of therapy and institute appropriate treatment as needed.
Review current and past medications. If patient is currently taking or has taken antineoplastic, immunosuppressive, or immune-modulating therapies, consider possible unintended additive immunosuppressive effects before initiating treatment.

Lab Test Considerations:

Verify negative pregnancy test before stating therapy.

Obtain baseline AST, ALT, and total bilirubin within 6 mo of initiating therapy.
Obtain CBC within 6 mo of initiating ozanimod or discontinuing prior MS therapy.
Assess for varicella zoster virus (VZV) antibodies before starting therapy.

Implementation

Before initiating therapy (≥ 1 mo), administer VZV vaccine to patients who are antibody negative.
PO Administer once daily without regard to food. DNC: Swallow capsules whole; do not crush, open, or chew.
If a dose is missed during first 2 wk of therapy, restart using initial dosing regimen.

Patient/Family Teaching

Instruct patient to take ozanimod as directed. If a dose is missed during first 14 days of therapy, contact health care professional. Starting doses will need to be repeated. Do not discontinue therapy without consulting health care professional; may cause severe ↑ in disability. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to avoid foods or beverages containing tyramine (see food sources for specific nutrients); may cause a hypertensive crisis.
Advise patient to notify health care professional if they develop signs and symptoms of liver dysfunction, infection, PML, new onset dyspnea, PRES (sudden headache, confusion, seizures, loss of vision, weakness), hypersensitivity reactions (rash or itchy hives; swelling of lips, tongue, or face), skin lesions, nodules (shiny pearly nodules), patches or open sores that do not heal within wks, or changes in vision.
Advise patient to notify health care professional if they develop signs and symptoms of slow HR (dizziness, shortness of breath, confusion, feeling of skipped heartbeats, chest pain).
Instruct patient not to receive live-attenuated vaccines during and for 3 mo after treatment due to risk of life-threatening infection. Advise patients who have not had a health care professional–confirmed history of chickenpox or a full course vaccination to be tested for antibodies to VZV before starting therapy.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
Caution patient to avoid exposure to sunlight and ultraviolet light, wear protective clothing, and use sunscreen with a high protection factor to minimize risk of cutaneous malignancies.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during therapy and for 3 mo after last dose. Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform patients of registry that monitors outcomes in women exposed to ozanimod during pregnancy. To enroll patient in the pregnancy registry, call 1-877-301-9314 or visit www.zeposiapregnancyregistry.com.

Evaluation/Desired Outcomes

Delayed disability progression and decreased frequency of relapses in patients with relapsing forms of MS.
Achievement of clinical remission in ulcerative colitis.