Ozanimod Hydrochloride (Monograph)

Brand name: Zeposia
Drug class: Sphingosine 1-Phosphate (S1P) Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Selective sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Ozanimod Hydrochloride

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Ozanimod is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Ulcerative Colitis

Treatment of moderate to severely active ulcerative colitis in adults.

Goals of therapy in ulcerative colitis include achieving and maintaining corticosteroid-free remission and promoting mucosal healing.

Specific treatments are selected according to disease severity, disease location/extent, prognosis, and previous therapies.

Ozanimod Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Obtain recent (i.e., ≤6 months or after discontinuance of previous MS or ulcerative colitis therapy) CBC, including lymphocyte count. Delay initiation of therapy in patients with an active infection until infection is resolved.

• Obtain baseline ECG. If patient has any of the following preexisting cardiac conditions, consult a cardiologist: significant QT_c prolongation (QT_c >450 msec in males or >470 msec in females); presence of an arrhythmia requiring treatment with a Class Ia or Class III antiarrhythmic drug; ischemic heart disease, heart failure, history of cardiac arrest or MI, cerebrovascular disease, or uncontrolled hypertension; history of a second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block.

• Obtain recent (i.e., ≤6 months) transaminase and bilirubin levels.

• Obtain a baseline evaluation of the fundus, including the macula, near initiation of therapy.

• Obtain a baseline skin examination prior to or shortly after initiation of therapy.

• Assess current or prior medications. Additive immunosuppressive effects can occur when taking concomitant antineoplastic, noncorticosteroid immunosuppressive, or immunomodulating therapies. Also assess whether patients are taking any medications that slow the heart rate or AV conduction.

• Test patients for varicella zoster antibodies if they do not have a healthcare professional-confirmed history of chickenpox or documentation of a full course of vaccination against varicella zoster virus; if the patient is antibody-negative, vaccination against varicella zoster is recommended.

Patient Monitoring

• Monitor BP during treatment.

• Evaluate pulmonary function with spirometry if clinically indicated.

• Evaluate any changes in vision promptly with an ophthalmic exam of the fundus, including the macula. In patients with diabetes mellitus or history of uveitis, perform ophthalmologic evaluation of the fundus, including the macula, regularly during therapy.

• Monitor for signs and symptoms of infection during therapy.

• Obtain transaminase and bilirubin concentrations periodically during treatment and until 2 months after ozanimod discontinuation. Check liver enzymes in patients who develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine).

Administration

Oral Administration

Administer orally once daily without regard to meals. Swallow capsules whole.

Dosage

Dosage of ozanimod hydrochloride is expressed in terms of ozanimod.

Initiate treatment with the following dosage titration schedule (see Table 1). For patients with hepatic impairment, see Hepatic Impairment under Dosage and Administration.

If a dose is missed during the first 2 weeks of treatment, reinitiate dosage titration. If a dose is missed after the first 2 weeks of treatment, resume regular dosing schedule.

Adults

Multiple Sclerosis

Oral

Titrate dosage over 7 days to recommended maintenance dosage of 0.92 mg once daily. (see Table 1)

Ulcerative Colitis

Oral

Titrate dosage over 7 days to recommended maintenance dosage of 0.92 mg once daily. (see Table 1)

Special Populations

Hepatic Impairment

In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), initiate with a 7-day titration, as shown in Table 1. After initial titration, recommended dosage is 0.92 mg once every other day, starting on Day 8.

Not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Ozanimod Hydrochloride

Contraindications

• Patients with any of the following conditions within the previous 6 months: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or class III or IV heart failure.

• Presence of 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 treatment with a monoamine oxidase (MAO) inhibitor.

Warnings/Precautions

Infectious Complications

Ozanimod can increase susceptibility to infection by decreasing peripheral blood lymphocytes. Rare and life-threatening infections have occurred.

Before initiating treatment, review a recent (i.e., ≤6 months or after discontinuance of previous therapy) CBC. Delay initiation of therapy in patients with severe active infections until infection has resolved.

Monitor patients for signs and symptoms of infection during and for 3 months after discontinuing therapy. Consider interruption of therapy if a serious infection develops.

Concomitant use with antineoplastic, immunosuppressive (including corticosteroids), or immunomodulating therapies may increase risk of immunosuppression.

Herpes viral infections reported. In patients without a professional-confirmed history of varicella (chickenpox) or without confirmed vaccination against varicella zoster virus (VZV), test for VZV antibodies before initiating ozanimod. VZV vaccination of antibody-negative patients is recommended; postpone initiation of ozanimod for 4 weeks following vaccination.

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, reported with S1P receptor modulators and other MS and UC therapies. If signs and symptoms consistent with cryptococcal meningitis occur, promptly evaluate and treat patient; interrupt ozanimod therapy until infection excluded. If cryptococcal meningitis is diagnosed, initiate appropriate treatment.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in patients receiving S1P receptor modulators and other MS and ulcerative colitis therapies. Immunocompromised patients or patients receiving multiple immunosuppressant therapies are at increased risk; PML usually leads to death or severe disability. Longer treatment duration increases PML risk; majority of PML cases occurred in patients treated for at least 18 months.

Monitor patients for clinical symptoms or MRI findings suggestive of PML. MRI signs may be apparent before clinical manifestations develop. If PML is suspected, interrupt ozanimod therapy until condition excluded.

Immune reconstitution inflammatory syndrome (IRIS) reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. Time to onset was generally within a few months after S1P receptor modulator discontinuation. Monitor for development of IRIS and treat appropriately.

Bradyarrhythmia and Atrioventricular Conduction Delays

Transient decreases in heart rate and AV conduction delays observed during initial dosing.

Prior to initiation of therapy, obtain baseline ECG. Do not use in patients with second-degree Mobitz type II or higher AV block or sick-sinus syndrome unless patient has a functioning pacemaker.

Usefulness of performing first-dose cardiac monitoring with ozanimod is not known. However, maximum cardiac effect of ozanimod is mild and observed at the end of the 7-day titration; therefore, first-dose cardiac monitoring is not included in the prescribing information of ozanimod unlike other S1P receptor modulators (e.g., fingolimod, siponimod).

Consult a cardiologist if treatment is considered in patients with substantial QT-interval prolongation (i.e., QT_c interval >450 msec in men or >470 msec in women), arrhythmias requiring treatment with class Ia or class III antiarrhythmic drugs, ischemic heart disease, heart failure, history of cardiac arrest or MI, cerebrovascular disease, uncontrolled hypertension, history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block, and in patients receiving concomitant drugs that prolong the QT interval or decrease heart rate.

Contraindicated in patients with a recent cardiovascular event (e.g., MI, unstable angina, stroke, TIA, heart failure).

Liver Injury

Clinically significant liver injury, including acute failure requiring transplantation, has occurred in the postmarketing setting. Signs of liver injury, including elevated liver enzymes and total bilirubin, reported in patients receiving ozanimod as early as 10 days after initial dose. In clinical studies, median time to ALT elevation to ≥3 times the ULN was 6 months. In most cases, elevated ALT concentrations returned to normal within 2–4 weeks without discontinuance of the drug.

Individuals with AST or ALT >1.5 times ULN were excluded from MS studies and >2 times ULN were excluded from ulcerative colitis studies. No data available to establish that patients with preexisting liver disease are at increased risk of developing elevated liver function test values. Adjust dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Use in patients with severe hepatic impairment (Child-Pugh class C) not recommended.

Obtain recent (i.e., ≤6 months) transaminase and bilirubin concentrations before initiating treatment, periodically during treatment, and until 2 months after ozanimod discontinuation. If patients develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, anorexia, fatigue, jaundice and/or dark urine), check liver enzymes and interrupt ozanimod therapy. If another etiology for signs and symptoms of hepatic dysfunction cannot be established, do not resume ozanimod therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity observed in animals.

Women of childbearing potential should use effective contraception during and for 3 months after drug discontinuance.

Blood Pressure Effects

Increased BP and hypertension reported. Hypertensive crises that was not clearly associated with a concomitantly used drug has occurred in a few patients who received ozanimod.

Monitor BP during therapy and manage as clinically indicated.

Respiratory Effects

May cause a decline in respiratory function. Dose-dependent reductions in FEV₁ and FVC observed at 3 months after initiating therapy.

Assess pulmonary function (e.g., spirometry) if clinically indicated.

Not known if the effects of ozanimod on FEV₁ and FVC are reversible.

Macular Edema

Risk of macular edema with S1P receptor modulators. Increased risk in patients with diabetes mellitus or a history of uveitis.

Perform ophthalmologic evaluation of the fundus, including the macula, at baseline, periodically while on therapy, and if there is any change in vision. Continued therapy in patients with macular edema not evaluated; consider discontinuation of therapy after weighing potential benefits and risks for the individual patient. Risk of rechallenge not evaluated.

Cutaneous Malignancies

Basal cell carcinoma and other skin malignancies reported. Skin evaluations recommended prior to or shortly after therapy initiation and periodically thereafter in all patients, particularly those with increased risk of skin cancer; in such patients, protective measures against sunlight and ultraviolet light also recommended. Promptly evaluate any suspicious skin lesions. Concurrent phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking ozanimod.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) reported rarely.

Monitor for any unexpected neurological or psychiatric signs or symptoms (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, increased intracranial pressure, accelerated neurological deterioration). Promptly perform complete physical and neurological examination if such manifestations occur and consider MRI evaluation.

A delay in diagnosis and treatment of PRES may lead to permanent neurologic sequelae.

If PRES is suspected, discontinue ozanimod.

Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies

When switching patients from drugs with prolonged immune effects to ozanimod, consider the half-life and mechanism of action of the drugs to avoid unintended additive immunosuppression. Initiation of ozanimod is not recommended after treatment with alemtuzumab.

Severe Increase in Disability Following Discontinuance of Therapy

MS exacerbation or disease rebound has occurred after stopping ozanimod. Observe patients after discontinuing treatment and treat with alternative agents if necessary.

Monitor for development of immune reconstitution inflammatory syndrome (IRIS) in patients with MS discontinuing ozanimod after developing PML.

Immunosuppression Following Discontinuance of Therapy

Ozanimod can lower the peripheral lymphocyte count for 3 months after discontinuation. Use of drugs with prolonged immune effects during this period can cause additive immunosuppressive effects and increase the risk of infection. Exercise caution if initiating treatment with other agents 4 weeks after the last dose of ozanimod.

Specific Populations

Pregnancy

No adequate data in pregnant females; may cause fetal harm.

Healthcare providers may register patients in pregnancy registry, or pregnant women may register themselves at [Web]or by calling 1-877-301-9314.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Potential effects on nursing infants or on milk production not known. Consider known benefits of breast-feeding along with mother's clinical need for ozanimod and any potential adverse effects of the drug or disease on the infant.

Females and Males of Reproductive Potential

Before initiating treatment, counsel females of reproductive potential on the risks of ozanimod to the developing fetus and need for effective contraceptive measures during treatment. Such females should use effective contraceptives for at least 3 months after stopping ozanimod therapy.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger patients. Monitor closely for cardiac and hepatic adverse reactions.

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of ozanimod not evaluated. Do not use in patients with hepatic impairment.

Renal Impairment

No dosage adjustment necessary in renal impairment. No clinically important effects on pharmacokinetics of ozanimod or its active CC112273 metabolite observed.

Smokers

No clinically relevant differences in the pharmacokinetics of ozanimod and its active CC112273 metabolite observed in smokers versus nonsmokers.

Other Special Populations

No clinically significant differences in the pharmacokinetics of ozanimod or its active CC112273 metabolite observed based on sex, weight, or racial/ethnic group.

Common Adverse Effects

MS trials (≥4%): Upper respiratory infection, liver enzyme elevations, orthostatic hypotension, urinary tract infection, back pain, hypertension.

UC trials (≥4%): Liver enzyme elevations, upper respiratory infection, headache.

Drug Interactions

Ozanimod and its metabolites do not inhibit CYP isoenzymes 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, or 3A, and do not induce CYP isoenzymes 1A2, 2B6, and 3A.

Ozanimod metabolites CC112273 and CC1084037 inhibit MAO-B.

Ozanimod and its metabolites do not inhibit P-glycoprotein (P-gp), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion transporter (MATE) 1, or MATE2K. The major ozanimod metabolites CC112273 and CC1084037 do not inhibit breast cancer resistance protein (BCRP) at clinically relevant concentrations.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP2C8 inhibitors: May increase systemic exposure of ozanimod and its active metabolites, which may increase risk of adverse effects. Avoid concomitant use.

Strong CYP2C8 inducers: May decrease systemic exposure of ozanimod and its active metabolites, which may decrease efficacy of the drug. Avoid concomitant use.

BCRP Inhibitors

Concomitant use of a BCRP inhibitor (e.g., cyclosporine) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

Antineoplastic, Immunomodulatory, or Immunosuppressive Agents

Additive immune system effects may occur. Consider duration and mechanism of these drugs when initiating ozanimod therapy.

Combination Beta-Blocker and Calcium-Channel Blocker

Concomitant use of ozanimod with both a β-adrenergic blocking agent (e.g., propranolol) and calcium-channel blocking agent (e.g., diltiazem) not studied. Due to potential additive effects on heart rate, consult a cardiologist before initiating treatment with ozanimod in patients receiving both of these drugs concomitantly.

Specific Drugs and Foods

Ozanimod Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 6–8 hours following oral administration.

Plasma concentrations and AUC of ozanimod and CC112273 (a major active metabolite) increase in a dose-proportional manner over dose range of 0.46–0.92 mg.

Steady-state ozanimod concentrations attained after approximately 102 hours. Steady-state concentrations of CC112273 attained after approximately 45 days with an accumulation ratio of 16-fold.

Food

High-fat, high-calorie meal does not affect peak plasma concentration or AUC of ozanimod.

Special Populations

Renal impairment: Effects on ozanimod or CC112273 pharmacokinetics not considered clinically important.

End-stage renal disease: Approximately 27% higher exposure to ozanimod and 23% lower exposure to the major CC112273 metabolite, respectively; not considered clinically important.

Hepatic impairment: Pharmacokinetics not fully characterized.

Distribution

Extent

Crosses blood-brain barrier.

Distributed into milk in rats; not known whether distributes into human milk.

Plasma Protein Binding

Ozanimod and its metabolites are approximately 98.2–99.8% bound to plasma proteins.

Elimination

Metabolism

Metabolized via multiple pathways to form major active metabolites (CC112273 and CC1084037) and minor active metabolites (RP101988, RP101075, and RP112509).

Also metabolized by alcohol/aldehyde dehydrogenase; one of the byproducts of this pathway is metabolized by MAO-B.

Elimination Route

Excreted in urine (26%) and feces (37%), mainly as inactive metabolites.

Half-life

Ozanimod: 21 hours.

CC112273 and CC1084037: Approximately 11 days.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

• S1P receptor modulator; binds with high affinity to S1P receptor subtype 1 (S1P1) and receptor subtype 5 (S1P5). Possesses similar affinity for S1P1 receptor as other S1P receptor modulators (e.g., fingolimod, siponimod), with 27-fold greater selectivity for S1P1 versus S1P5 receptors.

• S1P receptors are expressed in multiple organs and systems, and are involved in regulating a variety of physiological processes including endocytosis, cardiac function, lymphocyte/hematopoietic cell trafficking, and vascular tone.

• S1P1 receptor regulates lymphocyte egress from peripheral lymphoid organs and is essential for lymphocyte recirculation. Activation of the S1P1 receptor causes rapid and sustained receptor internalization and degradation, blocking the capacity of lymphocytes to egress from lymph nodes and results in reduced number of lymphocytes in peripheral blood.

• Ozanimod lacks substantial activity at other S1P receptor subtypes (S1P₂, S1P₃, and S1P₄), particularly S1P subtype 3, which is thought to mediate the cardiac conduction effects of this class of drugs.

• Exact mechanism in MS and UC not known, but may involve reduction of lymphocyte migration into the CNS.

• Mean lymphocyte count decreases to approximately 45% of baseline at 3 months following treatment initiation and remains low with continued treatment. Following discontinuance, peripheral lymphocyte counts generally return to normal within 30 days.

Advice to Patients

• Advise patients to read the manufacturer's patient information (medication guide).

• Risk of infection, which can be life-threatening, during ozanimod therapy and for 3 months after discontinuing treatment. Advise patients to immediately contact their clinician if they develop any symptoms of infection (e.g., fever; flu-like symptoms; cough; urinary symptoms; rash; or headache with fever, neck stiffness, sensitivity to light, nausea or confusion). Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

• Advise patients that if any immunizations are planned, they should be administered at least 1 month before starting ozanimod. Vaccines containing live viruses (live attenuated vaccines) should not be administered during ozanimod therapy and for 3 months after the drug is discontinued.

• Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients who received ozanimod and other S1P receptor modulators, which usually leads to death or severe disability over weeks or months; symptoms are diverse and progress over days to weeks. Advise patients to contact their healthcare provider if they develop any symptoms suggestive of PML (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).

• Risk of transient decreases in heart rate when starting treatment. To reduce this effect, dose titration is required. If a dose is missed within the first 14 days of starting treatment, the dose must be re-titrated.

• Risk of increased liver enzymes. Advise patients to contact their clinician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during ozanimod therapy.

• Risk of adverse respiratory effects. Advise patients to contact their clinician if they experience new onset or worsening dyspnea.

• Risk of hypertension. Advise patients to monitor blood pressure during treatment.

• Risk of macular edema. Inform patients to contact their clinician if they experience any changes in their vision during ozanimod therapy. Inform patients that their risk of developing macular edema is higher if they have diabetes mellitus or a history of uveitis.

• Risk of cutaneous malignancies. Inform patients that the risk of certain skin cancers is increased with ozanimod therapy. Advise patients to report any suspicious skin lesions promptly for evaluation and to limit exposure to sunlight and UV light by wearing protective clothing and sunscreen.

• Risk of posterior reversible encephalopathy syndrome (PRES). Advise patients to immediately inform their clinician if they experience sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.

• Severe increase in disability has been reported after discontinuation of another S1P receptor modulators in patients with MS. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuance of ozanimod.

• Inform patients that the immune system effects of ozanimod (decreased peripheral lymphocyte count) may last up to for 3 months after the drug is discontinued.

• Risk of fetal harm. Discuss possible fetal risk with women of childbearing potential and advise such women of the need for effective contraception during and for 3 months after discontinuance of ozanimod. Stress importance of women informing clinicians if they are or plan to become pregnant or breast-feed.

• Encourage patients with MS to enroll in the ZEPOSIA Pregnancy Registry if they become pregnant while taking ozanimod.

• Stress importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ozanimod is available through a specialty pharmacy network. Clinicians may consult the Zeposia website at [Web] or call 833-937-6742 for specific availability information.

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