Zeposia

— THERAPEUTIC CATEGORIES —
  • Colorectal disorders
  • Multiple sclerosis
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Zeposia Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ozanimod 0.23mg, 0.46mg, 0.92mg; caps.

    Pharmacological Class

    Sphingosine 1-phosphate receptor modulator.

    How Supplied

    Caps 0.92mg—30; 7-Day Starter Pack—7 (4 × 0.23mg + 3 × 0.46mg); Starter Pack—37 (7-cap starter pack + 30 × 0.92mg)

    How Supplied

    0.23mg capsule: Light grey body/light grey cap imprinted with OZA on the cap and 0.23mg on the body.

    0.46mg capsule: Light grey body/orange cap imprinted with OZA on the cap and 0.46mg on the body.

    0.92mg capsule: Orange body/orange cap imprinted with OZA on the cap and 0.92mg on the body.

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Bristol Myers Squibb

    Generic Availability

    NO

    Mechanism of Action

    Ozanimod binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.

    Zeposia Indications

    Indications

    Moderately to severely active ulcerative colitis (UC) in adults.

    Zeposia Dosage and Administration

    Prior to Treatment Evaluations

    • Obtain CBC, including lymphocyte count (within the last 6 months or after discontinuation of prior MS or UC therapy).
    • Obtain ECG to determine whether preexisting conduction abnormalities are present; confer with cardiologist regarding patients with preexisting conditions.
    • Obtain recent (within the last 6 months) transaminase and bilirubin levels.
    • History of uveitis or macular edema: Obtain an evaluation of the fundus, including the macula.
    • Consider possible unintended additive immunosuppressive effects in patients taking antineoplasitc, noncorticosteroid, immunosuppressive or immunomodulatory drugs or in patients with a history of prior use.
    • Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction.
    • Test for antibodies to varicella zoster virus (VZV) in patients without confirmed chickenpox history; vaccination is recommended prior to treatment in antibody-negative patients.
    • Administer live attenuated vaccines at least 1 month prior to initiating Zeposia.

    Adult

    Swallow whole. Initiate dose titration regimen (Days 1–4): 0.23mg once daily; (Days 5–7): 0.46mg once daily. Maintenance (starting Day 8): 0.92mg once daily. Re-initiation after dose interruption (during 1st 2 weeks): start with Day 1 of titration regimen; (after the 1st 2 weeks): continue treatment as planned. Mild or moderate hepatic impairment: 0.92mg once every other day starting on Day 8 after initial titration.

    Children

    Not established.

    Zeposia Contraindications

    Contraindications

    Recent (within last 6 months) occurrence of: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, Class III/IV heart failure. Presence of Mobitz Type II 2nd- or 3rd-degree AV block, sick sinus syndrome, or sino-atrial block, unless paced. Severe untreated sleep apnea. Concomitant MAOIs during and within 14 days (eg, selegiline, phenelzine, linezolid).

    Zeposia Boxed Warnings

    Not Applicable

    Zeposia Warnings/Precautions

    Warnings/Precautions

    Increased risk of infections (may be fatal). Obtain recent CBC (within last 6 months or after discontinuation of prior MS or UC therapy) prior to initiation. Monitor for infections during and for up to 3 months after discontinuation. Consider treatment interruption if serious infection develops. Active infection: do not start until infection resolved. Test for antibodies to varicella zoster virus prior to initiation; if negative, consider immunization before starting ozanimod. Withhold and evaluate at first sign/symptom of progressive multifocal leukoencephalopathy (PML); discontinue if confirmed and monitor for immune reconstitution inflammatory syndrome (IRIS). Immunosuppressed. Risk of bradyarrhythmia, AV conduction delays: titration is required for treatment initiation. Obtain ECG prior to initiation to determine if preexisting conduction abnormalities are present. Significant QT prolongation, arrhythmias, ischemic heart disease, HF, history of cardiac arrest or MI, cerebrovascular disease, uncontrolled hypertension: refer to cardiologist if treatment is considered. Monitor BP during treatment. Obtain recent LFTs (within 6 months) prior to initiation. Monitor for hepatic dysfunction; discontinue if significant liver injury is confirmed. History of severe liver disease. Respiratory function: perform spirometric evaluation as needed. Diabetes, history of uveitis: increased risk of macular edema. Do ophthalmic exam at baseline, and if any change in vision during therapy. MS: monitor for severe increase in disability after treatment discontinuation. Severe hepatic impairment: not recommended. Elderly. Pregnancy. Advise females of reproductive potential to use effective contraception during and for 3 months after discontinuation. Nursing mothers.

    Warnings/Precautions

    Risk of Infections

    • Because of reversible sequestration of lymphocytes in lymphoid tissues, Zeposia can cause a reduction in peripheral blood lymphocyte count to ~45% of baseline values.
    • After discontinuing Zeposia 0.92mg, the median time for peripheral blood lymphocytes to return to the normal range was ~30 days; ~80-90% of patients were in the normal range within 3 months.
    • Life-threatening and rare fatal infections have occurred.
    • Increased risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections.
    • CBCs should be obtained before initiating therapy.
    • Delay treatment in those with active infection until it has resolved; consider interrupting treatment if a serious infection develops.
    • Continue monitoring for infections for 3 months after discontinuing treatment.
    • Monitor for cryptococcal infection; suspend treatment until infection is excluded.
    • Concomitant use of Zeposia with immunomodulating medications may increase the risk of immunosuppression.
    • Test for antibodies to VZV; provide vaccination for antibody-negative patients prior to initiating Zeposia and delay Zeposia for 4 weeks to allow full effect of vaccination to occur.
    • Live attenuated vaccines: Administer at least 1 month prior to initiation; avoid use during and for 3 months after treatment with Zeposia.

    Progressive Multifocal Leukoencephalopathy

    • An opportunistic viral infection of the brain caused by the JC virus.
    • Typically occurs in patients who are immunocompromised.
    • Usually leads to death or severe disability.
    • Typical symptoms: Progressive weakness on 1 side of the body, clumsiness of the limbs, vision disturbances, changes in thinking, memory, and orientation leading to confusion and personality changes.
    • PML has been reported with S1P receptor modulators, including Zeposia.
    • MRI findings of PML may be apparent before clinical signs/symptoms.
    • Withhold Zeposia and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML.
    • If PML confirmed, discontinue Zeposia and monitor for the development of immune reconstitution syndrome (IRIS) and treat appropriately.

    Bradyarrhythmia and Atrioventricular Conduction Delays

    • Up-titration scheme should be used to reach the maintenance dosage of Zeposia since treatment may result in a transient decrease in heart rate and atrioventricular conduction delays.
    • Zeposia was not studied in patients with the following conditions: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization within the last 6 months; NYHA Class III/IV heart failure; cardiac conduction or rhythm disorders; other preexisting stable cardiac conditions without clearance from cardiologist; severe untreated sleep apnea; resting heart rate <55 beats per minute at baseline.
    • For patients with the following conditions, advice from a cardiologist should be sought before considering Zeposia treatment: Significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females); arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs; ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension; history of or with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block.

    Liver Injury

    • Elevations of aminotransferases may occur with Zeposia.
    • Transaminase and bilirubin levels should be obtained before initiating treatment.
    • In MS clinical trials, patients with AST or ALT >1.5 times ULN were excluded; in UC trails, patients with AST or ALT >2 times the ULN were excluded.
    • For patients with mild or moderate hepatic impairment: adjust dose (see Adult dose). For patients with severe hepatic impairment: not recommended.
    • Zeposia should be discontinued if significant liver injury develops.

    Increased Blood Pressure

    • Hypertension was reported as an adverse reaction in clinical trials; blood pressure should be monitored during treatment.
    • Avoid foods that contain very large amounts of tyramine while taking Zeposia. 

    Respiratory Effects

    • Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) have been observed with Zeposia.
    • Spirometric evaluation of respiratory function should be performed during treatment if clinically indicated.

    Macular Edema

    • S1P receptor modulators have been associated with increased risk of macular edema.
    • If the patient experiences vision changes while on Zeposia, an ophthalmic evaluation of the fundus, including the macula, is recommended.
    • Consider the benefits of therapy and the risks to the patient when evaluating whether to continue treatment.
    • History of uveitis, diabetes: Increased risk of macular edema with Zeposia.

    Posterior Reversible Encephalopathy Syndrome

    • Rare cases of PRES have been reported with S1P receptor modulators.
    • Promptly schedule a complete physical and neurological examination and consider MRI in patients who develop unexpected neurological or psychiatric symptoms.
    • PRES symptoms are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage.
    • Discontinue Zeposia if PRES is suspected.

    Severe Increase in MS Disability After Stopping Zeposia

    • Severe exacerbations have been rarely reported after discontinuing S1P modulators.
    • Observe MS patients for increase in disability  upon discontinuation; appropriate treatment should be instituted.

    Immune System Effects After Stopping Zeposia

    • Median time for peripheral blood lymphocytes to return to normal range after discontinuing Zeposia: 30 days
    • Approximately 80-90% of patients return to normal range within 3 months.
    • Use caution when initiating other drugs 4 weeks after the last dose of Zeposia; additive effects possible with immunosuppressants.

    Pregnancy Considerations

    No adequate and well-controlled studies in pregnant women. Zeposia may cause fetal harm.

    Pregnancy exposure registry: www.zeposiapregnancyregistry.com or call 1-877-301-9314.

    Nursing Mother Considerations

    No data available on the presence of ozanimod in human milk or its effect on the breastfed infant. Consider the benefits of treatment to the mother vs the potential risks to the breastfed infant.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established. 

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients 65 years of age and older. No significant differences in pharmacokinetics were observed based on age. Monitor elderly patients for cardiac and hepatic adverse reactions.

    Renal Impairment Considerations

    Renal impairment does not appear to have clinically important effects on the pharmacokinetics of ozanimod or its metabolite.

    Hepatic Impairment Considerations

    Use in patients with severe hepatic impairment is not recommended as its effect on the pharmacokinetics of ozanimod is unknown.

    Other Considerations for Specific Populations

    Women of childbearing age: Use effective contraception to avoid pregnancy during treatment and for 3 months after stopping Zeposia.

    Zeposia Pharmacokinetics

    Absorption

    The Tmax of ozanimod is approximately 6–8 hours.

    Distribution

    Plasma protein bound: between 98-99%.

    Metabolism

    Metabolized by multiple enzymes to form circulating major active metabolites.

    Elimination

    Fecal (37%), renal (26%). Half-life: ~21 hours.

    Zeposia Interactions

    Interactions

    See Contraindications. Concomitant antineoplastic, immunosuppressant or immune-modulating therapies may increase risk of immunosuppression; use caution when switching from long-acting immunotherapies or initiating other drugs 4 weeks after discontinuing ozanimod. Initiation after treatment with alemtuzumab: not recommended. Concomitant QT prolonging drugs (eg, quinidine, procainamide, amiodarone, sotalol): risk of torsades de pointes (in bradycardia). Avoid live attenuated vaccines during and for up to 3 months after discontinuing ozanimod; may have suboptimal response; if live vaccines are required, administer at least 1 month prior to initiating ozanimod. Potentiated by strong CYP2C8 (eg, gemfibrozil); avoid concomitant use. Antagonized by strong CYP2C8 inducers (eg, rifampin); avoid concomitant use. Concomitant drugs or OTC meds that increase norepinephrine or serotonin (eg, opioids, SSRIs, SNRIs, tricyclics, tyramine): not recommended. Potential additive effects on HR when concomitant with both a beta blocker and a calcium channel blocker (eg, verapamil, diltiazem); do not initiate ozanimod, if necessary, refer to cardiologist. Avoid high amounts (>150mg) of tyramine-containing food (eg, aged cheese, pickled herring).

    Interactions

    Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies

    • Use caution because of the risk of additive immune effects.
    • When switching from drugs with prolonged immune effects, the half-life and mode of action should be considered in order to avoid additive immunosuppressant effects.
    • Initiating treatment with Zeposia after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. 
    • Zeposia can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.

    Antiarrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate

    • Confer with cardiologist prior to initiating Zeposia in patients on Class Ia or Class III antiarrhythmics.
    • Concurrent QT prolonging drugs; Zeposia treatment should generally not be initiated; discuss with cardiologist first.

    Adrenergic and Serotonergic Drugs

    • Active metabolite of ozanimod inhibits MAO-B.
    • Potential for hypertensive crisis when Zeposia coadministered with drugs that increase norepinephrine or serotonin (eg, opioids, SSRIs, SNRIs, tricyclics, tyramine); coadministration is not recommended.
    • Concomitant pseudoephedrine did not potentiate the effects on blood pressure.
    • Hypertensive crisis was reported with Zeposia alone and during coadministration of other selective or nonselective MAOIs (eg, rasagiline) with sympathomimetic medications.
    • Monitor for hypertension with concomitant use.

    Combination Beta Blocker and Calcium Channel Blocker

    • Potential of additive effects on heart rate.
    • Patients who are concurrently being treated with calcium channel blocker (eg, verapamil, diltiazem) and beta blocker: Zeposia should generally not be initiated.
    • Confer with cardiologist if treatment is being considered for these patients.

    Tyramine

    • Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines may cause release of norepinephrine resulting in a rise in BP.
    • Avoid foods containing large amounts of tyramine while taking Zeposia.

    Vaccination

    • Vaccines may be less effective during, and for up to 3 months after, discontinuing Zeposia.
    • Use of live attenuated vaccines may carry the risk of infection; avoid during Zeposia treatment and for up to 3 months after ending treatment.

    Monoamine Oxidase Inhibitors (MAOIs)

    • Coadministration with MOA-B inhibitors may decrease exposure of the active metabolites of ozanimod. 
    • Selegiline, phenelzine, linezolid, other MAOIs: Coadministration with Zeposia is contraindicated.
    • Allow 14 days to elapse between discontinuation of Zeposia and initiation of MOAIs.

    Strong CYP2C8 Inhibitors

    • Coadministration with strong CYP2C8 inhibitors increases exposure of the active metabolite of ozanimod, which may increase the risk of adverse effects.
    • Coadministration with strong CYP2C8 inhibitors (eg, gemfibrozil) is not recommended.

    Strong CYP2C8 Inducers

    • Coadministration with strong CYP2C8 inducers (eg, rifampin) reduces exposure of the active metabolite of ozanimod, which may decrease efficacy.
    • Avoid coadministration of Zeposia with strong CYP2C8 inducers.

    Zeposia Adverse Reactions

    Adverse Reactions

    Upper respiratory infection, hepatic transaminase elevation, headache; also for MS: orthostatic hypotension, urinary tract infection, back pain, hypertension; transient reduction in HR, malignancies, macular edema, respiratory effects, PML, IRIS; rare: posterior reversible encephalopathy syndrome (discontinue if suspected).

    Zeposia Clinical Trials

    Clinical Trials

    The approval was based on data from the double-blind, placebo-controlled phase 3 True North trial that assessed the efficacy and safety of Zeposia as an induction and maintenance therapy for adults with moderately to severely active ulcerative colitis who had an inadequate response to prior treatment.

    In the induction phase, patients were randomly assigned to receive either Zeposia 0.92mg orally once daily (n=429) or placebo (n=216) for 10 weeks. Patients who achieved a clinical response in the induction phase or who were part of an open-label arm were eligible to proceed into the maintenance phase in which they were randomly assigned to receive Zeposia 0.92mg (n=230) or placebo (n=227) for a total of 52 weeks of treatment.

    Results showed that Zeposia met the primary endpoints in both phases, achieving statistically significant clinical remission at week 10 in the induction phase (18% vs 6% for placebo; treatment difference: 12% [95% CI, 8-17]; P<.0001) and at week 52 in the maintenance phase (37% vs 19% for placebo; treatment difference: 19% [95% CI, 11-26]; P<.0001).

    Additionally, Zeposia treatment led to improvements in clinical response, endoscopic improvement, and endoscopic-histologic mucosal healing compared with placebo at week 10 and at week 52 (secondary endpoints).  In the maintenance period, corticosteroid-free clinical remission was observed in 32% of Zeposia-treated patients vs 17% of patients who received placebo.

    Zeposia Note

    Not Applicable

    Zeposia Patient Counseling

    Patient Counseling

    Risk of infection increased while on Zeposia and for 3 months after stopping treatment. 

    Avoid live attenuated vaccines during and for 3 months after Zeposia treatment. If immunizations are planned, administer at least 1 month before initiating Zeposia.

    Zeposia treatment may result in a transient decrease in heart rate. Dose titration is required to reduce this effect.

    May increase live enzymes; seek medical attention if unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice or dark urine develop.

    May cause fetal harm. Use effective contraception during treatment and for 3 months after stopping Zeposia.

    New onset or worsening dyspnea: Contact health care provider.

    May cause macular edema. Report vision changes.

    Contact a health care provider immediately if sudden onset of severe headache, altered mental status, visual disturbances, or seizure develops. Delayed treatment could lead to permanent neurological consequences.

    In patients with MS, severe disability has been reported after discontinuing treatment with an S1P receptor modulator like Zeposia. Contact a health care provider if worsening symptoms develop.

    Peripheral lymphocyte count may continue to be low for up to 3 months after the last dose of Zeposia.

    Cost Savings Program

    Zeposia 360 Support

    Zeposia Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ozanimod 0.23mg, 0.46mg, 0.92mg; caps.

    Pharmacological Class

    Sphingosine 1-phosphate receptor modulator.

    How Supplied

    Caps 0.92mg—30; 7-Day Starter Pack—7 (4 × 0.23mg + 3 × 0.46mg); Starter Pack—37 (7-cap starter pack + 30 × 0.92mg)

    How Supplied

    0.23mg capsule: Light grey body/light grey cap imprinted with OZA on the cap and 0.23mg on the body.

    0.46mg capsule: Light grey body/orange cap imprinted with OZA on the cap and 0.46mg on the body.

    0.92mg capsule: Orange body/orange cap imprinted with OZA on the cap and 0.92mg on the body.

     

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Bristol Myers Squibb

    Generic Availability

    NO

    Mechanism of Action

    Ozanimod binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into the central nervous system.

    Zeposia Indications

    Indications

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

    Zeposia Dosage and Administration

    Prior to Treatment Evaluations

    • Obtain CBC, including lymphocyte count (within the last 6 months or after discontinuation of prior MS or UC therapy).
    • Obtain ECG to determine whether preexisting conduction abnormalities are present; confer with cardiologist regarding patients with preexisting conditions.
    • Obtain recent (within the last 6 months) transaminase and bilirubin levels.
    • History of uveitis or macular edema: Obtain an evaluation of the fundus, including the macula.
    • Consider possible unintended additive immunosuppressive effects in patients taking antineoplasitc, noncorticosteroid, immunosuppressive or immunomodulatory drugs or in patients with a history of prior use.
    • Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction.
    • Test for antibodies to varicella zoster virus (VZV) in patients without confirmed chickenpox history; vaccination is recommended prior to treatment in antibody-negative patients.
    • Administer live attenuated vaccines at least 1 month prior to initiating Zeposia.

    Adult

    Swallow whole. Initiate dose titration regimen (Days 1–4): 0.23mg once daily; (Days 5–7): 0.46mg once daily. Maintenance (starting Day 8): 0.92mg once daily. Re-initiation after dose interruption (during 1st 2 weeks): start with Day 1 of titration regimen; (after the 1st 2 weeks): continue treatment as planned. Mild or moderate hepatic impairment: 0.92mg once every other day starting on Day 8 after initial titration.

    Children

    Not established.

    Zeposia Contraindications

    Contraindications

    Recent (within last 6 months) occurrence of: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, Class III/IV heart failure. Presence of Mobitz Type II 2nd- or 3rd-degree AV block, sick sinus syndrome, or sino-atrial block, unless paced. Severe untreated sleep apnea. Concomitant MAOIs during and within 14 days (eg, selegiline, phenelzine, linezolid).

    Zeposia Boxed Warnings

    Not Applicable

    Zeposia Warnings/Precautions

    Warnings/Precautions

    Increased risk of infections (may be fatal). Obtain recent CBC (within last 6 months or after discontinuation of prior MS or UC therapy) prior to initiation. Monitor for infections during and for up to 3 months after discontinuation. Consider treatment interruption if serious infection develops. Active infection: do not start until infection resolved. Test for antibodies to varicella zoster virus prior to initiation; if negative, consider immunization before starting ozanimod. Withhold and evaluate at first sign/symptom of progressive multifocal leukoencephalopathy (PML); discontinue if confirmed and monitor for immune reconstitution inflammatory syndrome (IRIS). Immunosuppressed. Risk of bradyarrhythmia, AV conduction delays: titration is required for treatment initiation. Obtain ECG prior to initiation to determine if preexisting conduction abnormalities are present. Significant QT prolongation, arrhythmias, ischemic heart disease, HF, history of cardiac arrest or MI, cerebrovascular disease, uncontrolled hypertension: refer to cardiologist if treatment is considered. Monitor BP during treatment. Obtain recent LFTs (within 6 months) prior to initiation. Monitor for hepatic dysfunction; discontinue if significant liver injury is confirmed. History of severe liver disease. Respiratory function: perform spirometric evaluation as needed. Diabetes, history of uveitis: increased risk of macular edema. Do ophthalmic exam at baseline, and if any change in vision during therapy. MS: monitor for severe increase in disability after treatment discontinuation. Severe hepatic impairment: not recommended. Elderly. Pregnancy. Advise females of reproductive potential to use effective contraception during and for 3 months after discontinuation. Nursing mothers.

    Warnings/Precautions

    Risk of Infections

    • Because of reversible sequestration of lymphocytes in lymphoid tissues, Zeposia can cause a reduction in peripheral blood lymphocyte count to ~45% of baseline values.
    • After discontinuing Zeposia 0.92mg, the median time for peripheral blood lymphocytes to return to the normal range was ~30 days; ~80-90% of patients were in the normal range within 3 months.
    • Life-threatening and rare fatal infections have occurred.
    • Increased risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections.
    • CBCs should be obtained before initiating therapy.
    • Delay treatment in those with active infection until it has resolved; consider interrupting treatment if a serious infection develops.
    • Continue monitoring for infections for 3 months after discontinuing treatment.
    • Monitor for cryptococcal infection; suspend treatment until infection is excluded.
    • Concomitant use of Zeposia with immunomodulating medications may increase the risk of immunosuppression.
    • Test for antibodies to VZV; provide vaccination for antibody-negative patients prior to initiating Zeposia and delay Zeposia for 4 weeks to allow full effect of vaccination to occur.
    • Live attenuated vaccines: Administer at least 1 month prior to initiation; avoid use during and for 3 months after treatment with Zeposia.

    Progressive Multifocal Leukoencephalopathy

    • An opportunistic viral infection of the brain caused by the JC virus.
    • Typically occurs in patients who are immunocompromised.
    • Usually leads to death or severe disability.
    • Typical symptoms: Progressive weakness on 1 side of the body, clumsiness of the limbs, vision disturbances, changes in thinking, memory, and orientation leading to confusion and personality changes.
    • PML has been reported with S1P receptor modulators, including Zeposia.
    • MRI findings of PML may be apparent before clinical signs/symptoms.
    • Withhold Zeposia and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML.
    • If PML confirmed, discontinue Zeposia and monitor for the development of immune reconstitution syndrome (IRIS) and treat appropriately.

    Bradyarrhythmia and Atrioventricular Conduction Delays

    • Up-titration scheme should be used to reach the maintenance dosage of Zeposia since treatment may result in a transient decrease in heart rate and atrioventricular conduction delays.
    • Zeposia was not studied in patients with the following conditions: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization within the last 6 months; NYHA Class III/IV heart failure; cardiac conduction or rhythm disorders; other preexisting stable cardiac conditions without clearance from cardiologist; severe untreated sleep apnea; resting heart rate <55 beats per minute at baseline.
    • For patients with the following conditions, advice from a cardiologist should be sought before considering Zeposia treatment: Significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females); arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs; ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension; history of or with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block.

    Liver Injury

    • Elevations of aminotransferases may occur with Zeposia.
    • Transaminase and bilirubin levels should be obtained before initiating treatment.
    • In MS clinical trials, patients with AST or ALT >1.5 times ULN were excluded; in UC trails, patients with AST or ALT >2 times the ULN were excluded.
    • For patients with mild or moderate hepatic impairment: adjust dose (see Adult dose). For patients with severe hepatic impairment: not recommended.
    • Zeposia should be discontinued if significant liver injury develops.

    Increased Blood Pressure

    • Hypertension was reported as an adverse reaction in clinical trials; blood pressure should be monitored during treatment.
    • Avoid foods that contain very large amounts of tyramine while taking Zeposia. 

    Respiratory Effects

    • Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) have been observed with Zeposia.
    • Spirometric evaluation of respiratory function should be performed during treatment if clinically indicated.

    Macular Edema

    • S1P receptor modulators have been associated with increased risk of macular edema.
    • If the patient experiences vision changes while on Zeposia, an ophthalmic evaluation of the fundus, including the macula, is recommended.
    • Consider the benefits of therapy and the risks to the patient when evaluating whether to continue treatment.
    • History of uveitis, diabetes: Increased risk of macular edema with Zeposia.

    Posterior Reversible Encephalopathy Syndrome

    • Rare cases of PRES have been reported with S1P receptor modulators.
    • Promptly schedule a complete physical and neurological examination and consider MRI in patients who develop unexpected neurological or psychiatric symptoms.
    • PRES symptoms are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage.
    • Discontinue Zeposia if PRES is suspected.

    Severe Increase in MS Disability After Stopping Zeposia

    • Severe exacerbations have been rarely reported after discontinuing S1P modulators.
    • Observe MS patients for increase in disability  upon discontinuation; appropriate treatment should be instituted.

    Immune System Effects After Stopping Zeposia

    • Median time for peripheral blood lymphocytes to return to normal range after discontinuing Zeposia: 30 days
    • Approximately 80-90% of patients return to normal range within 3 months.
    • Use caution when initiating other drugs 4 weeks after the last dose of Zeposia; additive effects possible with immunosuppressants.

    Pregnancy Considerations

    No adequate and well-controlled studies in pregnant women. Zeposia may cause fetal harm.

    Pregnancy exposure registry: www.zeposiapregnancyregistry.com or call 1-877-301-9314.

    Nursing Mother Considerations

    No data available on the presence of ozanimod in human milk or its effect on the breastfed infant. Consider the benefits of treatment to the mother vs the potential risks to the breastfed infant.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established. 

    Geriatric Considerations

    Clinical studies did not include a sufficient number of patients 65 years of age and older. No significant differences in pharmacokinetics were observed based on age. Monitor elderly patients for cardiac and hepatic adverse reactions.

    Renal Impairment Considerations

    Renal impairment does not appear to have clinically important effects on the pharmacokinetics of ozanimod or its metabolite.

    Hepatic Impairment Considerations

    Use in patients with severe hepatic impairment is not recommended as its effect on the pharmacokinetics of ozanimod is unknown.

    Other Considerations for Specific Populations

    Women of childbearing age: Use effective contraception to avoid pregnancy during treatment and for 3 months after stopping Zeposia.

    Zeposia Pharmacokinetics

    Absorption

    The Tmax of ozanimod is approximately 6–8 hours.

    Distribution

    Plasma protein bound: between 98-99%.

    Metabolism

    Metabolized by multiple enzymes to form circulating major active metabolites.

    Elimination

    Fecal (37%), renal (26%). Half-life: ~21 hours.

    Zeposia Interactions

    Interactions

    See Contraindications. Concomitant antineoplastic, immunosuppressant or immune-modulating therapies may increase risk of immunosuppression; use caution when switching from long-acting immunotherapies or initiating other drugs 4 weeks after discontinuing ozanimod. Initiation after treatment with alemtuzumab: not recommended. Concomitant QT prolonging drugs (eg, quinidine, procainamide, amiodarone, sotalol): risk of torsades de pointes (in bradycardia). Avoid live attenuated vaccines during and for up to 3 months after discontinuing ozanimod; may have suboptimal response; if live vaccines are required, administer at least 1 month prior to initiating ozanimod. Potentiated by strong CYP2C8 (eg, gemfibrozil); avoid concomitant use. Antagonized by strong CYP2C8 inducers (eg, rifampin); avoid concomitant use. Concomitant drugs or OTC meds that increase norepinephrine or serotonin (eg, opioids, SSRIs, SNRIs, tricyclics, tyramine): not recommended. Potential additive effects on HR when concomitant with both a beta blocker and a calcium channel blocker (eg, verapamil, diltiazem); do not initiate ozanimod, if necessary, refer to cardiologist. Avoid high amounts (>150mg) of tyramine-containing food (eg, aged cheese, pickled herring).

    Interactions

    Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies

    • Use caution because of the risk of additive immune effects.
    • When switching from drugs with prolonged immune effects, the half-life and mode of action should be considered in order to avoid additive immunosuppressant effects.
    • Initiating treatment with Zeposia after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. 
    • Zeposia can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.

    Antiarrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate

    • Confer with cardiologist prior to initiating Zeposia in patients on Class Ia or Class III antiarrhythmics.
    • Concurrent QT prolonging drugs; Zeposia treatment should generally not be initiated; discuss with cardiologist first.

    Adrenergic and Serotonergic Drugs

    • Active metabolite of ozanimod inhibits MAO-B.
    • Potential for hypertensive crisis when Zeposia coadministered with drugs that increase norepinephrine or serotonin (eg, opioids, SSRIs, SNRIs, tricyclics, tyramine); coadministration is not recommended.
    • Concomitant pseudoephedrine did not potentiate the effects on blood pressure.
    • Hypertensive crisis was reported with Zeposia alone and during coadministration of other selective or nonselective MAOIs (eg, rasagiline) with sympathomimetic medications.
    • Monitor for hypertension with concomitant use.

    Combination Beta Blocker and Calcium Channel Blocker

    • Potential of additive effects on heart rate.
    • Patients who are concurrently being treated with calcium channel blocker (eg, verapamil, diltiazem) and beta blocker: Zeposia should generally not be initiated.
    • Confer with cardiologist if treatment is being considered for these patients.

    Tyramine

    • Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines may cause release of norepinephrine resulting in a rise in BP.
    • Avoid foods containing large amounts of tyramine while taking Zeposia.

    Vaccination

    • Vaccines may be less effective during, and for up to 3 months after, discontinuing Zeposia.
    • Use of live attenuated vaccines may carry the risk of infection; avoid during Zeposia treatment and for up to 3 months after ending treatment.

    Monoamine Oxidase Inhibitors (MAOIs)

    • Coadministration with MOA-B inhibitors may decrease exposure of the active metabolites of ozanimod. 
    • Selegiline, phenelzine, linezolid, other MAOIs: Coadministration with Zeposia is contraindicated.
    • Allow 14 days to elapse between discontinuation of Zeposia and initiation of MOAIs.

    Strong CYP2C8 Inhibitors

    • Coadministration with strong CYP2C8 inhibitors increases exposure of the active metabolite of ozanimod, which may increase the risk of adverse effects.
    • Coadministration with strong CYP2C8 inhibitors (eg, gemfibrozil) is not recommended.

    Strong CYP2C8 Inducers

    • Coadministration with strong CYP2C8 inducers (eg, rifampin) reduces exposure of the active metabolite of ozanimod, which may decrease efficacy.
    • Avoid coadministration of Zeposia with strong CYP2C8 inducers.

    Zeposia Adverse Reactions

    Adverse Reactions

    Upper respiratory infection, hepatic transaminase elevation, headache; also for MS: orthostatic hypotension, urinary tract infection, back pain, hypertension; transient reduction in HR, malignancies, macular edema, respiratory effects, PML, IRIS; rare: posterior reversible encephalopathy syndrome (discontinue if suspected).

    Zeposia Clinical Trials

    Clinical Trials

    The approval was based on data from 2 double-blind, parallel-group, active comparator-controlled clinical trials in patients with relapsing forms of MS. Both studies included patients who had experienced at least 1 relapse within the prior year, or 1 relapse within the prior 2 years with evidence of at least a gadolinium-enhancing (GdE) lesion in the prior year, and had an Expanded Disability Status Scale score from 0 to 5.0 at baseline.

    Patients were randomly assigned to receive Zeposia 0.92mg given orally once daily, beginning with a dose titration, or interferon beta-1a 30mcg given intramuscularly once weekly. The primary end point of both studies was annualized relapse rate (ARR) over the treatment period.

    Results showed that in both trials, the ARR was statistically significantly lower in patients treated with Zeposia than in patients who received interferon beta-1a (Study 1: ARR 0.181 vs 0.350, respectively; Study 2: ARR 0.172 vs 0.276, respectively). Compared with interferon beta-1a, Zeposia demonstrated a relative reduction in ARR of 48% (P<.0001) through 1 year (Study 1) and 38% (P <.0001) at 2 years (Study 2). A similar effect was observed in exploratory subgroups defined by sex, age, prior nonsteroid therapy for MS, and baseline disease activity. 

    Moreover, the number of new or enlarging T2 hyperintense lesions and the number of GdE lesions were found to be statistically significantly lower in ozanimod-treated patients compared with patients who received interferon beta-1a.

    Zeposia Note

    Not Applicable

    Zeposia Patient Counseling

    Patient Counseling

    Risk of infection increased while on Zeposia and for 3 months after stopping treatment. 

    Avoid live attenuated vaccines during and for 3 months after Zeposia treatment. If immunizations are planned, administer at least 1 month before initiating Zeposia.

    Zeposia treatment may result in a transient decrease in heart rate. Dose titration is required to reduce this effect.

    May increase live enzymes; seek medical attention if unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice or dark urine develop.

    May cause fetal harm. Use effective contraception during treatment and for 3 months after stopping Zeposia.

    New onset or worsening dyspnea: Contact health care provider.

    May cause macular edema. Report vision changes.

    Contact a health care provider immediately if sudden onset of severe headache, altered mental status, visual disturbances, or seizure develops. Delayed treatment could lead to permanent neurological consequences.

    In patients with MS, severe disability has been reported after discontinuing treatment with an S1P receptor modulator like Zeposia. Contact a health care provider if worsening symptoms develop.

    Peripheral lymphocyte count may continue to be low for up to 3 months after the last dose of Zeposia.

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