Zeposia Starter Pack (7-Day) (ozanimod hydrochloride)

Dosage of ozanimod hydrochloride is expressed in terms of ozanimod.

When initiating ozanimod therapy, dosage must be titrated to minimize the risk of adverse cardiac effects. The manufacturer recommends the following dosage titration schedule over the first 7 days of treatment (see Table 1).

Table 1: Ozanimod Dosage Titration Regimen

Days Dosage Days 1-4 0.23 mg once daily Days 5-7 0.46 mg once daily Day 8 and after 0.92 mg once daily

If a dose is missed during the first 2 weeks of treatment, reinitiate the dosage titration regimen. If a dose is missed after the first 2 weeks of treatment, retitration of the dosage is not necessary; skip the missed dose and resume the regular dosing schedule the following day.

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

No dosing information is available for this tab.

Ozanimod and its metabolites do not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, or 3A, and do not induce CYP isoenzymes 1A2, 2B6, and 3A.

Major metabolites (CC112273 and CC1084037) inhibit monoamine oxidase-B (MAO-B) with over 1000-fold selectivity over MAO-A.

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 do not inhibit breast cancer resistance protein (BCRP) at clinically relevant concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).

PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.

PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)

DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)

Ozanimod/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ozanimod is metabolized by CYP3A4 to RP101075 (a minor active metabolite), which is further metabolized by monoamine oxidase-B (MAO-B) to major active metabolites that make up the predominant circulating active species in the plasma. The major and minor active metabolites have similar activity as ozanimod. Inhibition of MAO-B may alter exposure to ozanimod and its metabolites.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod and MAO inhibitors may result in altered exposure to ozanimod and its active metabolites and may result in decreased efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of ozanimod with MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of ozanimod and initiation of MAO inhibitors.(1)

DISCUSSION: The combination of ozanimod with MAO inhibitors has not been studied. The combination of steady state ozanimod 0.92 mg or 1.84 mg with tyramine, an MAO substrate, did not have an effect on tyramine plasma concentrations or tyramine-induced pressor response. However, MAO inhibitors may alter the exposure to ozanimod and its metabolites.(1) Metaxalone is a weak inhibitor of MAO.(2,3)

Ozanimod/Moderate Cyp2c8 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ozanimod is a substrate of CYP2C8. Moderate inducers of CYP2C8 may induce the metabolism of ozanimod.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP2C8 may result in decreased levels and effectiveness of ozanimod and the active metabolites CC112273 and CC1084037.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of ozanimod states to avoid concurrent administration with moderate CYP2C8 inducers.(1)

DISCUSSION: Coadministration of rifampin (a strong CYP3A4 and P-gp inducer, and moderate CYP2C8 inducer - 600 mg once daily) decreased the area-under-curve (AUC) of ozanimod, CC112273, and CC1084037 by 24%, 60%, and 55%, respectively.(1) Moderate CYP2C8 inducers linked to this monograph include: carbamazepine and rifampin.(2-3)

Ozanimod/Procarbazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ozanimod is metabolized by CYP3A4 to RP101075 (a minor active metabolite), which is further metabolized by monoamine oxidase-B (MAO-B) to major active metabolites that make up the predominant circulating active species in the plasma. The major and minor active metabolites have similar activity as ozanimod. Inhibition of MAO-B may alter exposure to ozanimod and its metabolites.(1) Procarbazine, although used therapeutically as an antineoplastic agent, is an inhibitor of monoamine oxidase (MAO).(2) Ozanimod in combination with immunosuppressives such as procarbazine suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod and MAO inhibitors may result in altered exposure to ozanimod and its active metabolites and may result in decreased efficacy.(1) Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The concurrent use of ozanimod with MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of ozanimod and initiation of MAO inhibitors.(1) The ozanimod US prescribing information state this information regarding this interaction: Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)

DISCUSSION: The combination of ozanimod with MAO inhibitors has not been studied. The combination of steady state ozanimod 0.92 mg or 1.84 mg with tyramine, an MAO substrate, did not have an effect on tyramine plasma concentrations or tyramine-induced pressor response. However, MAO inhibitors may alter the exposure to ozanimod and its metabolites.(1) Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients taking ozanimod who previously received immunomodulators or immunosuppressants.(1)

Selected Immunosuppressants/Nadofaragene Firadenovec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)

CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)

DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)

Selected Immunosuppressants/Talimogene Laherparepvec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)

CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.

DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

Selected Immunosuppressive Agents/Live Vaccines; Live Bcg

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)

CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)

PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.

PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)

DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Immunosuppressives; Immunomodulators/Etrasimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.

CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.

PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)

Ozanimod/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of clozapine with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Initiation of ozanimod has a negative chronotropic effect and may cause bradycardia, which may increase the risk of QT prolongation.(2-3) Clozapine and concurrent use with other myelosuppressive agents, including ozanimod, may be associated with additive risk of neutropenia or agranulocytosis.(1)

CLINICAL EFFECTS: Concurrent use of clozapine with agents that prolong the QTc interval may result in life-threatening cardiac arrhythmias.(1) Ozanimod lowers heart rate (HR) within 5 hours of the 1st dose. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval.(2,3) Moderate neutropenia may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder. Ozanimod therapy may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of ozanimod. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4) Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.(1)

PATIENT MANAGEMENT: Approach the concurrent use of clozapine and other agents that prolong the QTc interval with caution.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If a patient stabilized on clozapine therapy requires treatment with other myelosuppressive agents the clozapine prescriber should consult with the prescriber of the myelosuppressive agent to discuss treatment and monitoring options. More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(6) Australia, Canada and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(1) Patients receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be referred to a cardiologist. Consult the prescribing information for recommendations regarding cardiac monitoring.(2-3)

DISCUSSION: Treatment with clozapine has been associated with QT prolongation as well as ventricular arrhythmia, torsades de pointes, cardiac arrest, and sudden death.(1) After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, max heart rate effect occurred on day 8.(2,3)

Ozanimod/Immunosuppressives; Immunomodulators

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Ozanimod/Immunosuppressives;Immunomodulators That Prolong Qt

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2) Initiation of ozanimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1,2)

CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2) The initial heart rate lowering effect of ozanimod usually occurs within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications may increase the risk from this interaction. Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The ozanimod US prescribing information includes this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1,2) Patients receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should receive consultation with a cardiologist. Consult the prescribing information for recommendations regarding cardiac monitoring.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, max heart rate effect occurred on day 8.(1,2)

Ozanimod/Moderate Cyp2c8 Inducers That Prolong Qt

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ozanimod is a substrate of CYP2C8. Moderate inducers of CYP2C8 may induce the metabolism of ozanimod.(1) Initiation of ozanimod has a negative chronotropic effect and may cause bradycardia. Concurrent use with CYP2C8 inducers that prolong the QT interval may increase the risk of bradycardia and QT prolongation.(1,2)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP2C8 may result in decreased levels and effectiveness of ozanimod and the active metabolites CC112273 and CC1084037.(1) The heart rate lowering effect of ozanimod in the initial decrease is usually within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1,2)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of ozanimod states to avoid concurrent administration with moderate CYP2C8 inducers.(1) Patients receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be consult with a cardiologist. Consult the prescribing information for recommendations regarding cardiac monitoring.(1)

DISCUSSION: Coadministration of rifampin (a strong CYP3A4 and P-gp inducer, and moderate CYP2C8 inducer - 600 mg once daily) decreased the area-under-curve (AUC) of ozanimod, CC112273, and CC1084037 by 24%, 60%, and 55%, respectively.(1) After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, max heart rate effect occurred on day 8.(1) Moderate CYP2C8 inducers linked to this monograph include: ivosidenib.(3-4)

Ozanimod/Strong Cyp2c8 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP2C8 inhibitors may inhibit the metabolism of ozanimod.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C8 inhibitor may increase levels and effects of ozanimod, including increased infection risk, bradyarrhythmias, atrioventricular conduction delays, liver injury, and hypertension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP2C8 inhibitors and ozanimod is not recommended.(1) If concurrent use is warranted, monitor patients closely for increased effects of ozanimod, including increased infection risk, bradyarrhythmias, atrioventricular conduction delays, liver injury, and hypertension.

DISCUSSION: Concurrent use of ozanimod with gemfibrozil increased the area-under-curve (AUC) of active metabolites CC112273 and CC1084037 by 47% and 69%, respectively. There were no clinically significant changes in the AUC of ozanimod.(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ozanimod/Non-Live Or Non-Replicating Vaccines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ozanimod is an immunosuppressant and may alter the immune system's response to vaccines.(1)

CLINICAL EFFECTS: Administration of a vaccine during and for up to 3 months after discontinuation of ozanimod therapy may result in decreased effectiveness of the vaccine. Ozanimod treatment should be paused 3 months prior and for 1 month after vaccination.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Ideally, administer vaccines prior to initiating ozanimod therapy. The immune response to non-live vaccines should be monitored in patients receiving ozanimod or who have received ozanimod in the previous 3 months. Vaccinations given during and for up to 3 months after discontinuation of ozanimod therapy may need to be repeated.(1) The Centers for Disease Control's (CDC) Advisory Committee on Immunization Practices (ACIP) states that non-live vaccines should be used with caution in patients who are severely immunosuppressed. Patients who are vaccinated within the 14 days prior to initiating immunosuppressive therapy should be considered unvaccinated and should be revaccinated at least 3 months after immunosuppressive therapy is discontinued when immune competence is restored.(2)

DISCUSSION: Vaccinations may be less effective if administered during and for up to 3 months after ozanimod treatment.(1) However they are considered safe to administer.

Ozanimod/Qt Prolonging Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator. Initiation of ozanimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block.(1,2) 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.

CLINICAL EFFECTS: The initial heart rate lowering effect of ozanimod usually occurs within 5 hours. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. Symptomatic bradycardia and heart block, including third degree block, have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1,2)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to ozanimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to ozanimod.(1,2) The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Prior to initiation of ozanimod, obtain an ECG to determine if preexisting conduction abnormalities are present. Patients with preexisting cardiac conditions, significant QT prolongation (QTc >450 msec in males, >470 msec in females), concurrent Class Ia or Class III antiarrhythmics, or receiving concurrent treatment with a QT prolonging agent at the time ozanimod is initiated or resumed should be referred to a cardiologist.(1) The US recommendations state: Dose titration is recommended with initiation of ozanimod due to transient decrease in heart rate and AV conduction delays.(1) United Kingdom recommendations:(2) Due to the risk of transient decreases in HR with the initiation of ozanimod, first dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure. Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended. Additional monitoring after 6 hours is recommended in patients with: heart rate less than 45 bpm, heart rate at the lowest value post-dose (suggesting that the maximum decrease in HR may not have occurred yet), evidence of a new onset second-degree or higher AV block at the 6-hour post dose ECG, or QTc interval greater than 500 msec. In these cases, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2,3)

DISCUSSION: After the first dose of ozanimod heart rate decline is usually maximal at approximately 5 hours, returning to baseline at 6 hours. With continued, chronic dosing, maximum heart rate effect occurred on day 8.(1,2)

*Patients with any of the following conditions within the previous 6 months: myocardial infarction (MI), unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III or IV heart failure.

*Presence of Mobitz type II second-degree or third-degree atrioventricular (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.

• Acute myocardial infarction
• Atrioventricular block
• Progressive multifocal leukoencephalopathy

• Bradycardia
• Cerebrovascular disorder
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Congenital long QT syndrome
• Disease of liver
• Hypertension
• Infection
• Myocardial ischemia
• Pregnancy
• Sick sinus syndrome
• Sinoatrial block
• Sleep apnea

• Child-pugh class C hepatic impairment
• Diabetes mellitus
• Macular retinal edema
• Pre-malignant skin lesion
• Uveitis

The most common adverse reactions reported with ozanimod in MS trials (occurring in >=4% of patients) were upper respiratory infection, liver enzyme elevations, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

The most common adverse reactions reported with ozanimod in ulcerative colitis trials (occurring in >=4% of patients) were liver enzyme elevations, upper respiratory infection, and headache.

More Frequent

• Abnormal hepatic function tests
• Hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Infection
• Lymphopenia

Less Frequent

• Decrease in forced vital capacity

Rare or Very Rare

• Atrioventricular block
• Bradycardia
• Herpes zoster
• Hypersensitivity drug reaction
• Hypertensive crisis
• Macular retinal edema
• Malignancy
• Posterior reversible encephalopathy syndrome
• Progressive multifocal leukoencephalopathy

More Frequent

• Acute abdominal pain
• Arthralgia
• Back pain
• Fever
• Headache disorder
• Orthostatic hypotension
• Upper respiratory infection
• Urinary tract infection

Less Frequent

• Peripheral edema
• Upper abdominal pain

Rare or Very Rare

• Skin rash
• Urticaria

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Safety and efficacy of ozanimod have not been established in pediatric patients.

There are insufficient data on the developmental risk associated with ozanimod during pregnancy. However, the S1P receptor targeted by ozanimod has been demonstrated to have an important role in embryogenesis, including neural and vascular development. In animal studies, administration of ozanimod during pregnancy had adverse effects on fetal development, including embryolethality, increased fetal malformation, and neurobehavioral changes in the absence of maternal toxicity.

A pregnancy exposure registry that monitors pregnancy outcomes in women with MS exposed to ozanimod during pregnancy is available. Healthcare providers are encouraged to register patients, or pregnant women may register themselves at https://www.zeposiapregnancyregistry.com/ or by calling 1-877-301-9314.

It is not known whether ozanimod is distributed into human milk; however, the drug is distributed into milk in rats at concentrations higher than those in maternal plasma. The effects of ozanimod on the nursing infant or on milk production are not known.

Consider the developmental and health benefits of breast-feeding along with the importance of ozanimod to the female and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Clinical studies of ozanimod did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger patients. No clinically significant differences in the metabolism of ozanimod and its major metabolite CC112273 were observed in clinical studies based on age. Because of the greater frequency of decreased hepatic and cardiac function in geriatric patients, monitor such patients for cardiac and hepatic adverse reactions during ozanimod therapy.