Ozanimod Hydrochloride

5 WARNINGS AND PRECAUTIONS Infections : ZEPOSIA may increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment. Monitor for infection during treatment and for 3 months after discontinuation. Do not start ZEPOSIA in patients with active infections. ( 5.1 ) Progressive Multifocal Leukoencephalopathy (PML) : Withhold ZEPOSIA at the first sign or symptom suggestive of PML. ( 5.2 ) Bradyarrhythmia and Atrioventricular Conduction Delays : ZEPOSIA may result in transient decrease in heart rate; titration is required for treatment initiation. Check an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting ZEPOSIA. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. ( 2.1 , 2.2 , 5.3 , 7 ) Liver Injury : Obtain liver enzyme results before initiation and periodically during treatment. Discontinue if there is evidence of liver injury without other cause. ( 5.4 ) Fetal Risk : Women of childbearing potential should use effective contraception during treatment and for 3 months after stopping ZEPOSIA. ( 5.5 , 8.3 ) Increased Blood Pressure (BP) : Monitor BP during treatment. ( 5.6 ) Respiratory Effects : May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. ( 5.7 ) Macular Edema : Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA. Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing ZEPOSIA if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.8 ) Cutaneous Malignancies : Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. ( 5.9 )

5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2) ]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature . Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA . Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. In MS Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received interferon (IFN) beta-1a (35% vs. 34% and 1% vs. 0.8%, respectively). In UC Study 1 and Study 3, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). In UC Study 2, the overall rate of infections in patients treated with ZEPOSIA was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections [see Adverse Reactions (6.1) ]. The proportion of patients treated with ZEPOSIA who experienced lymphocyte counts less than 0.2 × 10 9 /L was 3.3% in MS Study 1 and Study 2. The proportion of patients treated with ZEPOSIA with lymphocyte counts less than 0.2 × 10 9 /L was 2% in UC Study 1 and Study 3 and 2.3% in UC Study 2. These values generally returned to greater than 0.2 × 10 9 /L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2) ]. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period. Herpes Viral Infection Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA. In MS Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. In UC Study 1 and Study 3, herpes zoster was reported in 0.4% of patients who received ZEPOSIA and none in patients who received placebo. In UC Study 2, herpes zoster was reported in 2.2% of patients who received ZEPOSIA and 0.4% of patients who received placebo. None were serious or disseminated. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below). Cryptococcal Infection Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating Therapies In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. In UC studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ZEPOSIA [see Clinical Studies (14.2) ]. Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA.

5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include 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. PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other multiple sclerosis (MS) and UC therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants,duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months. Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, treatment with ZEPOSIA should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

5.3 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays , an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2) ] . ZEPOSIA was not studied in patients who had: A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months New York Heart Association Class III / IV heart failure Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient's health Other pre-existing stable cardiac conditions without clearance from a cardiologist Severe untreated sleep apnea A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate occurred at Hour 5 on Day 1 (decrease of 1.2 bpm in MS Study 1 and Study 2, and 0.7 bpm in UC Study 1 and Study 3), returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2) ]. In MS Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. In UC Study 1 and Study 3, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) treated with ZEPOSIA compared to none in patients who received placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with ZEPOSIA. In UC Study 2, bradycardia was not reported. Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in MS Study 1 and Study 2 and UC Study 1 and Study 3 with dose titration, Mobitz type 2 second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4) ] 5.4 Liver Injury Clinically significant liver injury, including acute liver failure requiring transplant, has occurred in patients treated with ZEPOSIA in the postmarketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. In MS Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2-4 weeks. ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients with MS treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a. In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 0.9% of patients and no patients, respectively. In UC Study 1, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 2.3% of patients and no patients, respectively. In controlled and uncontrolled UC studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2 to 4 weeks. Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg, and none in patients who received placebo in the controlled UC studies. Individuals with an AST or ALT greater than 1.5-fold ULN were excluded from MS Study 1 and Study 2 and greater than 2 times the ULN for UC Study 1 and Study 3. There are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA. Dosage adjustment in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) is required [see Dosage and Administration (2.3) ] , and use of ZEPOSIA in patients with severe hepatic impairment (Child-Pugh class C) is not recommended [see Use in Specific Populations (8.6) ] . Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Obtain transaminase levels and total bilirubin levels periodically during treatment and until two months after ZEPOSIA discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes promptly checked, and ZEPOSIA should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

5.5 Fetal Risk There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1) ] . Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.3) ] .

5.6 Increased Blood Pressure In MS Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in MS Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. The mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated with ZEPOSIA is similar to patients with MS. In UC Study 1 and Study 3, the average increase from baseline in SBP was 3.7 mm Hg in patients treated with ZEPOSIA and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the average increase from baseline in SBP was 5.1 mm Hg in patients treated with ZEPOSIA and 1.5 mm Hg in patients treated with placebo. There was no effect on DBP. Hypertension was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA 0.92 mg and none in patients treated with placebo in UC Study 1 and Study 3, and in 2.2% and 2.2% of patients in UC Study 2, respectively. Hypertensive crisis was reported in two patients receiving ZEPOSIA and one patient receiving placebo. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately.

5.7 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV 1 ) were observed in MS patients treated with ZEPOSIA as early as 3 months after treatment initiation. In the MS pooled analyses of Study 1 and Study 2, the decline in absolute FEV 1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV 1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a [60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)], though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV 1 or FVC after drug discontinuation. One patient in MS Study 1 discontinued ZEPOSIA because of dyspnea. In UC Study 1 the mean difference in decline in absolute FEV 1 from baseline in patients treated with ZEPOSIA compared to patients who received placebo was 22 mL (95% CI: -84, 39) at 10 weeks. The mean difference in percent predicted normal (PPN) FEV 1 at 10 weeks between patients treated with ZEPOSIA compared to those who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVC (absolute value and %-predicted) seen at Week 10 in UC Study 1, comparing patients who were treated with ZEPOSIA to those who received placebo was 44 mL, 95% CI (-114, 26); 0.5%, 95% CI (-2.3, 1.2), respectively. There is insufficient information to determine the reversibility of observed decreases in FEV 1 or FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with continued use. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.

5.8 Macular Edema S1P receptor modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA. Perform an examination of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. In MS Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. Macular edema was reported in a total of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%) patient in UC Study 2 treated with ZEPOSIA, and in no patients who received placebo. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing ZEPOSIA if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated. Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy.

5.9 Cutaneous Malignancies The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Cases of BCC, SCC, and melanoma have been reported in patients treated with ZEPOSIA; melanoma and BCC were reported in controlled trials [see Adverse Reactions (6.1) ] . Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking ZEPOSIA.

5.10 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In MS controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued.

5.11 Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions (7) ].

5.12 Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required. After stopping ZEPOSIA in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [see Warnings and Precautions (5.2) ] .

5.13 Immune System Effects after Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2) ]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7) ].

Tables 5 and 6 include drugs with clinically important drug and vaccine interactions when administered concomitantly with ZEPOSIA and instructions for preventing or managing them. Table 5: Clinically Relevant Interactions Affecting Drugs and Vaccines Co-administered with ZEPOSIA Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Clinical Impact: ZEPOSIA has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which had no pharmacokinetic interaction [see Clinical Pharmacology (12.3) ] . Prevention or Management: Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1) ] . 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 [see Warnings and Precautions (5.11) ] . Alemtuzumab : Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. Beta interferon or glatiramer acetate : ZEPOSIA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate Clinical Impact: ZEPOSIA has not been studied in patients taking QT prolonging drugs. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Prevention or Management: If treatment with ZEPOSIA is considered in patients on Class Ia or Class III anti-arrhythmic drugs, advice from a cardiologist should be sought [see Warnings and Precautions (5.3) ] . Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties [see Warnings and Precautions (5.3) ]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought. Combination Beta Blocker and Calcium Channel Blocker Clinical Impact : The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker has not been studied. However, there is a potential of additive effects on heart rate. Prevention or Management: Treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem) and beta blocker [see Warnings and Precautions (5.3) ]. If treatment initiation with ZEPOSIA is considered in patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from a cardiologist should be sought. Vaccination Clinical Impact: During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection. Prevention or Management: Live attenuated vaccines should be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions (5.1) ] . Table 6: Clinically Relevant Interactions Affecting ZEPOSIA When Co-administered with Other Drugs Monoamine Oxidase (MAO) Inhibitors Clinical Impact: The effect of MAO inhibition on ozanimod and/or its metabolites has not been studied clinically. Potential effects on efficacy or safety with co-administration of MAO inhibitors because of altered exposures of ozanimod and/or its metabolites cannot be ruled out. Prevention or Management: Co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors. Strong CYP2C8 Inhibitors Clinical Impact: Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3) ] , which may increase the risk of ZEPOSIA adverse reactions. Prevention or Management: Co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Strong CYP2C8 Inducers Clinical Impact: Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3) ] , which may decrease the efficacy of ZEPOSIA. Prevention or Management: Co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided. Vaccination : Avoid use of live attenuated vaccines during and for up to 3 months after treatment with ZEPOSIA. ( 7 ) See full prescribing information for a list of clinically important drug interactions. ( 7 )

The following serious adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.2) ] Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.3) ] Liver Injury [see Warnings and Precautions (5.4) ] Fetal Risk [see Warnings and Precautions (5.5) ] Increased Blood Pressure [see Warnings and Precautions (5.6) ] Respiratory Effects [see Warnings and Precautions (5.7) ] Macular Edema [see Warnings and Precautions (5.8) ] Cutaneous Malignancies [see Warnings and Precautions (5.9) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10) ] Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.11) ] Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA [see Warnings and Precautions (5.12) ] Immune System Effects after Stopping ZEPOSIA [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥4%) are: Multiple Sclerosis : upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. ( 6.1 ) Ulcerative Colitis : liver test increased, upper respiratory infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common Adverse Reactions Multiple Sclerosis The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies (MS Study 1 and MS Study 2) in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14.1) ]. Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1a in Patients with Multiple Sclerosis (Pooled MS Study 1 and Study 2) a a Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, viral respiratory tract infection, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, abnormal liver function test, and increased transaminases. d Includes hypertension, essential hypertension, and orthostatic hypertension. e ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2) ]. Adverse Reactions MS Studies 1 and 2 ZEPOSIA 0.92 mg Once Daily e (n=882) % IFN beta-1a 30 mcg Intramuscularly Once Weekly (n=885) % Upper respiratory infection b 26 23 Hepatic transaminase elevation c 10 5 Orthostatic hypotension 4 3 Urinary tract infection 4 3 Back pain 4 3 Hypertension d 4 2 Upper abdominal pain 2 1 Ulcerative Colitis The safety of ZEPOSIA was evaluated in two randomized, double-blind, placebo-controlled clinical studies [UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult patients with moderately to severely active ulcerative colitis [see Clinical Studies (14.2) ] . Additional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3, NCT01647516) included 67 patients who received ZEPOSIA 0.92 mg once daily. Common adverse reactions in UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 3 and 4, respectively. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received placebo were liver test increased, upper respiratory infection, and headache. Table 3: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than Placebo in Patients with Ulcerative Colitis (Pooled UC Study 1 and Study 3) a Includes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis, upper respiratory tract infection, pharyngitis, sinusitis, tonsillitis, viral upper respiratory tract infection, laryngitis, acute sinusitis, catarrh, chronic sinusitis, upper respiratory tract inflammation, chronic tonsillitis, viral pharyngitis, viral sinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngeal inflammation, and pharyngeal inflammation. b Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, blood alkaline phosphatase increased, and increased transaminases. c ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2) ]. d Percentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight. Adverse Reactions Induction Periods (UC Study 1 and Study 3) ZEPOSIA 0.92 mg Once Daily (n=496) c,d % Placebo (n=281) % d Upper respiratory infection a 5 4 Liver test increased b 5 0 Headache 4 3 Pyrexia 3 2 Nausea 3 2 Arthralgia 3 1 Table 4: Adverse Reactions with an Incidence of at Least 4% in ZEPOSIA-Treated Patients and at Least 1% Greater than Placebo in Patients with Ulcerative Colitis (UC Study 2) a Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased, liver function test increased, and blood alkaline phosphatase increased. Adverse Reactions Maintenance Period (UC Study 2) ZEPOSIA 0.92 mg Once Daily (n=230) % Placebo (n=227) % Liver test increased a 11 2 Headache 5 <1 Other Adverse Reactions Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate in MS and UC patients [see Warnings and Precautions (5.3) ]. Respiratory Effects Dose-dependent reductions in absolute FEV 1 and FVC were observed in MS and UC patients treated with ZEPOSIA [see Warnings and Precautions (5.7) ]. Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of MS and UC. An increased risk of cutaneous malignancies has been reported with S1P receptor modulators [see Warnings and Precautions (5.9) ]. Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials. Peripheral Edema Peripheral edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients who received placebo in UC Study 2.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZEPOSIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.4) ]

Hepatic Impairment : Use in severe hepatic impairment (Child-Pugh class C) is not recommended. ( 2.3 , 8.6 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPOSIA during pregnancy. Healthcare providers are encouraged to register patients on-line, or pregnant women may register themselves at https://www.zeposiapregnancyregistry.com/ or by calling 1-877-301-9314. Currently this registry is enrolling women with MS. Information regarding registration of pregnant women with UC will be made available in the future. Risk Summary There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women . In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data) . The receptor affected by ozanimod (sphingosine1-phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and neural development. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformed blood vessels) and skeletal variations at the mid and high doses. Maternal toxicity was not observed. At the no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod exposure (AUC) was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects on pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD.

8.2 Lactation Risk Summary There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Contraception Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific Populations (8.1) ] . Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on age [see Clinical Pharmacology (12.3) ]. Monitor elderly patients for cardiac and hepatic adverse reactions, because of the greater frequency of reduced cardiac and hepatic function in the elderly population.

8.6 Hepatic Impairment In patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B), the exposures of ozanimod and its active metabolites are higher than those in healthy controls [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Therefore, dosage adjustment in patients with mild or moderate hepatic impairment is required [see Dosage and Administration (2.3) ] . The pharmacokinetics of ozanimod and its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C). Therefore, use of ZEPOSIA in patients with severe hepatic impairment is not recommended.

12.1 Mechanism of Action Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that 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. Ozanimod has minimal or no activity on S1P 2 , S1P 3 , and S1P 4 . The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis and ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the central nervous system and intestine.

12.2 Pharmacodynamics Reduction in Blood Lymphocyte Counts In active-controlled MS and controlled UC clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 × 10 9 /L), and low lymphocyte counts were maintained during treatment with ZEPOSIA [see Warnings and Precautions (5.1) ]. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months. Reduction in Heart Rate ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing [see Warnings and Precautions (5.3) ]. An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions [see Dosage and Administration (2.2) ]. Tyramine Challenge Test No clinically significant effect in tyramine induced pressor response was observed when steady state ZEPOSIA 0.92 mg (recommended dose) or 1.84 mg was co-administered with increasing doses of oral tyramine (a monoamine oxidase substrate). Drug Interaction Studies Sympathomimetic Agents No clinically significant differences in heart rate or blood pressure was observed when ZEPOSIA 1.84 mg daily (two times the recommended dosage) for 28 days was co-administered with a single dose of 60 mg pseudoephedrine (a sympathomimetic agent) compared to pseudoephedrine alone. Beta Blocker or Calcium Channel Blocker The effect of co-administration of the maintenance dosage of ZEPOSIA, propranolol, or diltiazem, or administration with both a beta blocker and a calcium channel blocker taken together has not been studied [see Drug Interactions (7) ] . Pulmonary Function Dose-dependent reductions in FEV 1 and FVC were observed in patients treated with ZEPOSIA [see Warnings and Precautions (5.7) ]. Cardiac Electrophysiology Following a 14-day titration regimen of once daily doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg (2 times the maximum approved recommended dose) for 4 days in healthy subjects, ZEPOSIA did not prolong the QTc interval to any clinically relevant extent [see Warnings and Precautions (5.3) ].

12.3 Pharmacokinetics The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC. Table 7: Exposure Parameters of Ozanimod and its Major Metabolite a a Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. b In healthy subjects. C max,ss = maximum observed plasma concentration at steady state, AUC tau,ss = area under the plasma concentration-time curve during a dosage interval at steady state. Parameters Ozanimod CC112273 C max,ss 0.244 ng/mL (31.8%) 6.98 ng/mL (42.7%) AUC tau,ss 4.46 ng*h/mL (31.8%) 143.77 ng*h/mL (39.2%) Dose Proportionality The C max and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg. Time to Steady State 102 hours (28.2%) b 45 days (45%) Accumulation Ratio 2.40 (21.1%) b 16 (101%) Absorption The T max of ozanimod is approximately 6 to 8 hours. Effect of Food No clinically significant differences in the C max and AUC of ozanimod were observed following administration of ZEPOSIA with either a high-fat, high-calorie meal (1000 calories, 50% fat) or a low-fat, low-calorie meal (300 calories, 10% fat) compared to fasted conditions [see Dosage and Administration (2.2) ] . Distribution The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273 and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively. Elimination The mean (CV%) plasma half-life (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%). Metabolism Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP112509) with similar activity and selectivity for S1P 1 and S1P 5 . Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075. RP101075 is then metabolized either by NAT-2 to form a minor active metabolite RP101442 or by MAO-B to form CC112273. CC112273 is then metabolized by CYP2C8 to form RP112509 or reduced to form CC1084037. CC1084037 is metabolized by AKR 1C1/1C2 and/or 3β- and 11β-HSD to form CC112273. The interconversion between CC112273 and CC1084037 favors CC112273. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans. Excretion Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37% in feces, primarily composed of inactive metabolites. Specific Populations Geriatric Patients Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in UC patients over 65 years of age was approximately 3% to 4% greater than patients 45 to 65 years of age and 27% greater than adult patients under 45 years of age. There is no meaningful difference in the pharmacokinetics in elderly patients with UC [see Use in Specific Populations (8.5) ] . Male and Female Patients No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight. Racial or Ethnic Groups In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (C max and AUC tau ) were unchanged and CC112273 exposures (C max and AUC tau ) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful. Patients with Renal Impairment In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUC last ) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8). Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273. Patients with Hepatic Impairment In a hepatic impairment study, following an 8-day titration regimen of once daily doses of ZEPOSIA 0.23 mg on days 1 to 4, 0.46 mg on days 5 to 7, and 0.92 mg on day 8, in subjects with mild hepatic impairment (Child-Pugh class A, N=8), mean exposures (AUC last ) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 60%, 98%, and 107%, respectively, compared to healthy controls (N=8). In subjects with moderate hepatic impairment (Child-Pugh class B, N=8) mean exposures (AUC last ) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 17%, 38%, and 61%, respectively, compared to healthy controls. The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (8.6) ] . Smokers Population PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers, although for smokers this reduction in exposure did not result in meaningful differences in absolute lymphocyte count (ALC) reduction or an apparent impact on clinical efficacy. Drug Interaction Studies Clinical/In Vivo Studies Strong CYP3A and P-gp Inhibitors No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor). Strong CYP2C8 Inhibitors Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively, with no change in the AUC of ozanimod [see Drug Interactions (7) ]. BCRP Inhibitors Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037. Strong CYP2C8 Inducers Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively. The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8 [see Drug Interactions (7) ]. Prednisone and Prednisolone Population pharmacokinetic analyses showed that concomitant administration of prednisone or prednisolone in patients with UC did not alter the apparent clearance of the predominant active metabolite CC112273. The impact of prednisone or prednisolone on the pharmacokinetics of CC1084037 is unknown. Monoamine Oxidase Inhibitors No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted [see Drug Interactions (7) ]. Monoamine Oxidase Substrates Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate. Oral Contraceptives No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod. In Vitro Studies Cytochrome P450 (CYP) Enzymes Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A. In vitro, CC112273 and CC1084037 inhibited MAO-B (IC 50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A) [see Drug Interactions (7) ] . Transporter Systems Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2-K. CC112273 and CC1084037 do not inhibit BCRP at clinically relevant concentrations.

The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC. Table 7: Exposure Parameters of Ozanimod and its Major Metabolite a a Mean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. b In healthy subjects. C max,ss = maximum observed plasma concentration at steady state, AUC tau,ss = area under the plasma concentration-time curve during a dosage interval at steady state. Parameters Ozanimod CC112273 C max,ss 0.244 ng/mL (31.8%) 6.98 ng/mL (42.7%) AUC tau,ss 4.46 ng*h/mL (31.8%) 143.77 ng*h/mL (39.2%) Dose Proportionality The C max and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg. Time to Steady State 102 hours (28.2%) b 45 days (45%) Accumulation Ratio 2.40 (21.1%) b 16 (101%) Absorption The T max of ozanimod is approximately 6 to 8 hours. Effect of Food No clinically significant differences in the C max and AUC of ozanimod were observed following administration of ZEPOSIA with either a high-fat, high-calorie meal (1000 calories, 50% fat) or a low-fat, low-calorie meal (300 calories, 10% fat) compared to fasted conditions [see Dosage and Administration (2.2) ] . Distribution The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273 and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively. Elimination The mean (CV%) plasma half-life (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%). Metabolism Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP112509) with similar activity and selectivity for S1P 1 and S1P 5 . Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075. RP101075 is then metabolized either by NAT-2 to form a minor active metabolite RP101442 or by MAO-B to form CC112273. CC112273 is then metabolized by CYP2C8 to form RP112509 or reduced to form CC1084037. CC1084037 is metabolized by AKR 1C1/1C2 and/or 3β- and 11β-HSD to form CC112273. The interconversion between CC112273 and CC1084037 favors CC112273. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans. Excretion Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37% in feces, primarily composed of inactive metabolites. Specific Populations Geriatric Patients Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in UC patients over 65 years of age was approximately 3% to 4% greater than patients 45 to 65 years of age and 27% greater than adult patients under 45 years of age. There is no meaningful difference in the pharmacokinetics in elderly patients with UC [see Use in Specific Populations (8.5) ] . Male and Female Patients No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight. Racial or Ethnic Groups In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (C max and AUC tau ) were unchanged and CC112273 exposures (C max and AUC tau ) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful. Patients with Renal Impairment In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUC last ) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8). Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273. Patients with Hepatic Impairment In a hepatic impairment study, following an 8-day titration regimen of once daily doses of ZEPOSIA 0.23 mg on days 1 to 4, 0.46 mg on days 5 to 7, and 0.92 mg on day 8, in subjects with mild hepatic impairment (Child-Pugh class A, N=8), mean exposures (AUC last ) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 60%, 98%, and 107%, respectively, compared to healthy controls (N=8). In subjects with moderate hepatic impairment (Child-Pugh class B, N=8) mean exposures (AUC last ) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 17%, 38%, and 61%, respectively, compared to healthy controls. The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations (8.6) ] . Smokers Population PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers, although for smokers this reduction in exposure did not result in meaningful differences in absolute lymphocyte count (ALC) reduction or an apparent impact on clinical efficacy. Drug Interaction Studies Clinical/In Vivo Studies Strong CYP3A and P-gp Inhibitors No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor). Strong CYP2C8 Inhibitors Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively, with no change in the AUC of ozanimod [see Drug Interactions (7) ]. BCRP Inhibitors Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037. Strong CYP2C8 Inducers Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively. The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8 [see Drug Interactions (7) ]. Prednisone and Prednisolone Population pharmacokinetic analyses showed that concomitant administration of prednisone or prednisolone in patients with UC did not alter the apparent clearance of the predominant active metabolite CC112273. The impact of prednisone or prednisolone on the pharmacokinetics of CC1084037 is unknown. Monoamine Oxidase Inhibitors No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted [see Drug Interactions (7) ]. Monoamine Oxidase Substrates Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate. Oral Contraceptives No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod. In Vitro Studies Cytochrome P450 (CYP) Enzymes Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A. In vitro, CC112273 and CC1084037 inhibited MAO-B (IC 50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A) [see Drug Interactions (7) ] . Transporter Systems Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2-K. CC112273 and CC1084037 do not inhibit BCRP at clinically relevant concentrations.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risk of Infections Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions (5.1) ]. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. Advise patients that if immunizations are planned, they should be administered at least 1 month prior to initiation of ZEPOSIA. Inform patients that the use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. Progressive Multifocal Leukoencephalopathy Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients who received ZEPOSIA and other S1P receptor modulators. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include 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 [see Warnings and Precautions (5.2) ] . Cardiac Effects Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate . Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment [see Dosage and Administration (2.2 , 2.4) and Warnings and Precautions (5.3) ]. Liver Injury Inform patients that ZEPOSIA may cause liver injury. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine [see Warnings and Precautions (5.4) ]. Pregnancy and Fetal Risk Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm . Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions (5.5) and Use in Specific Populations (8.3) ]. Pregnancy Registry Encourage multiple sclerosis patients to enroll in the ZEPOSIA Pregnancy Registry if they become pregnant while taking ZEPOSIA [see Use in Specific Populations (8.1) ] . Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea [see Warnings and Precautions (5.7) ]. Macular Edema Advise patients that ZEPOSIA may cause macular edema, and that they should obtain an eye exam near the start of treatment with ZEPOSIA, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking ZEPOSIA. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema may be increased [see Warnings and Precautions (5.8) ]. Cutaneous Malignancies Inform patients that the risk of basal cell carcinoma, squamous cell carcinoma, and melanoma is increased in patients treated with S1P receptor modulators. Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with high protection factor [see Warnings and Precautions (5.9) ]. Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provide any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences [see Warnings and Precautions (5.10) ]. Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA Inform patients with multiple sclerosis that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA [see Warnings and Precautions (5.12) ]. Immune System Effects after Stopping ZEPOSIA Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose [see Warnings and Precautions (5.13) ].