b"IMPORTANT SAFETY INFORMATION (cont'd) ZEPOSIA(ozanimod) capsules, for oral use Because the elimination of ZEPOSIA (ozanimod) after discontinuation may take up to 3 months, continue101 monitoring for infections throughout this period.Progressive Multifocal Leukoencephalopathy (PML): (cont'd) Herpes Viral InfectionBrief Summary of Prescribing Information. For complete prescribinginformation consult official Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, andpackageinsert. of ZEPOSIA.other UC therapies and has been associated with some risk factors. If PML is suspected, withholdINDICATIONS AND USAGE In UC Study 1 and Study 3, herpes zoster was reported in 0.4% of patients who received ZEPOSIA and ZEPOSIA and perform an appropriate diagnostic evaluation. ZEPOSIA (ozanimod) is indicated for the treatment of: 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.If con rmed, treatment with ZEPOSIA should be discontinued. moderately to severely active ulcerative colitis (UC) in adults. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine DOSAGE AND ADMINISTRATION 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of BradyarrhythmiaandAtrioventricularConductionDelays:SinceinitiationofZEPOSIAmayvaricella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus Assessments Prior to First Dose of ZEPOSIAresult in a transient decrease in heart rate and atrioventricular conduction delays, dose titration isBefore initiation of treatment with ZEPOSIA, assess the following: (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below).recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation mayComplete Blood Count Cryptococcal InfectionCases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from aObtain a recent (i.e., within the last 6 months or after discontinuation of prior UC therapy) complete bloodwith S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients cardiologist should be sought for those individuals: count (CBC), including lymphocyte count [see Warnings and Precautions]. 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 beenwith signi cant QT prolongationCardiac Evaluation excluded. If CM is diagnosed, appropriate treatment should be initiated. with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present.Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings withischemicheartdisease,heartfailure,historyofcardiacarrestormyocardialinfarction,and Precautions]. modulating Therapiescerebrovascular disease, and uncontrolled hypertension Liver Function Tests In 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 with a history of Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino- Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings andtreatment of UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase atrial heart block Precautions]. the risk of immunosuppression. In UC studies, concomitant use of corticosteroids was allowed and did Ophthalmic Assessment not appear to influence the safety or efficacy of ZEPOSIA [see Clinical Studies (14.2) in full Prescribing Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liverIn patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including theInformation].function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patientsmacula [see Warnings and Precautions]. 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. who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checkedCurrent or Prior Medications When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and and ZEPOSIA should be discontinued if signi cant liver injury is con rmed. Caution should beIf patients are taking anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulatingtheir mode of action to avoid unintended additive immunosuppressive effects.therapies, or if there is a history of prior use of these drugs, consider possible unintended additive exercised when using ZEPOSIA in patients with history of signi cant liver disease. immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and PrecautionsVaccinationsand Drug Interactions]. Patients without a healthcare professional-confirmed history of chickenpox or without documentation of Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animalDetermine if patients are taking drugs that could slow heart rate or atrioventricular conduction [seea 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 studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effectiveWarnings and Precautions and Drug Interactions]. to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Vaccinations 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. Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months ofPatients without a healthcare professional-confirmed history of chickenpox or without documentation of aVaccinations may be less effective if administered during ZEPOSIA treatment.full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before treatmentandpersistedthroughouttreatment.Bloodpressureshouldbemonitoredduringinitiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencingIf live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of treatmentandmanagedappropriately.Certainfoodsthatmaycontainveryhighamountsoftreatment with ZEPOSIA [see Warnings and Precautions and Drug Interactions]. ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA.If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advisedof ZEPOSIA. Progressive Multifocal Leukoencephalopathyto avoid foods containing a very large amount of tyramine while taking ZEPOSIA. Recommended Dosage for Ulcerative Colitis 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 Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluationInitiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions]. After initialdeath or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, titration, the recommended dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and of respiratory function should be performed during therapy, if clinically indicated. Swallow ZEPOSIA capsules whole, with or without food [see Clinical Pharmacology (12.3) in full Prescribingchanges in thinking, memory, and orientation leading to confusion and personality changes.Macular Edema: S1P modulators have been associated with an increased risk of macular edema.Information]. PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other UC therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a historyTable 1:Dose Titration Regimen with immunosuppressants). 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, of these conditions should have an ophthalmic evaluation of the fundus, including the macula,Days 1-4 0.23 mg once daily treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic priortotreatmentinitiationandregularfollow-upexaminations.AnophthalmicevaluationisDays 5-7 0.46 mg once daily evaluation. recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA inDay 8 and thereafter 0.92 mg once daily If PML is confirmed, treatment with ZEPOSIA should be discontinued.patients with macular edema has not been evaluated; potential bene ts and risks for the individualBradyarrhythmia and Atrioventricular Conduction Delayspatient should be considered if deciding whether ZEPOSIA should be discontinued. Reinitiation of ZEPOSIA after Treatment Interruption Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titrationdelays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reportedregimen [see Dosage and Administration]. and Administration and Clinical Pharmacology (12.2) in full Prescribing Information].in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpectedIf a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned. ZEPOSIA was not studied in patients who had:A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranialCONTRAINDICATIONS hospitalization within the last 6 monthspressure, a complete physical and neurological examination should be conducted. Symptoms ofZEPOSIA is contraindicated in patients who: New York Heart Association Class III / IV heart failurePRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. DelayIn the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transientCardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure(QTcF 450 msec in males, 470 msec in females), risk factors for QT prolongation, or other in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected,[see Warnings and Precautions] conduction abnormalities or cardiac condition that in the opinion of the treating investigator could treatment with ZEPOSIA should be discontinued. Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sickjeopardize the patients healthsinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see WarningsOther pre-existing stable cardiac conditions without clearance from a cardiologistUnintendedAdditiveImmunosuppressiveEffectsFromPriorImmunosuppressiveorand Precautions] Severe untreated sleep apneaImmune-Modulating Drugs: When switching from drugs with prolonged immune effects, theHave severe untreated sleep apnea [see Warnings and Precautions] A resting heart rate less than 55 beats per minute (bpm) at baselinehalf-lifeandmodeofactionofthesedrugsmustbeconsideredtoavoidunintendedadditiveAre taking a monoamine oxidase (MAO) inhibitor [see Drug Interactions] Reduction in Heart Rateimmunosuppressive effects while at the same time minimizing risk of disease reactivation. InitiatingWARNINGS AND PRECAUTIONS Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of treatment with ZEPOSIA after treatment with alemtuzumab is not recommended. Infections ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate occurred at Hour 5 on Risk of Infections Day 1 (0.7 bpm in UC Study 1 and Study 3), returning to near baseline at Hour 6. With continued ImmuneSystemEffectsAfterStoppingZEPOSIA:AfterdiscontinuingZEPOSIA,themedianZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baselineup-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 time for lymphocyte counts to return to the normal range was 30 days with approximately 90%values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacologyto those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not (12.2) in full Prescribing Information]. ZEPOSIA may therefore increase the susceptibility to infections, some of patients in the normal range within 3 months. Use of immunosuppressants within this periodserious in nature. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration].may lead to an additive effect on the immune system, therefore caution should be applied whenObtain a recent (i.e., within 6 months or after discontinuation of prior UC therapy) complete blood countIn UC Study 1 and Study 3, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) initiating other drugs 4 weeks after the last dose of ZEPOSIA. (CBC) including lymphocyte count before initiation of ZEPOSIA. treated with ZEPOSIA compared to none in patients who received placebo. After Day 1, bradycardia was Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. reported in 1patient (0.2%) treated with ZEPOSIA. In UC Study 2, bradycardia was not reported.Most Common Adverse Reactions ( 4): liver test increased, upper respiratory infection, and headache. In UC Study 1 and Study 3, the overall rate of infections and rate of serious infections in patients treatedAtrioventricular Conduction DelaysUse in Speci c Populations: Hepatic Impairment: Use is not recommended. with ZEPOSIA were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%,Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher respectively). In UC Study 2, the overall rate of infections in patients treated with ZEPOSIA was higher than inthan the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).For additional safety information, please see Brief Summary of the Prescribing InformationZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpesblocks were observed in healthy volunteers; however, in 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.and the Medication Guide on the following pages. infections [see Adverse Reactions]. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:The proportion of patients treated with ZEPOSIA with lymphocytes less than 0.2 x 109/L was 2% in UC References: 1. ZEPOSIA. Prescribing information. Bristol-Myers Squibb Company; 2021. 2. Data on File. OZA 027. Princeton, NJ: Bristol Myers Squibb.Study 1 and Study 3 and 2.3% in UC Study 2. These values generally returned to greater than 0.2x109/LWith significant QT prolongation (QTcF 450 msec in males, 470 msec in females)3. Sandborn WJ, Feagan BG, DHaens G, et al; True North Study Group. Ozanimod as induction andwhile patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the medianWith arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugsmaintenance therapy for ulcerative colitis (supplementary appendix). N Engl J Med. 2021;385:1280-1291. time for peripheral blood lymphocytes to return to the normal range was approximately 30days, withWith ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, approximately 80% to 90% of patients in the normal range within 3 months [see Clinical Pharmacologycerebrovascular disease, and uncontrolled hypertensionZEPOSIA and ZEPOSIA logo are trademarks of Celgene Corporation, a Bristol Myers Squibb company. (12.2) in full Prescribing Information]. With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial2022 Bristol-Myers Squibb Company. Printed in the USA. 2084-US-2200376 02/22 Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. heart block [see Contraindications]2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 3 3/2/22 11:39 AM2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 4 3/2/22 11:39 AM"