b'B:8.5"T:8.25"S:7.25"body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and forTable 2:Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA (ozanimod)-Treated Patients 3 months after stopping ZEPOSIA (ozanimod) [see Use in Specific Populations]. and at Least 1% Greater than IFN beta-1a in Patients with Multiple Sclerosis (Pooled MS aStudy 1 and Study 2) Increased Blood PressureIn MS Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg inMS Studies 1 and 2systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolicIFN beta-1a pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. HypertensionAdverse Reactions ZEPOSIA30 mcg Intramuscularly was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who0.92 mg Once DailyOnce Weekly ereceived IFN beta-1a. Two patients treated with ZEPOSIA in MS Study 1 and one patient treated with interferon (IFN)(n=882)(n=885) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. % %Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Upper respiratory infection 26 23bcCertain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertensionHepatic transaminase elevation10 5because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses. Because of anOrthostatic hypotension 4 3increased sensitivity to tyramine, patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA. Urinary tract infection 4 3Respiratory Effects Back pain 4 3Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV 1 ) were observed in MS patientsHypertension4 2dtreated 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 1from baseline in patients treated with ZEPOSIA compared to patients who receivedUpper abdominal pain 2 1IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV 1at 12 monthsa Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control.between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose- b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 inbronchitis, rhinitis, viral respiratory tract infection, viral upper respiratory tract infection, rhinorrhea, tracheitis, and pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a [60 mL, 95% CI (-110,laryngitis.-10); 1.4%, 95% CI: (-2.6, -0.2)], though significant reductions were not seen at other timepoints. There is insufficientc Includes the following terms: alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate information to determine the reversibility of the decrease in FEV 1or FVC after drug discontinuation. One patient in MSaminotransferase increased, hepatic enzyme increased, abnormal liver function test, and increased transaminases.Study 1 discontinued ZEPOSIA because of dyspnea. d Includes hypertension, essential hypertension, and orthostatic hypertension.Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated. e ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration].Macular Edema Other Adverse ReactionsSphingosine 1-phosphate (S1P) receptor modulators, including ZEPOSIA, have been associated with an increased riskReduction in Heart Rateof macular edema.In MS Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% ofInitiation of ZEPOSIA may result in transient decrease in heart rate in MS patients [see Warnings and Precautions].patients who received IFN beta-1a. Respiratory EffectsAn ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is anyDose-dependent reductions in absolute FEV 1and FVC were observed in MS patients treated with ZEPOSIA [see Warnings change in vision while taking ZEPOSIA. and Precautions].Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision on whether or notMalignanciesZEPOSIA should be discontinued needs to take into account the potential benefits and risks for the individual patient. Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of MS. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator.Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edemaHypersensitivityduring ZEPOSIA therapy. The incidence of macular edema is also increased in patients with a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, patients with diabetes mellitus or aHypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials.history of uveitis should have regular follow-up examinations. DRUG INTERACTIONSPosterior Reversible Encephalopathy Syndrome Tables 3 and 4 include drugs with clinically important drug, tyramine, and vaccine interactions when administered Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1Pconcomitantly with ZEPOSIA and instructions for preventing or managing them.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, behavioralTable 3:Clinically Relevant Interactions Affecting Drugs, Tyramine, and Vaccines Co-administered changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestivewith ZEPOSIAof an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly scheduleS:9.875" T:10.5" B:11.375"a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversibleAnti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapiesbut 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. ZEPOSIA has not been studied in combination with anti-neoplastic, immune-modulating, or Clinical Impact:non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which had no Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune- pharmacokinetic interaction [see Clinical Pharmacology (12.3) in full Prescribing Information].Modulating DrugsWhen switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must beCaution should be used during concomitant administration because of the risk of additive considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of diseaseimmune effects during such therapy and in the weeks following administration [see Warnings reactivation, when initiating ZEPOSIA. and Precautions].When switching from drugs with prolonged immune effects, the half-life and mode of action of Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions]. Prevention orthese drugs must be considered in order to avoid unintended additive immunosuppressive effects Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA Management:[see Warnings and Precautions].Alemtuzumab:Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of aof the characteristics and duration of alemtuzumab immune suppressive effects.S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIABeta interferon or glatiramer acetate:ZEPOSIA can generally be started immediately after treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriatediscontinuation of beta interferon or glatiramer acetate.treatment should be instituted, as required.Immune System Effects after Stopping ZEPOSIA Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart RateAfter discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range wasZEPOSIA has not been studied in patients taking QT prolonging drugs.approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [see ClinicalClinical Impact:Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic Pharmacology (12.2) in full Prescribing Information]. Use of immunosuppressants within this period may lead to andrugs have been associated with cases of Torsades de Pointes in patients with bradycardia.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]. 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].ADVERSE REACTIONS Prevention orBecause of the potential additive effects on heart rate, treatment with ZEPOSIA should generally The following serious adverse reactions are described elsewhere in the labeling: Management:not be initiated in patients who are concurrently treated with QT prolonging drugs with known Infections [see Warnings and Precautions] arrhythmogenic properties [see Warnings and Precautions].If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions] a cardiologist should be sought.Liver Injury [see Warnings and Precautions]Fetal Risk [see Warnings and Precautions] Adrenergic and Serotonergic DrugsIncreased Blood Pressure [see Warnings and Precautions] Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious Respiratory Effects [see Warnings and Precautions] adverse reactions, including hypertensive crisis with co-administration of ZEPOSIA with drugs or Macular Edema [see Warnings and Precautions] over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs, Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions] selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune- (SNRIs), tricyclics, tyramine].Modulating Drugs [see Warnings and Precautions] Opioid DrugsSevere Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA [see Warnings and Precautions] Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs Immune System Effects after Stopping ZEPOSIA [see Warnings and Precautions] (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantly Clinical Trials Experience exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinicalClinical Impact:reaction from co-administration.trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the ratesSerotonergic Drugsobserved in clinical practice. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to Common Adverse Reactions serotonergic medications, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration.Multiple Sclerosis Sympathomimetic MedicationsThe safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies inConcomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects on blood which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14.1) in full Prescribing Information]. pressure [see Clinical Pharmacology (12.2) in full Prescribing Information]. However, hypertensive Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. Thecrisis has occurred with administration of ZEPOSIA alone [see Warnings and Precautions] and most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patientshypertensive crisis has been reported with co-administration of other selective and nonselective who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension,MAO inhibitors (e.g., rasagiline) with sympathomimetic medications.urinary tract infection, back pain, and hypertension. (Continued)PREPARED BY 11707081 BMS_MS_Spread Journal Ad - A-size M7FR11707081_BMS_MS_Spread Journal Ad_Asize_M7FR.indd 4 3/19/22 11:10 AMJob info Images FontsSpecial InstructionsDate: 3-19-2022 11:06 AM 2084_US_2200588_ZEPOSIA MS PML PBSArial Narrow (Regular) NoneClient: BMS 7.25x9.875_0322_wip2FNL.pdf (100%; 152KB)Product: ZEPOSIAClient Code: None Additional InformationWF Issue # None NoneReleasing as: PDFx1AFinal Size:Finishing: NoneGutter: None Inks Additional Comments for SizingColors: NoneBlack NoneTeam 4CProducer: Jessica SbailoAD: Joe MaranzinoAE: Carin Caselli Scale: 1"= 1"QC: None Bleed 16.25" w x 10.5" h 16.25" w x 10.5" hProduction: Steve Curry Trim/Flat 16.25" w x 10.5" h 16.25" w x 10.5" hDigital Artist: Kolosick, Tanya (NYC-SRX) Live/Safety 15.25" w x 9.875" h 15.25" w x 9.875" h Path: PrePress:BMS:OZANIMOD:11707081:_Packaged_Jobs:11707081_BMS_MS_Spread Journal Ad_Asize_M7FR:11707081_BMS_MS_Spread Journal Ad_Asize_M7FR.inddPDFX1A _'