b'B:8.75"T:8.25"S:7.25"(96%) of patients with ALT greater than 3-fold the ULN continued treatment with ZEPOSIA (ozanimod) with valuesClinical Trials Experiencereturning to less than 3-fold the ULN within approximately 2 to 4 weeks. Overall, the discontinuation rate becauseBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg, and none in patients whoclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect received placebo in the controlled UC studies. the rates observed in clinical practice.Individuals with an AST or ALT greater than 2 times the ULN were excluded from UC Study 1 and Study 3. ThereCommon Adverse Reactionsare no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA. Use of ZEPOSIA in patients with hepatic impairment is notUlcerative Colitisrecommended [see Use in Specific Populations]. The safety of ZEPOSIA (ozanimod) was evaluated in two randomized, double-blind, placebo-controlled clinical Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting,studies [UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult patients with moderately abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, andto severely active ulcerative colitis [see Clinical Studies (14.2) in full Prescribing Information]. Additional data from ZEPOSIA should be discontinued if significant liver injury is confirmed. 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.Fetal Risk Common adverse reactions in UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 2 and 3, respectively. There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA mayThe most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in cause fetal harm [see Use in Specific Populations]. Because it takes approximately 3 months to eliminate ZEPOSIApatients who received placebo were liver test increased, upper respiratory infection, and headache.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].Table 2:Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least Increased Blood Pressure 1% Greater than Placebo in Patients with Ulcerative Colitis (Pooled UC Study 1 and Study 3)In UC Study 1 and Study 3, the average increase from baseline in SBP was 3.7 mm Hg in patients treated withInduction Periods (UC Study 1 and Study 3)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 wasZEPOSIA no effect on DBP. Adverse Reactions 0.92 mg Once DailyPlacebo Hypertension was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA 0.92 mg and nonec,d d(n=496)(n=281) 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. aUpper respiratory infection 5 4Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. bLiver test increased5 0Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could cause severeHeadache 4 3hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at the recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid foods containing a veryPyrexia 3 2large amount of tyramine while taking ZEPOSIA. Nausea 3 2Respiratory Effects Arthralgia 3 1In UC Study 1, the mean difference in decline in absolute FEV 1from baseline in patients treated with ZEPOSIAa Includes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis, 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 1at 10 weeks between patients treated with ZEPOSIA compared to thoseupper respiratory tract infection, pharyngitis, sinusitis, tonsillitis, viral upper respiratory tract infection, laryngitis, who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVC (absolute value andacute sinusitis, catarrh, chronic sinusitis, upper respiratory tract inflammation, chronic tonsillitis, viral pharyngitis, viral %-predicted) seen at Week 10 in UC Study 1, comparing patients who were treated with ZEPOSIA to those whosinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngeal inflammation, and received placebo was 44 mL, 95% CI (-114, 26); 0.5%, 95% CI (-2.3, 1.2), respectively. There is insufficientbpharyngeal inflammation.information to determine the reversibility of observed decreases in FEV 1or FVC after discontinuation of ZEPOSIA, orIncludes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate whether changes could be progressive with continued use. aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, blood alkaline phosphatase increased, and transaminases increased.Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinicallyc ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration].indicated. d Percentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight.Macular EdemaSphingosine 1-phosphate (S1P) receptor modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. Table 3:Adverse Reactions with an Incidence of at Least 4% in ZEPOSIA-Treated Patients and at Least 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 UC1% Greater than Placebo in Patients with Ulcerative Colitis (UC Study 2) S:9.875" T:10.875" B:11.375"Study 2 treated with ZEPOSIA, and in no patients who received placebo. Maintenance Period (UC Study 2)An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is any change in vision while taking ZEPOSIA. Adverse Reactions ZEPOSIAPlacebo 0.92 mg Once Daily (n=230)(n=227) Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision on whether% % or not ZEPOSIA should be discontinued needs to take into account the potential benefits and risks for the aindividual patient. Liver test increased11 2Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Headache 5 1Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of maculara Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate edema during ZEPOSIA therapy. The incidence of macular edema is also increased in patients with a history ofaminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased, liver function test uveitis. In addition to the examination of the fundus, including the macula, prior to treatment, patients with diabetesincreased, and blood alkaline phosphatase increased.mellitus or a history of uveitis should have regular follow-up examinations.Posterior Reversible Encephalopathy Syndrome Other Adverse ReactionsRare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatricReduction in Heart Ratesymptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurologicalInitiation of ZEPOSIA may result in transient decrease in heart rate in UC patients [see Warnings and Precautions].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 neurologicalRespiratory Effectsexamination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemicDose-dependent reductions in absolute FEV 1and FVC were observed in UC patients treated with ZEPOSIA stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae.[see Warnings and Precautions].If PRES is suspected, treatment with ZEPOSIA should be discontinued. MalignanciesUnintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune- Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and Modulating Drugs adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of UC. An When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs mustincreased risk of cutaneous malignancies has been reported with another S1P receptor modulator.be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk ofPeripheral Edemadisease reactivation, when initiating ZEPOSIA.Peripheral edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients who received placebo Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions]. in UC Study 2.Immune System Effects after Stopping ZEPOSIA DRUG INTERACTIONSAfter discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range wasTables 4 and 5 include drugs with clinically important drug, tyramine, and vaccine interactions when administered approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [seeconcomitantly with ZEPOSIA and instructions for preventing or managing them.Clinical Pharmacology (12.2) in full Prescribing Information]. 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].ADVERSE REACTIONSThe following serious adverse reactions are described elsewhere in the labeling:Infections [see Warnings and Precautions]Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions]Liver Injury [see Warnings and Precautions]Fetal Risk [see Warnings and Precautions]Increased Blood Pressure [see Warnings and Precautions]Respiratory Effects [see Warnings and Precautions]Macular Edema [see Warnings and Precautions]Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions]Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions]Immune System Effects after Stopping ZEPOSIA [see Warnings and Precautions]Cosmos Communications 1 Q1 Q2K ej44878b 07.14.21 133 1 Cosmos Communications 1 Q1 Q2K ej44878a 07.13.21 133 1PREPARED BY 11561844 US Branded Journal Ad A SIZE M25FRJob info Images FontsSpecial InstructionsDate: 7-1-2021 6:46 PM 2084_US_2100924_ZEPOSIA UC PBSNone 3 PG 4/C ad: spread followed by single page-Client: BMS 7x9.875_0521_wip2FNL.pdf (98%; 78KB) Create 5 pgs blank or greeked Brief Summary Product: OZANIMOD US pages for nowBuild mech to final A size specs Client Code: 2084-US-2101341 Additional InformationWF Issue # 8935889 NoneReleasing as: Native FilesFinal Size: NoneFinishing: NoneGutter: None Inks Additional Comments for SizingColors: 4/C & B/WBlack Single page 4/C specs: 8.25in x 10.875inLIVE: 7.25in*x 10in (.50 from trim edge)BLEED: 8.50in Team x 11.375inProducer: NoneAD: Phoebe FelizAE: Leah OKeeffe Scale: 1"= 1"QC: None Bleed 17" w x 11.375" h 17" w x 11.375" hProduction: Debi Post Trim/Flat 16.5" w x 10.875" h 16.5" w x 10.875" hDigital Artist: Eberhart, Thomas (NYC-FCB) Live/Safety 15.5" w x 9.875" h 15.5" w x 9.875" h FR Spellcheck:NonePath: PrePress:BMS:OZANIMOD:11561844:11561844_US_Branded_Ad_M25FR.indd_ _'