b'102 Liver Injury ADVERSE REACTIONSElevations of aminotransferases may occur in patients receiving ZEPOSIA (ozanimod). The following serious adverse reactions are described elsewhere in the labeling:Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiationInfections [see Warnings and Precautions]of ZEPOSIA. Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions]In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated withLiver Injury [see Warnings and Precautions]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 greaterFetal Risk [see Warnings and Precautions]occurred in 2.6% of UC patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo,Increased Blood Pressure [see Warnings and Precautions]and in UC Study 2 elevations occurred in 2.3% of patients and no patients, respectively. In controlled andRespiratory Effects [see Warnings and Precautions]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.Macular Edema [see Warnings and Precautions]Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated withPosterior Reversible Encephalopathy Syndrome [see Warnings and Precautions]ZEPOSIA 0.92 mg, and none in patients who received placebo in the controlled UC studies. Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Individuals with an AST or ALT greater than 2 times the ULN were excluded from UC Study 1 and Study 3.Immune-Modulating Drugs [see Warnings and Precautions]There are no data to establish that patients with preexisting liver disease are at increased risk to developImmune System Effects after Stopping ZEPOSIA (ozanimod) [see Warnings and Precautions]elevated liver function test values when taking ZEPOSIA. Use of ZEPOSIA in patients with hepatic impairment is not recommended [see Use in Specific Populations]. Clinical Trials ExperiencePatients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting,Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, andclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not ZEPOSIA should be discontinued if significant liver injury is confirmed. reflect the rates observed in clinical practice.Fetal Risk Common Adverse ReactionsThere are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIAUlcerative Colitismay cause fetal harm [see Use in Specific Populations]. Because it takes approximately 3 months toThe safety of ZEPOSIA was evaluated in two randomized, double-blind, placebo-controlled clinical studies eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception[UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult patients with moderately to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specificto severely active ulcerative colitis [see Clinical Studies (14.2) in full Prescribing Information]. Additional Populations]. data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3, Increased Blood Pressure NCT01647516) included 67 patients who received ZEPOSIA 0.92 mg once daily.In UC Study 1 and Study 3, the average increase from baseline in SBP was 3.7 mm Hg in patients treatedCommon adverse reactions in UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 2 and 3, with ZEPOSIA and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the average increase fromrespectively. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients baseline in SBP was 5.1 mm Hg in patients treated with ZEPOSIA and 1.5 mm Hg in patients treated withand greater than in patients who received placebo were liver test increased, upper respiratory infection, placebo. There was no effect on DBP. and headache.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 UCTable 2:Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and Study 2, respectively. Hypertensive crisis was reported in two patients receiving ZEPOSIA and one patientat Least 1% Greater than Placebo in Patients with Ulcerative Colitis (Pooled UC Study 1 receiving placebo. and Study 3)Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Induction Periods (UC Study 1 and Study 3)Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could causeZEPOSIA severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at theAdverse Reactions 0.92 mg Once DailyPlacebo recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid(n=496)(n=281) c,dfoods containing a very large amount of tyramine while taking ZEPOSIA. % % daRespiratory Effects Upper respiratory infection 5 4In UC Study 1, the mean difference in decline in absolute FEV 1from baseline in patients treated withLiver test increased5 0bZEPOSIA 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 ZEPOSIAHeadache 4 3compared to those who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVCPyrexia 3 2(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),Nausea 3 2respectively. There is insufficient information to determine the reversibility of observed decreases in FEV 1or FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with continued use. Arthralgia 3 1Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinicallya Includes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis, indicated. 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, Macular Edema viral sinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngeal Sphingosine 1-phosphate (S1P) receptor modulators, including ZEPOSIA, have been associated with anbinflammation, and pharyngeal inflammation.increased risk of macular edema. Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test Macular edema was reported in a total of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%)increased, blood alkaline phosphatase increased, and transaminases increased.patient in UC Study 2 treated with ZEPOSIA, and in no patients who received placebo. c ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration].An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time ifd Percentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-there is any change in vision while taking ZEPOSIA. Haenszel weight.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 individual patient. Table 3: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)Macular Edema in Patients with a History of Uveitis or Diabetes MellitusPatients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk ofMaintenance Period (UC Study 2)macular edema during ZEPOSIA therapy. The incidence of macular edema is also increased in patients withAdverse Reactions ZEPOSIAPlacebo a history of uveitis. In addition to the examination of the fundus, including the macula, prior to treatment,0.92 mg Once Daily (n=230)(n=227) patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. % % Posterior Reversible Encephalopathy Syndrome Liver test increased11 2aRare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patientsHeadache 5 1receiving a S1P receptor modulator. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visuala Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestiveaspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased, of an increase of intracranial pressure, or accelerated neurological deterioration, the physicianliver function test increased, and blood alkaline phosphatase increased.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.Other Adverse ReactionsIf PRES is suspected, treatment with ZEPOSIA should be discontinued. Reduction in Heart RateUnintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive orInitiation of ZEPOSIA may result in transient decrease in heart rate in UC patients [see Warnings and Immune-Modulating Drugs Precautions].When switching from drugs with prolonged immune effects, the half-life and mode of action of theseRespiratory Effectsdrugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Dose-dependent reductions in absolute FEV 1and FVC were observed in UC patients treated with ZEPOSIA Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug[see Warnings and Precautions].Interactions]. MalignanciesImmune System Effects after Stopping ZEPOSIA Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normaladenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of UC. range was approximately 30 days, with approximately 80% to 90% of patients in the normal range withinAn increased risk of cutaneous malignancies has been reported with another S1P receptor modulator.3 months [see Clinical Pharmacology (12.2) in full Prescribing Information]. Use of immunosuppressantsPeripheral Edemawithin this period may lead to an additive effect on the immune system, and therefore caution should bePeripheral edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients who received applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions]. placebo in UC Study 2.DRUG INTERACTIONSTables 4 and 5 include drugs with clinically important drug, tyramine, and vaccine interactions when administered concomitantly with ZEPOSIA and instructions for preventing or managing them.2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 5 3/2/22 11:39 AM'