b'Liver Injury ADVERSE REACTIONS Table 4:Clinically Relevant Interactions Affecting Drugs, Tyramine, and Vaccines Co-administeredTable 5:Clinically Relevant Interactions Affecting ZEPOSIA (ozanimod) When Co-administered103 Elevations of aminotransferases may occur in patients receiving ZEPOSIA (ozanimod). The following serious adverse reactions are described elsewhere in the labeling: with ZEPOSIA (ozanimod) with Other DrugsObtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiationInfections [see Warnings and Precautions] Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Monoamine Oxidase (MAO) Inhibitorsof 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 has not been studied in combination with anti-neoplastic, immune-modulating, orCo-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the active ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred inClinical Impact:non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, whichmetabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see 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] had no pharmacokinetic interaction [see Clinical Pharmacology (12.3) in full PrescribingClinical Impact:Clinical Pharmacology (12.3) in full Prescribing Information]. The potential for a clinical 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] Information]. interaction with MAO inhibitors has not been studied; however, the increased risk of and in UC Study 2 elevations occurred in 2.3% of patients and no patients, respectively. In controlled andRespiratory Effects [see Warnings and Precautions] nonselective MAO inhibition may lead to a hypertensive crisis.uncontrolled UC studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continuedCaution should be used during concomitant administration because of the risk of additive 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] immune effects during such therapy and in the weeks following administration [seePrevention orCo-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated withPosterior Reversible Encephalopathy Syndrome [see Warnings and Precautions] Warnings and Precautions]. Management:contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and 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 orWhen switching from drugs with prolonged immune effects, the half-life and modeinitiation of treatment with MAO inhibitors.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] Prevention orof action of these drugs must be considered in order to avoid unintended additiveStrong CYP2C8 InhibitorsThere 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] Management:immunosuppressive effects [see Warnings and Precautions].elevated liver function test values when taking ZEPOSIA. Use of ZEPOSIA in patients with hepatic impairmentAlemtuzumab:Initiating treatment with ZEPOSIA after alemtuzumab is not recommendedCo-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of theis not recommended [see Use in Specific Populations]. Clinical Trials Experience because of the characteristics and duration of alemtuzumab immune suppressive effects. Clinical Impact:active metabolites of ozanimod [see Clinical Pharmacology (12.3) in full Prescribing Patients 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 theBeta interferon or glatiramer acetate:ZEPOSIA can generally be started immediately afterInformation], which may increase the risk of ZEPOSIA adverse reactions.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 notdiscontinuation of beta interferon or glatiramer acetate.ZEPOSIA should be discontinued if significant liver injury is confirmed. reflect the rates observed in clinical practice. Prevention orCo-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not Common Adverse Reactions Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate Management:recommended.Fetal RiskThere are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIAUlcerative Colitis ZEPOSIA has not been studied in patients taking QT prolonging drugs.Strong CYP2C8 Inducersmay 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 moderatelyClinical Impact:Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti- Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the 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]. Additionalarrhythmic drugs have been associated with cases of Torsades de Pointes in patients withClinical Impact:exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3) in Populations]. data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3,bradycardia. full Prescribing Information], which may decrease the efficacy of ZEPOSIA.Increased Blood Pressure NCT01647516) included 67 patients who received ZEPOSIA 0.92 mg once daily. If treatment with ZEPOSIA is considered in patients on Class Ia or Class III anti-arrhythmicPrevention or 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,drugs, advice from a cardiologist should be sought [see Warnings and Precautions]. Management:Co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided.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 patientsBecause of the potential additive effects on heart rate, treatment with ZEPOSIA should 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,Prevention orgenerally not be initiated in patients who are concurrently treated with QT prolonging placebo. There was no effect on DBP. and headache. Management:drugs with known arrhythmogenic properties [see Warnings and Precautions]. If treatmentUSE IN SPECIFIC POPULATIONSHypertension was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA 0.92 mg andinitiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from aPregnancynone 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 andcardiologist should be sought.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 1Risk Summaryreceiving placebo. and Study 3) Adrenergic and Serotonergic Drugs There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. Induction Periods (UC Study 1 and Study 3) Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential forwomen. In animal studies, administration of ozanimod during pregnancy produced adverse effects on serious adverse reactions, including hypertensive crisis with co-administration of ZEPOSIAdevelopment, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, Certain foods that may contain very high amounts (i.e., more than 150 mg) of tyramine could causeZEPOSIAwith drugs or over-the-counter medications that can increase norepinephrine or serotoninin the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant severe hypertension because of potential tyramine interaction in patients taking ZEPOSIA, even at theAdverse Reactions 0.92 mg Once DailyPlacebo[e.g., opioid drugs, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrinematernal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine1-c,d phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and recommended doses. Because of an increased sensitivity to tyramine, patients should be advised to avoid(n=496)(n=281)reuptake inhibitors (SNRIs), tricyclics, tyramine].foods containing a very large amount of tyramine while taking ZEPOSIA. % %neural development.da Opioid Drugs In the U.S. general population, the estimated background risk of major birth defects and miscarriage in Respiratory Effects Upper respiratory infection 5 4 Serious, sometimes fatal reactions have been precipitated with concomitant use of opioidclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major In UC Study 1, the mean difference in decline in absolute FEV 1from baseline in patients treated withLiver test increased5 0 drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, includingbirth defects and miscarriage for the indicated population is unknown.bZEPOSIA compared to patients who received placebo was 22 mL (95% CI: -84, 39) at 10 weeks. The meanselective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were difference in percent predicted normal (PPN) FEV 1at 10 weeks between patients treated with ZEPOSIAHeadache 4 3 concomitantly exposed to opioids, this exposure was not adequate to rule out the possibilityDatacompared to those who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVCPyrexia 3 2 of an adverse reaction from co-administration. Animal Data(absolute value and %-predicted) seen at Week 10 in UC Study 1, comparing patients who were treatedClinical Impact:Serotonergic Drugs Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in 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 1orAlthough a small number of patients treated with ZEPOSIA were concomitantly exposed toa marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with continued use. Arthralgia 3 1 serotonergic medications, this exposure was not adequate to rule out the possibility of andelayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was aadverse reaction from co-administration. observed. Atthe no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinicallyIncludes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis,ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum indicated. upper respiratory tract infection, pharyngitis, sinusitis, tonsillitis, viral upper respiratory tract infection, laryngitis,Sympathomimetic Medications recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 acute sinusitis, catarrh, chronic sinusitis, upper respiratory tract inflammation, chronic tonsillitis, viral pharyngitis,Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects onand CC1084037, were similar to and less than, respectively, those in humans at the MRHD.Macular Edema viral sinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngealblood pressure [see Clinical Pharmacology (12.2) in full Prescribing Information]. However,Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis Sphingosine 1-phosphate (S1P) receptor modulators, including ZEPOSIA, have been associated with anbinflammation, and pharyngeal inflammation. hypertensive crisis has occurred with administration of ZEPOSIA alone [see Warningsresulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal increased risk of macular edema. Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased,and Precautions] and hypertensive crisis has been reported with co-administration ofmalformations (malformed blood vessels) and skeletal variations at the mid and high doses. Maternal aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function testother selective and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic Macular edema was reported in a total of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%)cincreased, blood alkaline phosphatase increased, and transaminases increased. medications. toxicity was not observed. Atthe no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal patient in UC Study 2 treated with ZEPOSIA, and in no patients who received placebo. ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration]. development in rabbit, plasma ozanimod exposure (AUC) was approximately 2 times that in humans at the 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- Co-administration of ZEPOSIA with drugs or over-the-counter medications that canMRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in there is any change in vision while taking ZEPOSIA. Haenszel weight. Prevention orincrease norepinephrine or serotonin (e.g., opioid drugs, SSRIs, SNRIs, tricyclics, tyramine)humans at the MRHD.Management:is not recommended. Monitor patients for hypertension with concomitant use. Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. A decision onlactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged whether or not ZEPOSIA should be discontinued needs to take into account the potential benefits and risksCombination Beta Blocker and Calcium Channel Blocker estrus cycle) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, for the individual patient. Table 3:Adverse Reactions with an Incidence of at Least 4% in ZEPOSIA-Treated Patients and atwhich was not associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Least 1% Greater than Placebo in Patients with Ulcerative Colitis (UC Study 2) The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blockeron pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the Maintenance Period (UC Study 2) Clinical Impact:has not been studied. However, there is a potential of additive effects on heart rate. MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk ofhumans at the MRHD.macular edema during ZEPOSIA therapy. The incidence of macular edema is also increased in patients withAdverse Reactions ZEPOSIAPlaceboTreatment with ZEPOSIA should generally not be initiated in patients who are concurrently 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)treated with both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem)Lactationpatients with diabetes mellitus or a history of uveitis should have regular follow-up examinations. % %Prevention orand beta blocker [see Warnings and Precautions]. If treatment initiation with ZEPOSIA isRisk Summarya Management:considered in patients on both a heart rate lowering calcium channel blocker and beta Posterior Reversible Encephalopathy Syndrome Liver test increased11 2 blocker, advice from a cardiologist should be sought. There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patientsHeadache 5 1 the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or receiving a S1P receptor modulator. Should a ZEPOSIA-treated patient develop any unexpectedTyramine metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma.neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visuala Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased,The developmental and health benefits of breastfeeding should be considered along with the mothers disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestiveaspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased,MAO in the gastrointestinal tract and liver (primarily type A) provides protection fromclinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the of an increase of intracranial pressure, or accelerated neurological deterioration, the physicianliver function test increased, and blood alkaline phosphatase increased. exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead tounderlying maternal condition.should promptly schedule a complete physical and neurological examination and should considersevere hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebralClinical Impact:pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickledFemales and Males of Reproductive Potentialhemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae.Other Adverse Reactions herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramineContraceptionIf PRES is suspected, treatment with ZEPOSIA should be discontinued. Reduction in Heart Rate reaction).Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive orInitiation of ZEPOSIA may result in transient decrease in heart rate in UC patients [see Warnings andPrevention orPatients should be advised to avoid foods containing a large amount of tyramine whilefor a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use Immune-Modulating Drugs Precautions]. Management:taking recommended doses of ZEPOSIA [see Warnings and Precautions]. in Specific Populations]. Because of the time it takes to eliminate the drug from the body after stopping When switching from drugs with prolonged immune effects, the half-life and mode of action of theseRespiratory Effects treatment, the potential risk to the fetus may persist and women of childbearing age should also use drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time1and FVC were observed in UC patients treated with ZEPOSIAVaccination effective contraception for 3 months after stopping ZEPOSIA.minimizing risk of disease reactivation, when initiating ZEPOSIA. Dose-dependent reductions in absolute FEV[see Warnings and Precautions]. Pediatric UseInitiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see DrugDuring, and for up to three months after, discontinuation of treatment with ZEPOSIA,Safety and effectiveness in pediatric patients have not been established.Interactions]. Malignancies Clinical Impact:vaccinations may be less effective. The use of live attenuated vaccines may carry the risk Immune System Effects after Stopping ZEPOSIA Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, andof infection. Geriatric UseAfter 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.Prevention orLive attenuated vaccines should be avoided during ZEPOSIA treatment and for up to 3Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine 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. Management:months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions]. whether they respond differently from younger subjects. No clinically significant differences in the 3 months [see Clinical Pharmacology (12.2) in full Prescribing Information]. Use of immunosuppressantsPeripheral Edema pharmacokinetics of ozanimod and CC112273 were observed based on age [see Clinical Pharmacology (12.3) in full Prescribing Information]. Monitor elderly patients for cardiac and hepatic adverse reactions, within 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 receivedbecause of the greater frequency of reduced cardiac and hepatic function in the elderly population.applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions]. placebo in UC Study 2.Hepatic ImpairmentDRUG INTERACTIONS The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is Tables 4 and 5 include drugs with clinically important drug, tyramine, and vaccine interactions whenunknown [see Clinical Pharmacology (12.3) in full Prescribing Information]. Use of ZEPOSIA in patients with administered concomitantly with ZEPOSIA and instructions for preventing or managing them. hepatic impairment is not recommended.2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 5 3/2/22 11:39 AM2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 6 3/2/22 11:39 AM'