b'B:8.75"T:8.25"S:7.25"Table 4:Clinically Relevant Interactions Affecting Drugs, Tyramine, and Vaccines Co-administered withTable 5:Clinically Relevant Interactions Affecting ZEPOSIA (ozanimod) When Co-administered with ZEPOSIA (ozanimod) Other DrugsAnti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Monoamine Oxidase (MAO) InhibitorsZEPOSIA 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 Clinical Impact:non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which hadmetabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see Clinical no pharmacokinetic interaction [see Clinical Pharmacology (12.3) in full Prescribing Information]. Clinical Impact:Pharmacology (12.3) in full Prescribing Information]. The potential for a clinical interaction with MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibition Caution should be used during concomitant administration because of the risk of additivemay lead to a hypertensive crisis.immune effects during such therapy and in the weeks following administration [see Warnings and Precautions]. Prevention orCo-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is When switching from drugs with prolonged immune effects, the half-life and mode of actionManagement:contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and Prevention orof these drugs must be considered in order to avoid unintended additive immunosuppressiveinitiation of treatment with MAO inhibitors.Management:effects [see Warnings and Precautions]. Strong CYP2C8 InhibitorsAlemtuzumab:Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of theBeta interferon or glatiramer acetate:ZEPOSIA can generally be started immediately afterClinical Impact:active metabolites of ozanimod [see Clinical Pharmacology (12.3) in full Prescribing Information], discontinuation of beta interferon or glatiramer acetate. which may increase the risk of ZEPOSIA adverse reactions.Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate Prevention orCo-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not Management:recommended.ZEPOSIA has not been studied in patients taking QT prolonging drugs.Strong CYP2C8 InducersClinical Impact:Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure Clinical Impact:of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3) in full Prescribing If treatment with ZEPOSIA is considered in patients on Class Ia or Class III anti-arrhythmic drugs,Information], which may decrease the efficacy of ZEPOSIA.advice from a cardiologist should be sought [see Warnings and Precautions].Prevention orBecause of the potential additive effects on heart rate, treatment with ZEPOSIA should generallyPrevention orCo-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided.Management:not be initiated in patients who are concurrently treated with QT prolonging drugs with knownManagement: arrhythmogenic properties [see Warnings and Precautions]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought.Adrenergic and Serotonergic Drugs USE IN SPECIFIC POPULATIONSPregnancyBecause an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for seriousRisk Summaryadverse reactions, including hypertensive crisis with co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs,There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitorsIn animal studies, administration of ozanimod during pregnancy produced adverse effects on development, (SNRIs), tricyclics, tyramine]. including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of Opioid Drugs maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine1-phosphate) has been Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugsdemonstrated to have an important role in embryogenesis, including vascular and neural development.(e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selectiveIn the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantlyrecognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects exposed to opioids, this exposure was not adequate to rule out the possibility of an adverseand miscarriage for the indicated population is unknown.Clinical Impact:reaction from co-administration.Serotonergic Drugs DataAlthough a small number of patients treated with ZEPOSIA were concomitantly exposed toAnimal Dataserotonergic medications, this exposure was not adequate to rule out the possibility of anOral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in aS:9.875" T:10.875" B:11.375"adverse reaction from co-administration. marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed Sympathomimetic Medications ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. Atthe no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects onfor ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) blood pressure [see Clinical Pharmacology (12.2) in full Prescribing Information]. However,of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less hypertensive crisis has occurred with administration of ZEPOSIA alone [see Warnings andthan, respectively, those in humans at the MRHD.Precautions] and hypertensive crisis has been reported with co-administration of other selectiveOral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic medications. in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations Co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase(malformed blood vessels) and skeletal variations at the mid and high doses. Maternal toxicity was not observed. Prevention ornorepinephrine or serotonin (e.g., opioid drugs, SSRIs, SNRIs, tricyclics, tyramine) is notAtthe no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod Management:recommended. Monitor patients for hypertension with concomitant use. exposure (AUC) was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD.Combination Beta Blocker and Calcium Channel Blocker Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resulted in persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker hasand neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not Clinical Impact:not been studied. However, there is a potential of additive effects on heart rate. associated with maternal toxicity. At the no-effect dose (0.7 mg/kg/day) for adverse effects on pre- and postnatal development, plasma ozanimod exposure (AUC) was 30 times that in humans at the MRHD; plasma AUCs for major Treatment with ZEPOSIA should generally not be initiated in patients who are concurrentlyhuman metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD.Prevention ortreated with both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem) andLactationManagement:beta blocker [see Warnings and Precautions]. If treatment initiation with ZEPOSIA is consideredRisk Summaryin patients on both a heart rate lowering calcium channel blocker and beta 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 the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were Tyramine detected in the milk of lactating rat at levels higher than those in maternal plasma.MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenousThe developmental and health benefits of breastfeeding should be considered along with the mothers clinical amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension,need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying Clinical Impact:including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containingmaternal condition.large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release ofFemales and Males of Reproductive Potentialnorepinephrine resulting in a rise in blood pressure (tyramine reaction). ContraceptionPrevention orPatients should be advised to avoid foods containing a large amount of tyramine while takingBefore initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for Management:recommended doses of ZEPOSIA [see Warnings and Precautions]. a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific Populations]. Because of the time it takes to eliminate the drug from the body after stopping treatment, the Vaccination potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA.Clinical Impact:During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinationsPediatric Usemay be less effective. The use of live attenuated vaccines may carry the risk of infection. Safety and effectiveness in pediatric patients have not been established.Prevention orLive attenuated vaccines should be avoided during ZEPOSIA treatment and for up to 3 monthsGeriatric UseManagement:after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions]. Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No clinically significant differences in the 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, because of the greater frequency of reduced cardiac and hepatic function in the elderly population.Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown [see Clinical Pharmacology (12.3) in full Prescribing Information]. Use of ZEPOSIA in patients with hepatic impairment is not recommended.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_ _'