b'B:8.5"T:8.25"S:7.25"Table 3:Clinically Relevant Interactions Affecting Drugs, Tyramine, and Vaccines Co-administered withFemales and Males of Reproductive Potential(Continued) ZEPOSIA (ozanimod) ContraceptionPrevention orCo-administration of ZEPOSIA with drugs or over-the-counter medications that can increaseBefore initiation of ZEPOSIA (ozanimod) treatment, women of childbearing potential should be counseled on the potential Management:norepinephrine or serotonin (e.g., opioid drugs, SSRIs, SNRIs, tricyclics, tyramine) is notfor a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA [see Use in Specific recommended. Monitor patients for hypertension with concomitant use. Populations]. Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after Combination Beta Blocker and Calcium Channel Blocker stopping ZEPOSIA.Clinical Impact:The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker has notPediatric Usebeen studied. However, there is a potential of additive effects on heart rate. Safety and effectiveness in pediatric patients have not been established.Treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated Prevention orwith both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem) and betaGeriatric UseManagement:blocker [see Warnings and Precautions]. If treatment initiation with ZEPOSIA is considered inClinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from arespond differently from younger subjects. No clinically significant differences in the pharmacokinetics of ozanimod cardiologist should be sought. and CC112273 were observed based on age [see Clinical Pharmacology (12.3) in full Prescribing Information]. Monitor Tyramine elderly patients for cardiac and hepatic adverse reactions, because of the greater frequency of reduced cardiac and hepatic function in the elderly population.MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenousHepatic Impairmentamines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, Clinical Impact:including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containingThe effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of[see Clinical Pharmacology (12.3) in full Prescribing Information]. Use of ZEPOSIA in patients with hepatic impairment norepinephrine resulting in a rise in blood pressure (tyramine reaction). is not recommended.Prevention orPatients should be advised to avoid foods containing a large amount of tyramine while takingNONCLINICAL TOXICOLOGYManagement:recommended doses of ZEPOSIA [see Warnings and Precautions]. Carcinogenesis, Mutagenesis, Impairment of FertilityVaccination CarcinogenesisClinical Impact:During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinationsOral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in may be less effective. The use of live attenuated vaccines may carry the risk of infection. hemangioma and hemangiosarcoma (combined) in males and females at the mid and high doses tested.Prevention orLive attenuated vaccines should be avoided during ZEPOSIA treatment and for up to 3 monthsOral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase in tumors. At the Management:after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions]. highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximately 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD.Table 4:Clinically Relevant Interactions Affecting ZEPOSIA When Co-administered with Other Drugs MutagenesisMonoamine Oxidase (MAO) Inhibitors Ozanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus) assays. Co-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the activeMetabolite CC112273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell) assays. Metabolite metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO [see ClinicalCC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) Clinical Impact:Pharmacology (12.3) in full Prescribing Information]. The potential for a clinical interaction withcells but negative in an in vivo rat micronucleus/comet assay.MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibitionImpairment of Fertilitymay lead to a hypertensive crisis. Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and during mating and Co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) iscontinuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), Prevention orcontraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiationplasma ozanimod exposure (AUC) was approximately 1600 times that in humans at the maximum recommended human Management:of treatment with MAO inhibitors. dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273 and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD.Strong CYP2C8 InhibitorsPATIENT COUNSELING INFORMATIONCo-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the activeAdvise the patient to read the FDA-approved patient labeling (Medication Guide).Clinical Impact:metabolites of ozanimod [see Clinical Pharmacology (12.3) in full Prescribing Information], which may increase the risk of ZEPOSIA adverse reactions. Risk of InfectionsPrevention orCo-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is notInform patients that they may be more likely to get infections, some of which could be life-threatening, when taking Management:recommended. ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they developS:9.875" T:10.5" B:11.375"symptoms of infection [see Warnings and Precautions]. Inform patients that prior or concomitant use of drugs that Strong CYP2C8 Inducers suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. Advise patients that if immunizations are Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposureplanned, they should be administered at least 1 month prior to initiation of ZEPOSIA. Inform patients that the use of live Clinical Impact:of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3) in full Prescribingattenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA.Information], which may decrease the efficacy of ZEPOSIA. Cardiac EffectsPrevention orCo-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided. Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that Management:to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment [see Dosage and Administration and Warnings and Precautions].USE IN SPECIFIC POPULATIONS Liver InjuryPregnancy Inform patients that ZEPOSIA may increase liver enzymes. Advise patients that they should contact their healthcare Risk Summary provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women.[see Warnings and Precautions].In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, includingPregnancy and Fetal Riskembryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity.Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of childbearing In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposuresage whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing (see Data). The receptor affected by ozanimod (sphingosine1-phosphate) has been demonstrated to have an importantpotential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. role in embryogenesis, including vascular and neural development. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically[see Warnings and Precautions and Use in Specific Populations].recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects andRespiratory Effectsmiscarriage for the indicated population is unknown.Data Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea [see Warnings and Precautions].Animal Data Macular EdemaOral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a markedAdvise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification),experience any changes in their vision. Inform patient with diabetes mellitus or a history of uveitis that their risk of and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dosemacular edema may be increased [see Warnings and Precautions].(1 mg/kg/day) for adverse effects on embryofetal development, plasma ozanimod exposure (AUC) for ozanimod was approximately 60 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. PlasmaPosterior Reversible Encephalopathy SyndromeAUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those inAdvise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe humans at the MRHD. headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in apermanent neurological consequences [see Warnings and Precautions].marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformedSevere Increase in Multiple Sclerosis Disability after Stopping ZEPOSIAblood vessels) and skeletal variations at the mid and high doses. Maternal toxicity was not observed. At the no-effect dose (0.2 mg/kg/day) for adverse effects on embryofetal development in rabbit, plasma ozanimod exposure (AUC)Inform patients with multiple sclerosis that severe increase in disability has been reported after discontinuation of a S1P was approximately 2 times that in humans at the MRHD; plasma AUCs for major human metabolites, CC112273 andreceptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS CC1084037, were less than those in humans at the MRHD. following discontinuation of ZEPOSIA [see Warnings and Precautions].Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to female rats throughout gestation and lactation resultedImmune System Effects after Stopping ZEPOSIAin persistent body weight reductions and long-term effects on reproductive (prolonged estrus cycle) and neurobehavioralAdvise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up (increased motor activity) function in offspring at the highest dose tested, which was not associated with maternalto 3 months after the last dose [see Warnings and Precautions].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 human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD. Manufactured for: Celgene Corporation Lactation Summit, NJ 07901Risk Summary ZEPOSIA is a trademark of Celgene Corporation, a Bristol Myers Squibb company. 2022 Bristol-Myers Squibb CompanyThere are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of theZEPPI/ZEPMG.004drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in theDecember 2021milk of lactating rat at levels higher than those in maternal plasma.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical2084-US-220058803/22need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.PREPARED BY 11707081 BMS_MS_Spread Journal Ad - A-size M7FR11707081_BMS_MS_Spread Journal Ad_Asize_M7FR.indd 5 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 _'