b'104 NONCLINICAL TOXICOLOGY Liver InjuryCarcinogenesis, Mutagenesis, Impairment of Fertility Inform patients that ZEPOSIA (ozanimod) may increase liver enzymes. Advise patients that they should Carcinogenesis contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine [see Warnings and Precautions].Oral administration of ozanimod (0, 8, 25, or 80 mg/kg/day) to Tg.rasH2 mice for 26-weeks resulted in an increase in hemangioma and hemangiosarcoma (combined) in males and females at the mid and highPregnancy and Fetal Riskdoses tested. Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of Oral administration of ozanimod (0, 0.2, 0.7, or 2 mg/kg/day) to rats for 2 years resulted in no increase inchildbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise tumors. At the highest dose tested (2 mg/kg/day), plasma exposure (AUC) for ozanimod was approximatelywomen of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and 100 times that in humans at the maximum recommended human dose (MRHD) of 0.92 mg/day. Plasmafor 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively,if she is pregnant or planning to become pregnant [see Warnings and Precautions and Use in Specific those in humans at the MRHD. Populations].Mutagenesis Respiratory EffectsOzanimod was negative in a battery of in vitro (Ames, mouse lymphoma tk) and in vivo (rat micronucleus)Advise patients that they should contact their healthcare provider if they experience new onset or worsening assays. Metabolite CC112273 was negative in in vitro (Ames, chromosomal aberration in mammalian cell)dyspnea [see Warnings and Precautions].assays. Metabolite CC1084037 was negative in an Ames assay, and positive in an in vitro chromosomal aberration assay in human (TK6) cells but negative in an in vivo rat micronucleus/comet assay. Macular EdemaImpairment of Fertility Advise patients that ZEPOSIA may cause macular edema, and that they should contact their healthcare provider if they experience any changes in their vision. Inform patient with diabetes mellitus or a history of Oral administration of ozanimod (0, 0.2, 2, or 30 mg/kg/day) to male and female rats prior to and duringuveitis that their risk of macular edema may be increased [see Warnings and Precautions].mating and continuing through gestation day 7 resulted in no adverse effects on fertility. At the highest dose tested (30 mg/kg/day), plasma ozanimod exposure (AUC) was approximately 1600 times that in humans atPosterior Reversible Encephalopathy Syndromethe maximum recommended human dose (MRHD) (0.92 mg/day); plasma AUCs for metabolites, CC112273Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset and CC1084037, at 30 mg/kg/day were 13 and 3 times, respectively, those in humans at the MRHD. of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed PATIENT COUNSELING INFORMATION treatment could lead to permanent neurological consequences [see Warnings and Precautions].Advise the patient to read the FDA-approved patient labeling (Medication Guide). Immune System Effects after Stopping ZEPOSIARisk of Infections Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose [see Warnings and Precautions].Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA (ozanimod) and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions]. Inform patientsManufactured for: Celgene Corporation that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.Summit, NJ 07901Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. Advise patients that if immunizations are planned, they should be administered atZEPOSIA is a trademark of Celgene Corporation, a Bristol Myers Squibb company.least 1 month prior to initiation of ZEPOSIA. Inform patients that the use of live attenuated vaccines should 2022 Bristol-Myers Squibb Companybe avoided during and for 3 months after treatment with ZEPOSIA. ZEPPI/ZEPMG.004Cardiac Effects December 2021Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also2084-US-220048302/22required 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].2084-US-2200376_ZEP_UC_Branded_JournalAd_Gastro_and_Hepa_P0157262_v01.indd 7 3/2/22 11:39 AM'