b'B:8.5"T:8.25"S:7.25"ZEPOSIA(ozanimod) capsules, for oral use Cryptococcal InfectionCases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms Brief Summary of Prescribing Information. For complete prescribinginformation consult official package insert. or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA (ozanimod) treatment should be suspended until a cryptococcal infection has been excluded. If CM is INDICATIONS AND USAGE diagnosed, appropriate treatment should be initiated.ZEPOSIA (ozanimod) is indicated for the treatment of: Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, andTherapiesactive secondary progressive disease, in adults. In the MS clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, DOSAGE AND ADMINISTRATION non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. [see Clinical Assessments Prior to First Dose of ZEPOSIA Studies (14.2) in full Prescribing Information].Before initiation of treatment with ZEPOSIA, assess the following: Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be Complete Blood Count co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC),action to avoid unintended additive immunosuppressive effects.including lymphocyte count [see Warnings and Precautions]. VaccinationsCardiac Evaluation Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patientsof vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions]. for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, Liver Function Tests following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur.Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions]. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be Ophthalmic Assessment less effective if administered during ZEPOSIA treatment.In patients with a history of uveitis or macular edema, obtain an evaluation of the fundus, including the maculaIf live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. [see Warnings and Precautions]. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA.Current or Prior Medications Progressive Multifocal Leukoencephalopathy If patients are taking anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies, orProgressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects(JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. before initiating treatment with ZEPOSIA [see Warnings and Precautions and Drug Interactions]. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings andon one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation Precautions and Drug Interactions]. leading to confusion and personality changes.Vaccinations PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other multiple sclerosis Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course(MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating ZEPOSIA;immunosuppressants). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIAPML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA [see Warnings and Precautions and Drug Interactions]. should be suspended until PML has been excluded by an appropriate diagnostic evaluation.If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. If PML is confirmed, treatment with ZEPOSIA should be discontinued.Recommended Dosage for Multiple Sclerosis Bradyarrhythmia and Atrioventricular Conduction DelaysInitiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions]. After initial titration, theSince initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an recommended dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration and Swallow ZEPOSIA capsules whole, with or without food [see Clinical Pharmacology (12.3) in full Prescribing Information]. Clinical Pharmacology (12.2) in full Prescribing Information].ZEPOSIA was not studied in patients who had:Table 1:Dose Titration Regimen A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within Days 1-4 0.23 mg once daily the last 6 monthsNew York Heart Association Class III / IV heart failureDays 5-7 0.46 mg once daily Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcFS:9.875" T:10.5" B:11.375"Day 8 and thereafter 0.92 mg once daily 450 msec in males, 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patients healthReinitiation of ZEPOSIA after Treatment Interruption Other pre-existing stable cardiac conditions without clearance from a cardiologistSevere untreated sleep apneaIf a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment using the titration regimenA resting heart rate less than 55 beats per minute (bpm) at baseline[see Dosage and Administration]. Reduction in Heart RateIf a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned. Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg, the CONTRAINDICATIONS greatest mean decrease from baseline in heart rate occurred at Hour 5 on Day 1 (decrease of 1.2 bpm in MS Study 1 ZEPOSIA is contraindicated in patients who: and Study 2), returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attackcharacteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings andnot observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Precautions] Administration].Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome,In MS Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions] ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in Have severe untreated sleep apnea [see Warnings and Precautions] patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a.Are taking a monoamine oxidase (MAO) inhibitor [see Drug Interactions] Atrioventricular Conduction DelaysWARNINGS AND PRECAUTIONS Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the Infections recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in Risk of Infections healthy volunteers; however, in MS Study 1 and Study 2, Mobitz type 2 second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA.ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline valuesIf treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2) in full Prescribing Information]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature.With significant QT prolongation (QTcF 450 msec in males, 470 msec in females)Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugsObtain a recent (i.e., within 6 months or after discontinuation of prior MS therapy) complete blood count (CBC) includingWith ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, lymphocyte count before initiation of ZEPOSIA. and uncontrolled hypertensionDelay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications]In MS Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIALiver Injurywere similar to that in patients who received interferon (IFN) beta-1a (35% vs. 34% and 1% vs. 0.8%, respectively).ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections [seeElevations of aminotransferases may occur in patients receiving ZEPOSIA.Adverse Reactions]. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA.The proportion of patients treated with ZEPOSIA who experienced lymphocyte counts less than 0.2 x 109/L was 3.3%In MS Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of in MS Study 1 and Study 2. These values generally returned to greater than 0.2 x 109/L while patients remained onpatients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes togreater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal rangetime to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA within 3 months [see Clinical Pharmacology (12.2) in full Prescribing Information]. with values returning to less than 3 times the ULN within approximately 2-4 weeks. ZEPOSIA was discontinued for Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients with MS treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a.Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infectionsIndividuals with an AST or ALT greater than 1.5 times ULN were excluded from MS Study 1 and Study 2. There are no throughout this period. data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test Herpes Viral Infection values when taking ZEPOSIA. Use of ZEPOSIA in patients with hepatic impairment is not recommended [see Use in Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA. Specific Populations].In MS Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIAPatients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal 0.92 mg and in 0.2% of patients who received IFN beta-1a. pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed.Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P)Fetal Riskreceptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZVThere are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause before initiating ZEPOSIA (see Vaccinations below). fetal harm [see Use in Specific Populations]. Because it takes approximately 3 months to eliminate ZEPOSIA from the PREPARED BY 11707081 BMS_MS_Spread Journal Ad - A-size M7FR11707081_BMS_MS_Spread Journal Ad_Asize_M7FR.indd 3 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 _'