ZEPOSIA 7-Day Starter Pack

1 INDICATIONS AND USAGE ZEPOSIA is indicated for the treatment of: relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. moderately to severely active ulcerative colitis (UC) in adults. ZEPOSIA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of: Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. ( 1 ) Moderately to severely active ulcerative colitis (UC) in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Assessments are required prior to initiating ZEPOSIA. ( 2.1 ) Titration is required for treatment initiation. ( 2.2 ) The recommended maintenance dosage is 0.92 mg orally once daily. ( 2.2 ) The recommended maintenance dosage in patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B) is 0.92 mg once every other day. ( 2.3 ) If a dose is missed within the first 2 weeks of treatment, reinitiate with the titration regimen. If a dose is missed after the first 2 weeks of treatment, continue treatment as planned. ( 2.4 ) 2.1 Assessments Prior to First Dose of ZEPOSIA Before initiation of treatment with ZEPOSIA, assess the following: Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought [see Warnings and Precautions (5.3) ]. Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions (5.1) ]. Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.4) ]. Ophthalmic Assessment Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA [see Warnings and Precautions (5.8) ]. Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of ZEPOSIA. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions (5.9) ]. Current or Prior Medications If patients are taking anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7) ] . Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction [see Warnings and Precautions (5.3) and Drug Interactions (7) ]. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating ZEPOSIA; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with ZEPOSIA [see Warnings and Precautions (5.1) and Drug Interactions (7) ]. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. 2.2 Recommended Dosage for Multiple Sclerosis and Ulcerative Colitis Initiate ZEPOSIA with a 7-day titration, as shown in Table 1 [see Warnings and Precautions (5.3) ]. After initial titration, the recommended dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8. Swallow ZEPOSIA capsules whole, with or without food [see Clinical Pharmacology (12.3) ]. Table 1: Dose Titration Regimen Days 1-4 0.23 mg once daily Days 5-7 0.46 mg once daily Day 8 and thereafter 0.92 mg once daily* *Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) should take 0.92 mg once every other day [see Recommended Dosage in Patients with Hepatic Impairment (2.3) . ] 2.3 Recommended Dosage in Patients with Hepatic Impairment In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), initiate ZEPOSIA with a 7-day titration, as shown in Table 1. After initial titration, the recommended dosage of ZEPOSIA in these patients is 0.92 mg taken orally once every other day, starting on Day 8 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Reinitiation of ZEPOSIA after Treatment Interruption If a dose of ZEPOSIA is missed during the first 2 weeks of treatment, reinitiate treatment usi…

5 WARNINGS AND PRECAUTIONS Infections : ZEPOSIA may increase the risk of infections. Obtain a complete blood count (CBC) before initiation of treatment. Monitor for infection during treatment and for 3 months after discontinuation. Do not start ZEPOSIA in patients with active infections. ( 5.1 ) Progressive Multifocal Leukoencephalopathy (PML) : Withhold ZEPOSIA at the first sign or symptom suggestive of PML. ( 5.2 ) Bradyarrhythmia and Atrioventricular Conduction Delays : ZEPOSIA may result in transient decrease in heart rate; titration is required for treatment initiation. Check an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting ZEPOSIA. Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. ( 2.1 , 2.2 , 5.3 , 7 ) Liver Injury : Obtain liver enzyme results before initiation and periodically during treatment. Discontinue if there is evidence of liver injury without other cause. ( 5.4 ) Fetal Risk : Women of childbearing potential should use effective contraception during treatment and for 3 months after stopping ZEPOSIA. ( 5.5 , 8.3 ) Increased Blood Pressure (BP) : Monitor BP during treatment. ( 5.6 ) Respiratory Effects : May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. ( 5.7 ) Macular Edema : Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA. Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing ZEPOSIA if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.8 ) Cutaneous Malignancies : Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. ( 5.9 ) 5.1 Infections Risk of Infections ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues [see Clinical Pharmacology (12.2) ]. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature . Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA . Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. In MS Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received interferon (IFN) beta-1a (35% vs. 34% and 1% vs. 0.8%, respectively). In UC Study 1 and Study 3, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). In UC Study 2, the overall rate of infections in patients treated with ZEPOSIA was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%). ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections [see Adverse Reactions (6.1) ]. The proportion of patients treated with ZEPOSIA who experienced lymphocyte counts less than 0.2 × 10 9 /L was 3.3% in MS Study 1 and Study 2. The proportion of patients treated with ZEPOSIA with lymphocyte counts less than 0.2 × 10 9 /L was 2% in UC Study 1 and Study 3 and 2.3% in UC Study 2. These values generally returned to greater than 0.2 × 10 9 /L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to…

4 CONTRAINDICATIONS ZEPOSIA is contraindicated in patients who: In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions (5.3) ] Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker [see Warnings and Precautions (5.3) ] Have severe untreated sleep apnea [see Warnings and Precautions (5.3) ] Are taking a monoamine oxidase (MAO) inhibitor [see Drug Interactions (7) ] In the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure. ( 4 ) Presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. ( 4 ) Severe untreated sleep apnea. ( 4 ) Concomitant use of a monoamine oxidase inhibitor. ( 4 , 7 )

7 DRUG INTERACTIONS Tables 5 and 6 include drugs with clinically important drug and vaccine interactions when administered concomitantly with ZEPOSIA and instructions for preventing or managing them. Table 5: Clinically Relevant Interactions Affecting Drugs and Vaccines Co-administered with ZEPOSIA Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies Clinical Impact: ZEPOSIA has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which had no pharmacokinetic interaction [see Clinical Pharmacology (12.3) ] . Prevention or Management: Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1) ] . When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.11) ] . Alemtuzumab : Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. Beta interferon or glatiramer acetate : ZEPOSIA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate Clinical Impact: ZEPOSIA has not been studied in patients taking QT prolonging drugs. 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. Prevention or Management: If treatment with ZEPOSIA is considered in patients on Class Ia or Class III anti-arrhythmic drugs, advice from a cardiologist should be sought [see Warnings and Precautions (5.3) ] . Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties [see Warnings and Precautions (5.3) ]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought. Combination Beta Blocker and Calcium Channel Blocker Clinical Impact : The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker has not been studied. However, there is a potential of additive effects on heart rate. Prevention or Management: Treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem) and beta blocker [see Warnings and Precautions (5.3) ]. If treatment initiation with ZEPOSIA is considered in patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from a cardiologist should be sought. Vaccination Clinical Impact: During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection. Prevention or Management: Live attenuated vaccines should be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA [see Warnings and Precautions (5.1) ] . Table 6: Clinically Relevant Interactions Affecting ZEPOSIA When Co-administered with Other Drugs Monoamine Oxidase (MAO) Inhibitors Clinical Impact: The effect of MAO inhibition on ozanimod and/or its metabolites has not been studied clinically. Potential effects on efficacy or safety with co-administration of MAO inhibitors because of altered exposures of ozanimod and/or its metabolites cannot be ruled out. Prevention or Management: Co-administration of ZEPOSIA with MAO inhibitors (e.g., se…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPOSIA during pregnancy. Healthcare providers are encouraged to register patients on-line, or pregnant women may register themselves at https://www.zeposiapregnancyregistry.com/ or by calling 1-877-301-9314. Currently this registry is enrolling women with MS. Information regarding registration of pregnant women with UC will be made available in the future. Risk Summary There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women . In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of 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 demonstrated to have an important role in embryogenesis, including vascular and neural development. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of ozanimod (0, 0.2, 1, or 5 mg/kg/day) to female rats during organogenesis resulted in a marked increase in embryofetal mortality, increased fetal malformations and skeletal variations (abnormal/delayed ossification), and reduced fetal body weight at the highest dose tested. No maternal toxicity was observed. At the no-effect dose (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. Plasma AUCs for major human metabolites, CC112273 and CC1084037, were similar to and less than, respectively, those in humans at the MRHD. Oral administration of ozanimod (0, 0.2, 0.6, or 2.0 mg/kg/day) to female rabbits during organogenesis resulted in a marked increase in embryofetal mortality at the highest dose tested and increased fetal malformations (malformed blood 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) 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. 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) and neurobehavioral (increased motor activity) function in offspring at the highest dose tested, which was not 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 human metabolites, CC112273 and CC1084037, were less than those in humans at the MRHD.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.2) ] Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.3) ] Liver Injury [see Warnings and Precautions (5.4) ] Fetal Risk [see Warnings and Precautions (5.5) ] Increased Blood Pressure [see Warnings and Precautions (5.6) ] Respiratory Effects [see Warnings and Precautions (5.7) ] Macular Edema [see Warnings and Precautions (5.8) ] Cutaneous Malignancies [see Warnings and Precautions (5.9) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10) ] Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs [see Warnings and Precautions (5.11) ] Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA [see Warnings and Precautions (5.12) ] Immune System Effects after Stopping ZEPOSIA [see Warnings and Precautions (5.13) ] Most common adverse reactions (incidence ≥4%) are: Multiple Sclerosis : upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. ( 6.1 ) Ulcerative Colitis : liver test increased, upper respiratory infection, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Common Adverse Reactions Multiple Sclerosis The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies (MS Study 1 and MS Study 2) in which 882 patients received ZEPOSIA 0.92 mg [see Clinical Studies (14.1) ]. Table 2 lists adverse reactions that occurred in at least 2% of ZEPOSIA-treated patients and greater than comparator. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension. Table 2: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than IFN beta-1a in Patients with Multiple Sclerosis (Pooled MS Study 1 and Study 2) a a Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. b Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, viral respiratory tract infection, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. c Includes the following terms: alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, abnormal liver function test, and increased transaminases. d Includes hypertension, essential hypertension, and orthostatic hypertension. e ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2) ]. Adverse Reactions MS Studies 1 and 2 ZEPOSIA 0.92 mg Once Daily e (n=882) % IFN beta-1a 30 mcg Intramuscularly Once Weekly (n=885) % Upper respiratory infection b 26 23 Hepatic transaminase elevation c 10 5 Orthostatic hypotension 4 3 Urinary tract infection 4 3 Back pain 4 3 Hypertension d 4 2 Upper abdominal pain 2 1 Ulcerative Colitis The safety of ZEPOSIA was evaluated in two randomized, double-blind, placebo-controlled clinical studies [UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult …