ZEPOSIA 7-DAY STARTER PACK
(+2 other brands)
Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZEPOSIA is available as capsules in the following dosage strengths: • 0.23 mg ozanimod: light grey opaque body/light grey opaque cap imprinted with black ink "OZA" on the cap and "0.23 mg" on the body • 0.46 mg ozanimod: light grey opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.46 mg" on the body • 0.92 mg ozanimod: orange opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.92 mg" on the body Capsules are supplied in the following strengths and package configurations: Package configuration Tablet strength NDC number Bottles of 30 0.92 mg ozanimod 59572-820-30 7-Day Starter Pack 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 ozanimod mg capsules 59572-810-07 Starter Kit (7-Day Starter Pack and 0.92 mg 30-count Bottle) 37-capsule starter kit including: one 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 mg ozanimod capsules and one bottle containing: (30) 0.92 mg ozanimod capsules 59572-890-91 59572-890-07 59572-890-30 Starter Kit (7-Day Starter Pack and 0.92 mg 21-count Bottle) 28-capsule starter kit including: one 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 mg ozanimod capsules and one bottle containing: (21) 0.92 mg ozanimod capsules 59572-890-28 59572-890-07 59572-890-21 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].; PRINCIPAL DISPLAY PANEL - 0.92 mg Capsule Bottle Label NDC 59572-820-30 ZEPOSIA ® (ozanimod) capsules 0.92 mg Dispense the accompanying Medication Guide to each patient. Rx only 30 Capsules Bristol-Myers Squibb zeposia-bottle-label; PRINCIPAL DISPLAY PANEL - 7 Capsule Starter Pack Kit Carton NDC 59572-810-07 Rx only ZEPOSIA ® (ozanimod) capsules 7-DAY STARTER PACK This pack contains 7 capsules for dosing over 7 days. The contents of this pack are as follows: Four 0.23 mg capsules Three 0.46 mg capsules 7 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol-Myers Squibb zeposia-starter-carton; PRINCIPAL DISPLAY PANEL - Kit Carton Rx only NDC 59572-890-91 ZEPOSIA ® (ozanimod) capsules STARTER KIT STEP 1: (Days 1-7) Starting at Day 1, complete the 7-Day Starter Pack Days 1-4: Take one 0.23 mg capsule orally once daily Days 5-7: Take one 0.46 mg capsule orally once daily STEP 2: (Day 8 and thereafter) After completing the 7-Day Starter Pack, begin taking one 0.92 mg capsule once daily or as directed from the 30-count bottle. This Starter Kit contains 37 capsules for titration over 7 days up to prescribed maintenance dose of one 0.92 mg capsule taken once daily or as directed. The contents of the Starter Kit, which are not to be sold separately, are as follows: Four 0.23 mg capsules Three 0.46 mg capsules Thirty 0.92 mg capsules 37 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol Myers Squibb zeposia-28-kit-carton; Package/Label Display Panel Rx only NDC 59572-890-28 ZEPOSIA ® (ozanimod) capsules STARTER KIT STEP 1: (Days 1-7) Starting at Day 1, complete the 7-Day Starter Pack Days 1-4: Take one 0.23 mg capsule orally once daily Days 5-7: Take one 0.46 mg capsule orally once daily STEP 2: (Day 8 and thereafter) After completing the 7-Day Starter Pack, begin taking one 0.92 mg capsule a day or as directed from the 21-count bottle. This Starter Kit contains 28 capsules for titration over 7 days up to prescribed maintenance dose of one 0.92 mg capsule taken once daily or as directed. The contents of the Starter Kit, which are not to be sold separately, are as follows: Four 0.23 mg capsules Three 0.46 mg capsules Twenty One 0.92 mg capsules 28 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol Myers Squibb zeposia-28-kit-carton
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ZEPOSIA is available as capsules in the following dosage strengths: • 0.23 mg ozanimod: light grey opaque body/light grey opaque cap imprinted with black ink "OZA" on the cap and "0.23 mg" on the body • 0.46 mg ozanimod: light grey opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.46 mg" on the body • 0.92 mg ozanimod: orange opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.92 mg" on the body Capsules are supplied in the following strengths and package configurations: Package configuration Tablet strength NDC number Bottles of 30 0.92 mg ozanimod 59572-820-30 7-Day Starter Pack 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 ozanimod mg capsules 59572-810-07 Starter Kit (7-Day Starter Pack and 0.92 mg 30-count Bottle) 37-capsule starter kit including: one 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 mg ozanimod capsules and one bottle containing: (30) 0.92 mg ozanimod capsules 59572-890-91 59572-890-07 59572-890-30 Starter Kit (7-Day Starter Pack and 0.92 mg 21-count Bottle) 28-capsule starter kit including: one 7-capsule starter pack containing: (4) 0.23 mg ozanimod capsules and (3) 0.46 mg ozanimod capsules and one bottle containing: (21) 0.92 mg ozanimod capsules 59572-890-28 59572-890-07 59572-890-21 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
- PRINCIPAL DISPLAY PANEL - 0.92 mg Capsule Bottle Label NDC 59572-820-30 ZEPOSIA ® (ozanimod) capsules 0.92 mg Dispense the accompanying Medication Guide to each patient. Rx only 30 Capsules Bristol-Myers Squibb zeposia-bottle-label
- PRINCIPAL DISPLAY PANEL - 7 Capsule Starter Pack Kit Carton NDC 59572-810-07 Rx only ZEPOSIA ® (ozanimod) capsules 7-DAY STARTER PACK This pack contains 7 capsules for dosing over 7 days. The contents of this pack are as follows: Four 0.23 mg capsules Three 0.46 mg capsules 7 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol-Myers Squibb zeposia-starter-carton
- PRINCIPAL DISPLAY PANEL - Kit Carton Rx only NDC 59572-890-91 ZEPOSIA ® (ozanimod) capsules STARTER KIT STEP 1: (Days 1-7) Starting at Day 1, complete the 7-Day Starter Pack Days 1-4: Take one 0.23 mg capsule orally once daily Days 5-7: Take one 0.46 mg capsule orally once daily STEP 2: (Day 8 and thereafter) After completing the 7-Day Starter Pack, begin taking one 0.92 mg capsule once daily or as directed from the 30-count bottle. This Starter Kit contains 37 capsules for titration over 7 days up to prescribed maintenance dose of one 0.92 mg capsule taken once daily or as directed. The contents of the Starter Kit, which are not to be sold separately, are as follows: Four 0.23 mg capsules Three 0.46 mg capsules Thirty 0.92 mg capsules 37 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol Myers Squibb zeposia-28-kit-carton
- Package/Label Display Panel Rx only NDC 59572-890-28 ZEPOSIA ® (ozanimod) capsules STARTER KIT STEP 1: (Days 1-7) Starting at Day 1, complete the 7-Day Starter Pack Days 1-4: Take one 0.23 mg capsule orally once daily Days 5-7: Take one 0.46 mg capsule orally once daily STEP 2: (Day 8 and thereafter) After completing the 7-Day Starter Pack, begin taking one 0.92 mg capsule a day or as directed from the 21-count bottle. This Starter Kit contains 28 capsules for titration over 7 days up to prescribed maintenance dose of one 0.92 mg capsule taken once daily or as directed. The contents of the Starter Kit, which are not to be sold separately, are as follows: Four 0.23 mg capsules Three 0.46 mg capsules Twenty One 0.92 mg capsules 28 CAPSULES Dispense the accompanying Medication Guide to each patient. Bristol Myers Squibb zeposia-28-kit-carton
Overview
ZEPOSIA contains ozanimod, a sphingosine 1-phosphate receptor modulator and is supplied as ozanimod hydrochloride (HCl). The chemical name of ozanimod HCl is 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1 H -inden-4-yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile, monohydrochloride. Ozanimod HCl is a white to off-white solid that is freely soluble in water and alcohol with a molecular weight of 440.92 g/mol. The chemical structure is: ZEPOSIA capsules are provided as hard gelatin capsules for oral administration, containing 0.23, 0.46, or 0.92 mg of ozanimod (equivalent to 0.25, 0.5, and 1 mg ozanimod HCl, respectively). ZEPOSIA capsules consist of the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The capsule shell, imprinted with black ink, contains the following inactive ingredients: black iron oxide, gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. zeposia-chem-structure
Indications & 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 )
Dosage & 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 using the titration regimen [see Dosage and Administration (2.2) ] . If a dose of ZEPOSIA is missed after the first 2 weeks of treatment, continue with the treatment as planned .
Warnings & 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 return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2) ]. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period. Herpes Viral Infection Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA. In MS Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a. In UC Study 1 and Study 3, herpes zoster was reported in 0.4% of patients who received ZEPOSIA and none in patients who received placebo. In UC Study 2, herpes zoster was reported in 2.2% of patients who received ZEPOSIA and 0.4% of patients who received placebo. None were serious or disseminated. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor 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 VZV before initiating ZEPOSIA (see Vaccinations below). Cryptococcal Infection Cases 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 or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating Therapies In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. In UC studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ZEPOSIA [see Clinical Studies (14.2) ]. Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be 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 action to avoid unintended additive immunosuppressive effects. Vaccinations Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur. No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA. 5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other multiple sclerosis (MS) and UC therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants, duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months . Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, treatment with ZEPOSIA should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. 5.3 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays , an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2) ] . ZEPOSIA was not studied in patients who had: • A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months • New York Heart Association Class III / IV heart failure • Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 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 patient's health • Other pre-existing stable cardiac conditions without clearance from a cardiologist • Severe untreated sleep apnea • A resting heart rate less than 55 beats per minute (bpm) at baseline Reduction in Heart Rate Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate occurred at Hour 5 on Day 1 (decrease of 1.2 bpm in MS Study 1 and Study 2, and 0.7 bpm in UC Study 1 and Study 3), 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 characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate [see Dosage and Administration (2.2) ]. In MS Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. In UC Study 1 and Study 3, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) treated with ZEPOSIA compared to none in patients who received placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with ZEPOSIA. In UC Study 2, bradycardia was not reported. Atrioventricular Conduction Delays Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in MS Study 1 and Study 2 and UC Study 1 and Study 3 with dose titration, Mobitz type 2 second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals: • With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females) • With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs • With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension • With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block [see Contraindications (4) ] 5.4 Liver Injury Clinically significant liver injury, including acute liver failure requiring transplant, has occurred in patients treated with ZEPOSIA in the postmarketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. 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 patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2-4 weeks. ZEPOSIA was discontinued for 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. In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 0.9% of patients and no patients, respectively. In UC Study 1, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 2.3% of patients and no patients, respectively. In controlled and uncontrolled UC studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2 to 4 weeks. Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg, and none in patients who received placebo in the controlled UC studies. Individuals with an AST or ALT greater than 1.5-fold ULN were excluded from MS Study 1 and Study 2 and greater than 2 times the ULN for UC Study 1 and Study 3. There are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA. Dosage adjustment in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) is required [see Dosage and Administration (2.3) ] , and use of ZEPOSIA in patients with severe hepatic impairment (Child-Pugh class C) is not recommended [see Use in Specific Populations (8.6) ] . Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Obtain transaminase levels and total bilirubin levels periodically during treatment and until two months after ZEPOSIA discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes promptly checked, and ZEPOSIA should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury. 5.5 Fetal Risk There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm [see Use in Specific Populations (8.1) ] . Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA [see Use in Specific Populations (8.3) ] . 5.6 Increased Blood Pressure In MS Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in MS Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication. The mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated with ZEPOSIA is similar to patients with MS. In UC Study 1 and Study 3, the average increase from baseline in SBP was 3.7 mm Hg in patients treated with ZEPOSIA and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the average increase from baseline in SBP was 5.1 mm Hg in patients treated with ZEPOSIA and 1.5 mm Hg in patients treated with placebo. There was no effect on DBP. Hypertension was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA 0.92 mg and none in patients treated with placebo in UC Study 1 and Study 3, and in 2.2% and 2.2% of patients in UC Study 2, respectively. Hypertensive crisis was reported in two patients receiving ZEPOSIA and one patient receiving placebo. Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately. 5.7 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV 1 ) were observed in MS patients treated with ZEPOSIA as early as 3 months after treatment initiation. In the MS pooled analyses of Study 1 and Study 2, the decline in absolute FEV 1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV 1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a [60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)], though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV 1 or FVC after drug discontinuation. One patient in MS Study 1 discontinued ZEPOSIA because of dyspnea. In UC Study 1 the mean difference in decline in absolute FEV 1 from baseline in patients treated with ZEPOSIA compared to patients who received placebo was 22 mL (95% CI: -84, 39) at 10 weeks. The mean difference in percent predicted normal (PPN) FEV 1 at 10 weeks between patients treated with ZEPOSIA compared to those who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVC (absolute value and %-predicted) seen at Week 10 in UC Study 1, comparing patients who were treated with ZEPOSIA to those who received placebo was 44 mL, 95% CI (-114, 26); 0.5%, 95% CI (-2.3, 1.2), respectively. There is insufficient information to determine the reversibility of observed decreases in FEV 1 or FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with continued use. Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated. 5.8 Macular Edema S1P receptor modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA. Perform an examination of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. In MS Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. Macular edema was reported in a total of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%) patient in UC Study 2 treated with ZEPOSIA, and in no patients who received placebo. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing ZEPOSIA if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated. Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy. 5.9 Cutaneous Malignancies The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Cases of BCC, SCC, and melanoma have been reported in patients treated with ZEPOSIA; melanoma and BCC were reported in controlled trials [see Adverse Reactions (6.1) ] . Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking ZEPOSIA. 5.10 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In MS controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued. 5.11 Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended [see Drug Interactions (7) ]. 5.12 Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required. After stopping ZEPOSIA in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [see Warnings and Precautions (5.2) ] . 5.13 Immune System Effects after Stopping ZEPOSIA After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months [see Clinical Pharmacology (12.2) ]. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA [see Drug Interactions (7) ].
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 )
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 patients with moderately to severely active ulcerative colitis [see Clinical Studies (14.2) ] . Additional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3, NCT01647516) included 67 patients who received ZEPOSIA 0.92 mg once daily. Common adverse reactions in UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 3 and 4, respectively. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received placebo were liver test increased, upper respiratory infection, and headache. Table 3: Adverse Reactions with an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater than Placebo in Patients with Ulcerative Colitis (Pooled UC Study 1 and Study 3) a Includes the following terms: streptococcal pharyngitis, pharyngotonsillitis, bacterial pharyngitis, nasopharyngitis, upper respiratory tract infection, pharyngitis, sinusitis, tonsillitis, viral upper respiratory tract infection, laryngitis, acute sinusitis, catarrh, chronic sinusitis, upper respiratory tract inflammation, chronic tonsillitis, viral pharyngitis, viral sinusitis, bacterial sinusitis, bacterial upper respiratory tract infection, viral labyrinthitis, laryngeal inflammation, and pharyngeal inflammation. b Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, blood alkaline phosphatase increased, and increased transaminases. c ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2) ]. d Percentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight. Adverse Reactions Induction Periods (UC Study 1 and Study 3) ZEPOSIA 0.92 mg Once Daily (n=496) c,d % Placebo (n=281) % d Upper respiratory infection a 5 4 Liver test increased b 5 0 Headache 4 3 Pyrexia 3 2 Nausea 3 2 Arthralgia 3 1 Table 4: Adverse Reactions with an Incidence of at Least 4% in ZEPOSIA-Treated Patients and at Least 1% Greater than Placebo in Patients with Ulcerative Colitis (UC Study 2) a Includes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased, liver function test increased, and blood alkaline phosphatase increased. Adverse Reactions Maintenance Period (UC Study 2) ZEPOSIA 0.92 mg Once Daily (n=230) % Placebo (n=227) % Liver test increased a 11 2 Headache 5 <1 Other Adverse Reactions Reduction in Heart Rate Initiation of ZEPOSIA may result in transient decrease in heart rate in MS and UC patients [see Warnings and Precautions (5.3) ]. Respiratory Effects Dose-dependent reductions in absolute FEV 1 and FVC were observed in MS and UC patients treated with ZEPOSIA [see Warnings and Precautions (5.7) ]. Malignancies Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of MS and UC. An increased risk of cutaneous malignancies has been reported with S1P receptor modulators [see Warnings and Precautions (5.9) ]. Hypersensitivity Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials. Peripheral Edema Peripheral edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients who received placebo in UC Study 2. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZEPOSIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.4) ]
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., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors. Strong CYP2C8 Inhibitors Clinical Impact: Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod [see Clinical Pharmacology (12.3) ] , which may increase the risk of ZEPOSIA adverse reactions. Prevention or Management: Co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Strong CYP2C8 Inducers Clinical Impact: Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod [see Clinical Pharmacology (12.3) ] , which may decrease the efficacy of ZEPOSIA. Prevention or Management: Co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided. • Vaccination : Avoid use of live attenuated vaccines during and for up to 3 months after treatment with ZEPOSIA. ( 7 ) • See full prescribing information for a list of clinically important drug interactions. ( 7 )
Storage & Handling
16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
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