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ZEPOSIA® for UC Header Image ZEPOSIA® for UC Header Image

TRUE NORTH
Study Design
for ZEPOSIA

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ZEPOSIA® for UC Header Image ZEPOSIA® for UC Header Image

TRUE NORTH
Study Design
for ZEPOSIA

TRUE NORTH Study Design for ZEPOSIA

ZEPOSIA was evaluated in 2 multicenter, randomized, double-blind, placebo-controlled clinical studies1

TRUE NORTH Study Design1-3
2 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active UC 2 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active UC

TRUE NORTH OLE is an ongoing trial that enrolled patients who were nonresponders at the end of induction, experienced disease relapse during maintenance, or completed maintenance treatment in the Phase 3 TRUE NORTH study or remained at study closure and received once-daily oral ZEPOSIA 0.92 mg in the Phase 2 TOUCHSTONE OLE. A total of 823 patients from TRUE NORTH entered the TRUE NORTH OLE as of the cutoff date (January 10, 2022).2,4,5

OLE endpoints were evaluated at Week 46 and Week 94 for a subset of patients who were in clinical remission or clinical response at Week 52 of the TRUE NORTH parent study and who had continuous ZEPOSIA exposure. Endpoints include clinical remission, clinical response, endoscopic improvement, and CS-free remission. Safety was evaluated for all 823 patients who entered the OLE from the TRUE NORTH parent study. The mean exposure to ZEPOSIA through the OLE was 2.7 years.4-7

UC Study 1 (10-week induction): 645 patients were randomized 2:1 to either ZEPOSIA 0.92 mg given orally once daily or placebo for 10 weeks, beginning with a dosage titration. The trial included patients who had an inadequate response or were intolerant to any of the following: oral aminosalicylates, corticosteroids, immunomodulators, or a biologic. Patients were required to be on stable doses of oral aminosalicylates and/or corticosteroids.1

UC Study 2 (42-week maintenance): 457 patients who received ZEPOSIA in either UC Study 1 or in an open-label arm and achieved clinical response at Week 10 were re-randomized 1:1 and were treated with either ZEPOSIA 0.92 mg (n=230) or placebo (n=227) for 42 weeks (UC Study 2), for a total of 52 weeks of treatment.1

  • aPatients who had a clinical response while they were on placebo at the end of the induction period continued to receive double-blind placebo during the maintenance period and could enter the extension trial at Week 52 or after disease relapse.2
  • bResponders are those who achieved clinical response, defined as a reduction from baseline in the 3-component Mayo score of ≥2 and ≥35%, and a reduction from baseline in the RBS of ≥1 or an absolute RBS of 0 or 1.1

CS=corticosteroid; OLE=open-label extension; RBS=rectal bleeding subscore; UC=ulcerative colitis.

Select Endpoint Definitions1

Primary Endpoint1

Clinical Remission

3-component Mayo score consisting of rectal bleeding subscore (RBS)=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥ 1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability

Key Secondary Endpoints1

Clinical Response

A reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in RBS of ≥1 point or an absolute RBS of 0 or 1

Endoscopic Improvement

Mayo endoscopy subscore of 0 or 1 point without friability

Endoscopic-Histologic Mucosal Improvement

Mayo endoscopy subscore of 0 or 1 without friability and histologic improvement of colonic tissue (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, ie, Geboes <2.0)

CS-free Clinical Remission

Clinical remission at Week 52 while off corticosteroids for ≥12 weeks

Key Inclusion Criteria1,2
  • Moderately to severely active UC (Mayo score of 6 to 12)
    • With endoscopy subscore ≥2
    • With RBS ≥1
    • With SFS ≥1
  • An inadequate response or intolerance to any of the following: oral aminosalicylates, corticosteroids, immunomodulators, or a biologic
  • Patients were required to be on stable doses of oral aminosalicylates and/or corticosteroids (prednisone daily dose up to 20 mg equivalent or budesonide extended-release tablets)
Key Exclusion Criteria1,3
  • Clinically relevant cardiovascular conditions or other relevant diseases that could impact the implementation or interpretation of the trial, or put the patient at risk
  • History of uveitis or macular edema
  • Concomitant use of biologics or immunomodulators
  • Pregnant or lactating women

Among the patients considered for the UC studies, 98.8% (2152/2178)
passed protocol-defined preexisting cardiac
disorder screening8c

cIncludes UC Study 1 from the TRUE NORTH trial and the phase 2 TOUCHSTONE trial. ZEPOSIA was not studied in patients who had1,8:

  • 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 preexisting 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

CS=corticosteroid; QT=an extended interval between the heart contracting and relaxing; QTcF=corrected QT interval by Fridericia; RBS=rectal bleeding subscore; SFS=stool frequency subscore; TIA=transient ischemic attack.

UC Study 1 Baseline Characteristics1,2

Baseline Patient Characteristics1,2
Male ~60%
Age ~42 years
Time Since UC Diagnosis ~7 years
Total Mayo Score ~9
Disease Severity  
Moderate Disease
(Mayo Score 6-10)		 86%
Severe Disease
(Mayo Score 11-12)		 14%
Concomitant Medication Use  
Mesalamine 71%
Sulfasalazine 13%
Oral Corticosteroids 33%
Prior Medication Use  
TNFi (Previous
Failure or Intolerance)		 30%
Of these patients,
47% were exposed
to vedolizumab		  

At entry to UC Study 2 (maintenance),
35% of patients were in clinical remission;
29% of patients were on CS; and 31% of patients
had an inadequate response, loss of response,
or intolerance to TNFi.1

CS=corticosteroid; RBS=rectal bleeding subscore; TNFi=tumor necrosis factor inhibitor.

Explore the Efficacy
Data for ZEPOSIA

Review the
Demonstrated
Safety Profile1

IMPORTANT SAFETY INFORMATION
Contraindications:
  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a 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
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to infections. 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. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.
  • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.
Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.

If confirmed, treatment with ZEPOSIA should be discontinued.

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:
  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or 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 Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block
Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease.
Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.
Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA.
Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.
Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. 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.
Unintended Additive Immunosuppressive Effects From Prior 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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.
Severe Increase in Multiple Sclerosis (MS) 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 so patients should be monitored upon discontinuation.
Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.

Use in Specific Populations: Hepatic Impairment: Use is not recommended.
For additional safety information, please see the full Prescribing Information and Medication Guide.
INDICATIONS
ZEPOSIA® (ozanimod) is indicated for the treatment of:
  1. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
  2. Moderately to severely active ulcerative colitis (UC) in adults.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X.
  3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8.
  4. Selmaj KW et al. Poster presented at ECTRIMS; October 26-28, 2022; Amsterdam, Netherlands. Poster P334.
  5. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X.
  3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8.
  4. Selmaj KW et al. Poster at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); October 13-15, 2021; The Digital Experience. P737.
  5. Cree BAC, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944-1962. doi:10.1177/13524585221102584.
  6. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb Company.
  2. Selmaj KW et al. Poster at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); October 13-15, 2021; The Digital Experience. P737.
  3. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X
  4. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8
  5. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
  6. Cree BAC, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944-1962. doi:10.1177/13524585221102584
  7. DeLuca J et al. Presented at: ACTRIMS; February 23-25, 2023; San Diego, CA. Presentation 074.
  8. Polman CH, Rudick RA. The multiple sclerosis functional composite: a clinically meaningful measure of disability. Neurology. 2010;74(suppl 3):S8-S15.
References:
  1. Selmaj KW et al. Poster presented at ECTRIMS; October 26-28, 2022; Amsterdam, Netherlands. Poster P334.
  2. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  3. Data on file. BMS-REF-OZA-0038. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  4. Data on file. BMS-REF-OZA-0039. Princeton, NJ: Bristol-Myers Squibb Company; 2023.
  5. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X
  6. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8
  7. Lymphocytopenia. National Heart, Lung, and Blood Institute (NHLBI). Accessed June 7, 2022. www.nhlbi.nih.gov/health-topics/lymphocytopenia
  8. Steinman L, Comi G, Bar-Or A, et al. P1031. Poster presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); September 11-13, 2019; Stockholm, Sweden.
References:
  1. ZEPOSIA. Prescribing information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11(6):403-415. doi:10.1038/nri2974
  3. Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011;108(2):751-756. doi:10.1073/pnas.1014154108
  4. Prager B, Spampinato SF, Ransohoff RM. Sphingosine 1-phosphate signaling at the blood–brain barrier. Trends Mol Med. 2015;21(6):354-363. doi:10.1016/j.molmed.2015.03.006
  5. Li N, Zhang F. Implication of sphingosin-1-phosphate in cardiovascular regulation. Front Biosci (Landmark Ed). 2016;21:1296-1313. doi:10.2741/4458
  6. Peyrin-Biroulet L, Christopher R, Behan D, Lassen C. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16(5):495-503. doi:10.1016/j.autrev.2017.03.007
  7. Olesch C, Ringel C, Brune B, Weigert A. Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor S1PR4 as a modulator of innate immune cell activation. Mediators Inflamm. 2017;2017:6059203. doi:10.115/2017/6059203
  8. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778- 1792. doi:10.1111/bph.13476
Reference:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
IMPORTANT SAFETY INFORMATION
Contraindications:
  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a 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
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to infections. 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. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.
  • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.
Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.
If confirmed, treatment with ZEPOSIA should be discontinued.
Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:
  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or 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 Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block
Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease.
Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.
Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA.
Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.
Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. 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.
Unintended Additive Immunosuppressive Effects From Prior 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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.
Severe Increase in Multiple Sclerosis (MS) 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 so patients should be monitored upon discontinuation.
Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.
Use in Specific Populations: Hepatic Impairment: Use is not recommended.
For additional safety information, please see the full Prescribing Information and Medication Guide.
INDICATIONS
ZEPOSIA® (ozanimod) is indicated for the treatment of:
  1. Moderately to severely active ulcerative colitis (UC) in adults.
  2. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

References:

  1. Khan N, Abbas A, Williamson A, Balart L. Prevalence of corticosteroids use and disease course after initial steroid exposure in ulcerative colitis. Dig Dis Sci. 2013;58(10):29​63-29​69.
  2. Burri E, Maillard MH, Schoepfer AM, et al. Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion. 2020;101 Suppl 1:2-15.
  3. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68(suppl 3):s1-s106.
  4. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  5. Efficacy and safety study of ozanimod in ulcerative colitis (Touchstone). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/record/NCT01647516. Updated May 19, 2021. Accessed May 11, 2022.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280-1291.
  3. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis [supplementary appendix]. N Engl J Med. 2021;385(14):1280-1291.
  4. Danese S, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral Presentation at: ECCO 2022; February 16-19, 2022. Presentation DOP44.
  5. Data on File. BMS-REF-OZA-031. Princeton, NJ; Bristol-Myers Squibb Company; 2022.
  6. Data on File. BMS-REF-OZA-022. Princeton, NJ; Bristol-Myers Squibb Company; 2022.
  7. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  8. Long M, Cross R, Calkwood J, et al. Ozanimod first-dose cardiac effects in patients with moderately to severely active ulcerative colitis and relapsing multiple sclerosis. Poster presented at AIBD 2021; December 9-11, 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol-Myers Squibb Company; 2022.
  2. Data on File. BMS-REF-OZA-0031. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  3. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  4. Danese S, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral presentation at: 17th Congress of the European Crohn’s and Colitis Organization; February 16-19, 2022; Virtual. Session DOP44.
  5. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE Study. J Crohns Colitis. 2021;15(7):1120-1129.
  6. Data on File. BMS-REF-OZA-0022. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  7. Siegmund B, Axelrad J, Pondel M, et al. Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active ulcerative colitis: results from the induction period of True North. Oral presentation at: ECCO 2022; March 2022.
  8. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis [supplementary appendix]. N Engl J Med. 2021;385:1280-1291.
  9. Panaccione R, Afzali A, Hudesman D, et al. Extended therapy with ozanimod for delayed responders to ozanimod in moderately to severely active ulcerative colitis: data from the True North open-label study. Poster presented at: DDW 2022; May 21-24, 2022.

References:

  1. Friedman S, Blumberg RS. Inflammatory Bowel Disease. Jameson JL. Harrison's Principles of Internal Medicine. Vol 2. Ed 20. McGraw-Hill Education; 2017: p2263.
  2. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):1756-1770.
  3. Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2020;8:CD000543.
  4. Khan N, Abbas A, Williamson A, Balart L. Prevalence of corticosteroids use and disease course after initial steroid exposure in ulcerative colitis. Dig Dis Sci. 2013;58(10):29​63-29​69.
  5. Burri E, Maillard MH, Schoepfer AM, et al. Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion. 2020;101 Suppl 1:2-15.
  6. Rubin DT, Sninsky C, Siegmund B, et al. International perspectives on management of inflammatory bowel disease: opinion differences and similarities between patients and physicians from the IBD GAPPS survey. Inflamm Bowel Dis. 2021;27(12):1942-1953.
  7. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  8. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  9. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company.
  2. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  3. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol-Myers Squibb Company; 2022.
  2. Data on File. BMS-REF-OZA-0016. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  3. Data on File. BMS-REF-OZA-0017. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  4. Danese S, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral presentation at: 17th Congress of the European Crohn’s and Colitis Organization; February 16-19, 2022; Virtual. Session DOP44.
  5. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385:1280-1291.
  6. Long M, Cross RK, Lichtenstein GR, et al. Long-term cardiac safety of ozanimod in phase 3 clinical program of ulcerative colitis and relapsing multiple sclerosis. Presented at: Digestive Disease Week (DDW); San Diego, CA and Virtual, May 21-24, 2022. Presentation 15.
  7. Rieder F, Wolf DC, Charles L, Kollengode K, Patel A, Ghosh S. Incidence of infections in patients with moderately to severely active ulcerative colitis treated with ozanimod and relationship to significant lymphopenia: results from a pooled safety analysis. Poster presented at: DDW 2021 Virtual Digestive Disease Week; May 21-23, 2021.
  8. Danese S, Feagan BG, Wolf DC, et al. Ozanimod as maintenance therapy in patients with moderate-to-severe ulcerative colitis: results from the phase 3, randomized, double-blind, placebo-controlled TRUE NORTH study. Oral Presentation at: UEG Week; October 11-13, 2020. Presentation LB10.
  9. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  10. Data on File. BMS-REF-OZA-0031. Princeton, NJ: Bristol-Myers Squibb Company; 2022.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Pérez-Jeldres T, Tyler CJ, Boyer JD, et al. Cell trafficking interference in inflammatory bowel disease. Inflamm Bowel Dis. 2019;2(25):270-282.
  3. Al-Bawardy B, Shivashankar R, Proctor DD. Novel and emerging therapies for inflammatory bowel disease. Front Pharmacol. 2021; 12:651415.
  4. Nikolakis D, de Voogd FAE, Pruijit MJ, et al. The role of the lymphatic system in the pathogenesis and treatment of inflammatory bowel disease. Int J Mol Sci. 2022;23(3):1854.
  5. Harris S, Tran JQ, Southworth H, Spencer CM, Cree BAC, Zamvil SS. Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e839.
  6. Jaigirdar SA, Benson RA, Elmesmari A, et al. Sphingosine 1-phosphate promotes the persistence of activated CD4 T cells in inflamed sites. Front Immunol. 2017;8:1627.
  7. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine 1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173:1778-1792.
  8. Kayal M, Shah S. Ulcerative colitis: current and emerging treatment strategies. J Clin Med. 2019;9(1):94.
  9. Olivera P, Danese S, Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease. Gut. 2017;66(2)199-209.
  10. Lucaciu LA, Seicean R, Seicean A. Small molecule drugs in the treatment of inflammatory bowel diseases: which one, when and why? –a systematic review. Eur J Gastroenterol Hepatol. 2020;32(6):669-677.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company: 2022.
  2. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  3. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.
IMPORTANT SAFETY INFORMATION
INDICATIONS
ZEPOSIA® (ozanimod) is indicated for the treatment of:
  1. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
  2. Moderately to severely active ulcerative colitis (UC) in adults.
IMPORTANT SAFETY INFORMATION
Contraindications:
  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a 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
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to infections. 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. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.
  • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.
Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.

If confirmed, treatment with ZEPOSIA should be discontinued.

IMPORTANT SAFETY INFORMATION
Contraindications:
  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a 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
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to infections. 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. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.
  • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.
Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.

If confirmed, treatment with ZEPOSIA should be discontinued.

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:
  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or 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 Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block
Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease.
Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.
Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA.
Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.
Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. 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.
Unintended Additive Immunosuppressive Effects From Prior 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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.
Severe Increase in Multiple Sclerosis (MS) 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 so patients should be monitored upon discontinuation.
Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.

Use in Specific Populations: Hepatic Impairment: Use is not recommended.
For additional safety information, please see the full Prescribing Information and Medication Guide.
INDICATIONS
ZEPOSIA® (ozanimod) is indicated for the treatment of:
  1. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
  2. Moderately to severely active ulcerative colitis (UC) in adults.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X.
  3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8.
  4. Selmaj KW et al. Poster presented at ECTRIMS; October 26-28, 2022; Amsterdam, Netherlands. Poster P334.
  5. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X.
  3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8.
  4. Selmaj KW et al. Poster at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); October 13-15, 2021; The Digital Experience. P737.
  5. Cree BAC, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944-1962. doi:10.1177/13524585221102584.
  6. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
References:
  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb Company.
  2. Selmaj KW et al. Poster at 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); October 13-15, 2021; The Digital Experience. P737.
  3. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X
  4. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8
  5. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint ACTRIMS-ECTRIMS Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.
  6. Cree BAC, Selmaj KW, Steinman L, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022;28(12):1944-1962. doi:10.1177/13524585221102584
  7. DeLuca J et al. Presented at: ACTRIMS; February 23-25, 2023; San Diego, CA. Presentation 074.
  8. Polman CH, Rudick RA. The multiple sclerosis functional composite: a clinically meaningful measure of disability. Neurology. 2010;74(suppl 3):S8-S15.
References:
  1. Selmaj KW et al. Poster presented at ECTRIMS; October 26-28, 2022; Amsterdam, Netherlands. Poster P334.
  2. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  3. Data on file. BMS-REF-OZA-0028. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  4. Data on file. BMS-REF-OZA-0029. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  5. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009-1020 and Suppl 1-26. doi:10.1016/S1474-4422(19)30239-X
  6. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-1033 and Suppl 1-31. doi:10.1016/S1474-4422(19)30238-8
  7. Lymphocytopenia. National Heart, Lung, and Blood Institute (NHLBI). Accessed June 7, 2022. www.nhlbi.nih.gov/health-topics/lymphocytopenia
  8. Steinman L, Comi G, Bar-Or A, et al. P1031. Poster presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); September 11-13, 2019; Stockholm, Sweden.
References:
  1. ZEPOSIA. Prescribing information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11(6):403-415. doi:10.1038/nri2974
  3. Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011;108(2):751-756. doi:10.1073/pnas.1014154108
  4. Prager B, Spampinato SF, Ransohoff RM. Sphingosine 1-phosphate signaling at the blood–brain barrier. Trends Mol Med. 2015;21(6):354-363. doi:10.1016/j.molmed.2015.03.006
  5. Li N, Zhang F. Implication of sphingosin-1-phosphate in cardiovascular regulation. Front Biosci (Landmark Ed). 2016;21:1296-1313. doi:10.2741/4458
  6. Peyrin-Biroulet L, Christopher R, Behan D, Lassen C. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16(5):495-503. doi:10.1016/j.autrev.2017.03.007
  7. Olesch C, Ringel C, Brune B, Weigert A. Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor S1PR4 as a modulator of innate immune cell activation. Mediators Inflamm. 2017;2017:6059203. doi:10.115/2017/6059203
  8. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778- 1792. doi:10.1111/bph.13476
Reference:
  1. ZEPOSIA. Prescribing information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
IMPORTANT SAFETY INFORMATION
Contraindications:
  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a 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
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor
Infections: ZEPOSIA may increase the susceptibility to infections. 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. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.
  • Herpes zoster was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.
Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.
If confirmed, treatment with ZEPOSIA should be discontinued.
Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:
  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or 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 Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block
Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease.
Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.
Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA.
Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.
Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. 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.
Unintended Additive Immunosuppressive Effects From Prior 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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.
Severe Increase in Multiple Sclerosis (MS) 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 so patients should be monitored upon discontinuation.
Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.
In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.
Use in Specific Populations: Hepatic Impairment: Use is not recommended.
For additional safety information, please see the full Prescribing Information and Medication Guide.
INDICATIONS
ZEPOSIA® (ozanimod) is indicated for the treatment of:
  1. Moderately to severely active ulcerative colitis (UC) in adults.
  2. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

References:

  1. ZEPOSIA. Prescribing Information, Celgene Corporation, a Bristol Myers Squibb company.
  2. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  3. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385(14):1280-1291.
  3. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis [supplementary appendix]. N Engl J Med. 2021;385(14):1280-1291.
  4. Danese S, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral Presentation at: ECCO 2022; February 16-19, 2022. Presentation DOP44.
  5. Data on File. BMS-REF-OZA-031. Princeton, NJ; Bristol-Myers Squibb Company; 2022.
  6. Data on File. BMS-REF-OZA-022. Princeton, NJ; Bristol-Myers Squibb Company; 2022.
  7. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  8. Long M, Cross R, Calkwood J, et al. Ozanimod first-dose cardiac effects in patients with moderately to severely active ulcerative colitis and relapsing multiple sclerosis. Poster presented at AIBD 2021; December 9-11, 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol-Myers Squibb Company.
  2. Data on File. BMS-REF-OZA-0031. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  3. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  4. Danese S, Colombel J-F, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral presentation at: 17th Congress of the European Crohn’s and Colitis Organization; February 16-19, 2022; Virtual. Session DOP44.
  5. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE Study. J Crohns Colitis. 20​21;15(7):11​20-11​29.
  6. Data on File. BMS-REF-OZA-0022. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  7. Siegmund B, Axelrad J, Pondel M, et al. Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active ulcerative colitis: results from the induction period of True North. Oral presentation at: ECCO 20​22; March 20​22.
  8. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis [supplementary appendix]. N Engl J Med. 2021;385:1280-1291.
  9. Panaccione R, Afzali A, Hudesman D, et al. Extended therapy with ozanimod for delayed responders to ozanimod in moderately to severely active ulcerative colitis: data from the True North open-label study. Poster presented at: DDW 2022; May 21-24, 20​22.

References:

  1. Friedman S, Blumberg RS. Inflammatory Bowel Disease. Jameson JL. Harrison's Principles of Internal Medicine. Vol 2. Ed 20. McGraw-Hill Education; 20​17: p2​2​63.
  2. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389(10080):17​56-17​70.
  3. Murray A, Nguyen TM, Parker CE, Feagan BG, MacDonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 20​20;8:CD​00​05​43.
  4. Khan N, Abbas A, Williamson A, Balart L. Prevalence of corticosteroids use and disease course after initial steroid exposure in ulcerative colitis. Dig Dis Sci. 20​13;5​8(10):29​63-29​69.
  5. Burri E, Maillard MH, Schoepfer AM, et al. Treatment algorithm for mild and moderate-to-severe ulcerative colitis: an update. Digestion. 2020;101 Suppl 1:2-15.
  6. Rubin DT, Sninsky C, Siegmund B, et al. International perspectives on management of inflammatory bowel disease: opinion differences and similarities between patients and physicians from the IBD GAPPS survey. Inflamm Bowel Dis. 2021;27(12):1942-1953.
  7. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  8. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  9. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company.
  2. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  3. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol-Myers Squibb Company; 2022.
  2. Data on file. BMS-REF-OZA-0016. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  3. Data on file. BMS-REF-OZA-0017. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  4. Danese S, Colombel J-F, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral presentation at: 17th Congress of the European Crohn’s and Colitis Organization; February 16-19, 2022; Virtual. Session DOP44.
  5. Sandborn WJ, Feagan BG, D’Haens G, et al; True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385:1280-1291.
  6. Long M, Cross RK, Lichtenstein GR, et al. Long-term cardiac safety of ozanimod in phase 3 clinical program of ulcerative colitis and relapsing multiple sclerosis. Presented at: Digestive Disease Week (DDW); San Diego, CA and Virtual, May 21-24, 2022. Presentation 15.
  7. Rieder F, Wolf DC, Charles L, Kollengode K, Patel A, Ghosh S. Incidence of infections in patients with moderately to severely active ulcerative colitis treated with ozanimod and relationship to significant lymphopenia: results from a pooled safety analysis. Poster presented at: DDW 2021 Virtual Digestive Disease Week; May 21-23, 2021.
  8. Danese S, Feagan BG, Wolf DC, et al. Ozanimod as maintenance therapy in patients with moderate-to-severe ulcerative colitis: results from the phase 3, randomized, double-blind, placebo-controlled TRUE NORTH Study. Oral Presentation at: UEG Week; October 11-13, 2020. Presentation LB10.
  9. Wolf DC, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Poster presented at: Digestive Disease Week (DDW); San Diego, CA, and Virtual, May 21-24, 2022. Poster Tu1458.
  10. Data on file. BMS-REF-OZA-0031. Princeton, NJ: Bristol-Myers Squibb Company; 2022.

References:

  1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company; 2022.
  2. Pérez-Jeldres T, Tyler CJ, Boyer JD, et al. Cell Trafficking Interference in Inflammatory Bowel Disease: Therapeutic Interventions Based on Basic Pathogenesis Concepts. Inflamm Bowel Dis. 2019;25(2):270-282. doi:10.1093/ibd/izy269
  3. Al-Bawardy B, Shivashankar R, Proctor DD. Novel and Emerging Therapies for Inflammatory Bowel Disease. Front Pharmacol. 2021;12:651415. Published 2021 Apr 14. doi:10.3389/fphar.2021.651415
  4. Nikolakis D, de Voogd FAE, Pruijt MJ, Grootjans J, van de Sande MG, D'Haens GR. The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease. Int J Mol Sci. 2022;23(3):1854. Published 2022 Feb 6. doi:10.3390/ijms23031854
  5. Harris S, Tran JQ, Southworth H, Spencer CM, Cree BAC, Zamvil SS. Effect of the sphingosine-1-phosphate receptor modulator ozanimod on leukocyte subtypes in relapsing MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e839. Published 2020 Jul 31. doi:10.1212/NXI.0000000000000839v
  6. Jaigirdar SA, Benson RA, Elmesmari A, et al. Sphingosine-1-phosphate promotes the persistence of activated CD4 T cells in inflamed sites. Front Immunol. 2017;8:1627.
  7. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173:1778-1792.
  8. Kayal M, Shah S. Ulcerative Colitis: Current and Emerging Treatment Strategies. J Clin Med. 2019;9(1):94. Published 2019 Dec 30. doi:10.3390/jcm9010094
  9. Olivera P, Danese S, Peyrin-Biroulet L. Next generation of small molecules in inflammatory bowel disease. Gut. 2017;66(2):199-209. doi:10.1136/gutjnl-2016-312912
  10. Lucaciu LA, Seicean R, Seicean A. Small molecule drugs in the treatment of inflammatory bowel diseases: which one, when and why? — a systematic review. Eur J Gastroenterol Hepatol. 2020;32:669-677.

References:

  1. ZEPOSIA. Prescribing Information, Celgene Corporation, a Bristol Myers Squibb company.
  2. Rinvoq [package insert]. North Chicago, Illinois: AbbVie Biotechnology Ltd; 2022.
  3. Xeljanz [package insert]. New York, New York: Pfizer Inc; 2021.
  4. Data on File. BMS-REF-OZA-023. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:
  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or 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 Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block
Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease.
Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.
Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA.
Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.
Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. 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.
Unintended Additive Immunosuppressive Effects From Prior 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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.
Severe Increase in Multiple Sclerosis (MS) 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 so patients should be monitored upon discontinuation.
Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days with approximately 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.

Use in Specific Populations: Hepatic Impairment: Use is not recommended.
For additional safety information, please see the full Prescribing Information and Medication Guide.
This site is intended for U.S. Healthcare Professionals only.
ZEPOSIA, ZEPOSIA 360 Support and ZEPOSIA logo are trademarks of Celgene
Corporation, a Bristol Myers Squibb company.
All other trademarks are the property of their respective owners.
All other trademarks are the property of their respective owners.
© 20222023 2023 Bristol-Myers Squibb Company.
2084-US-2300609 06/23
2084-US-2300572 06/23
2084-US-2300609 06/23

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