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Well-established safety profile across multiple indicationsa

4 Clinical Trials, >1370 ZEPOSIA-Treated Patients Across Multiple Indications, >20,000 patient years of total exposure in clinical trials 4 Clinical Trials, >1370 ZEPOSIA-Treated Patients Across Multiple Indications, >20,000 patient years of total exposure in clinical trials

aZEPOSIA has been studied across multiple indications in 4 clinical trials, including TRUE NORTH (Ph 3); TOUCHSTONE (Ph 2); and SUNBEAM (Ph 3) and RADIANCE (Ph 3). 496 patients receiving the 0.92-mg dose of ZEPOSIA during induction in TRUE NORTH or TOUCHSTONE and 882 patients receiving the 0.92-mg dose of ZEPOSIA in SUNBEAM or RADIANCE were assessed in the safety analysis.1

bMS: Includes Phase 1, Phase 2, SUNBEAM, RADIANCE, and DAYBREAK (data cutoff: February 2, 2021). UC: Includes TOUCHSTONE, TRUE NORTH, TRUE NORTH OLE (data cutoff: September 30, 2020). Post-marketing Setting: data cutoff November 19, 2021. Exposure for patients with MS in clinical trials is 2631 patients and 11,938 patient-years. Exposure for patients with UC in clinical trials is 1158 patients and 2108 patient-years. Exposure for patients in the post-marketing setting across indications is 9738 patients and 6455 patient-years2-4

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 Induction Periods UC Study 1 and Study 3)c
Adverse Reaction
ZEPOSIA 0.92 mg
(n=496)fg
Placebo
(n=281)g
Upper Respiratory Infectiond 5% 4%
Liver Test Increasede 5% 0%
Headache 4% 3%
Pyrexia 3% 2%
Nausea 3% 2%
Arthralgia 3% 1%

UC Study 3 (8-week induction): TOUCHSTONE is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the clinical efficacy and safety of induction therapy with RPC1063 in 199 patients with moderately to severely active ulcerative colitis. Participants who completed the induction period and were responders at Week 8 continued to receive the same dose of ozanimod during the maintenance period up to Week 32.

For full study design of UC Study 1 and Study 2, click here.

  • cAdditional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3/TOUCHSTONE) included 67 patients who received ZEPOSIA 0.92 mg once daily.1
  • dIncludes 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.1
  • eIncludes 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, transaminases increased.1
  • fZEPOSIA was initiated with a 7-day titration.1
  • gPercentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight.1
Adverse Events from TRUE NORTH (UC Study 1) Induction Period5
ZEPOSIA 0.92 mg
(n=429)
Placebo
(n=216)
Adverse Event 40.1% 38%
Serious Adverse Event 4% 3.2%
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)
Maintenance Period.1
Adverse Reaction
ZEPOSIA 0.92 mg
(n=230)
Placebo
(n=227)
Liver Test Increasedh 11% 2%
Headache 5% <1%
  • hIncludes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, blood bilirubin increased, liver function test increased, blood alkaline phosphatase increased.1
Adverse Events from TRUE NORTH (UC Study 2) Maintenance Period5
ZEPOSIA 0.92 mg
(n=230)
Placebo
(n=227)
Adverse Event 49.1% 36.6%
Serious Adverse Event 5.2% 7.9%
In ZEPOSIA-treated patients, rates of thromboembolic events or major adverse cardiac events were similar to patients treated with placebo in TRUE NORTH.6ij
  • iIn the TRUE NORTH Phase 3 studies, 1 case of ischemic stroke (0.2%) was reported in ZEPOSIA-treated patients versus no reports in patients treated with placebo.6
  • jThromboembolic events include pulmonary embolism and venous arterial thrombosis. Major or adverse cardiac events include cardiovascular death, myocardial infarction, and stroke. 6

MS=multiple sclerosis; OLE=open-label extension; UC=ulcerative colitis.

UC Study 1 and Study 2
Adverse Reaction
Induction
Maintenance
 ZEPOSIA
0.92 mg
(n=429)		 Placebo
(n=216)		 ZEPOSIA
0.92 mg
(n=230)		 Placebo
(n=227)
ALT ≥3x ULN
 2.6% 0.5% 2.3% 0%
ALT ≥5x ULN
 0.9% 0.5% 0.9% 0%
  • In controlled and uncontrolled UC studies, the majority (96%) of patients with ALT >3X ULN continued treatment with ZEPOSIA, with values returning to <3X ULN within ~2-4 weeks1
  • The overall 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 studies1
  • 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 checked, and ZEPOSIA should be discontinued if significant liver injury is confirmed1

ALT=alanine aminotransferase; LFT=liver function test; UC=ulcerative colitis; ULN=upper limit of normal.

In controlled clinical trials with ZEPOSIA, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 x 109/L), and low lymphocyte counts were maintained during treatment with ZEPOSIA.1

  • The proportion of patients treated with ZEPOSIA with lymphocytes less than 0.2 x 109/L was 2.0% in UC Study 1 and Study 3 (phase 2) and 2.3% in UC Study 21
  • These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with ZEPOSIA1
  • After discontinuing treatment, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days1
    • Approximately 80% to 90% of patients were in the normal range within 3 months1
Pooled Analysis of Controlled and Uncontrolled Trials7
Pooled Analysis of Controlled and Uncontrolled Trials: Mean Absolute Lymphocyte Count by Visit Pooled Analysis of Controlled and Uncontrolled Trials: Mean Absolute Lymphocyte Count by Visit
  • Descriptive pooled analysis of controlled and uncontrolled trials including the 32-week phase 2 TOUCHSTONE trial, the 52-week phase 3 TRUE NORTH trial, and an open-label extension study. Patients completing ≥1 year of the TOUCHSTONE OLE could roll over into the TRUE NORTH OLE7
  • Reductions in ALC were observed at Week 5 (the first post-baseline assessment) and sustained through treatment7
  • 60 patients (5.3%) had ALC <0.2 x 109/L at least once during ZEPOSIA treatment7
    • Most patients (98.3%; n=59) returned to ALC ≥0.2 x 109/L at the time of the analysis; 89.8% returned to ≥0.2 x 109/L while continuing treatment with ZEPOSIA7
  • kPatients may be included in both placebo and ZEPOSIA treatment groups. The total count in the placebo group includes 227 patients who were treated with ZEPOSIA in the induction period and were re-randomized to placebo in the maintenance period of TRUE NORTH.7

ALC=absolute lymphocyte count; OLE=open-label extension; UC=ulcerative colitis.

Low Discontinuation Rates

Discontinuation Rates Due
to TEAEs That Are Comparable
to Placebo

Overall Discontinuation Rates5

UC Study 1—Induction:
6.5% for ZEPOSIA | 11.1% for Placebo

UC Study 2—Maintenance:
20.0% for ZEPOSIA | 45.4% for Placebo

Discontinuation Rates Due
to Treatment-Emergent
Adverse Events (TEAEs)5

Induction

3.3%
ZEPOSIA

vs 3.2%
for placebo

Maintenance

1.3%
ZEPOSIA

vs 2.6%
for placebo

One case of macular edema was reported during the maintenance phase in 1 person with preexisting risk factors at baseline; it resolved after discontinuation of treatment.1,8

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.1

TEAEs=treatment-emergent adverse events; UC=ulcerative colitis.

Infections and Malignancies

Rates of Serious Infection Were Low and Comparable to Placebo in Clinical Trials1

Rates of Serious Infection in
Clinical Trials1
Inductionl
Maintenance
Infection
 ZEPOSIA 0.92 mg
(n=496)		 Placebo
(n=281)		 ZEPOSIA 0.92 mg
(n=230)		 Placebo
(n=227)
Overall Rate of Infection
 9.9% 10.7% 23% 12%
Serious Infections
 0.8% 0.4% 0.9% 1.8%
Herpes Zoster
 0.4% 0% 2.2% 0.4%
  • 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 multiple sclerosis and UC. An increased risk of cutaneous malignancies has been reported with another S1P receptor modulator1
  • lAdditional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3/TOUCHSTONE) included 67 patients who received ZEPOSIA 0.92 mg once daily.1
Rates of Malignancies in Clinical Trials
Induction
Maintenance5
Malignancies
Malig-
nancies
 ZEPOSIA 0.92 mg
(n=429)		 Placebo
(n=216)		 ZEPOSIA 0.92 mg
(n=230)		 Placebo
(n=227)
Basal Cell
Carcinoma
 0% 0% 0.4% 0%
Rectal Adenocar-
cinoma
 0% 0% 0.4% 0%
Adenocar-
cinoma of
the Colon
 0% 0% 0% 0.4%
Breast
Cancer
 0% 0% 0% 0.4%
Infections and Malignancies Across All UC Trials With ZEPOSIA9
ZEPOSIA 0.92 mg
(n=1158)
PY=1922.5m
Placebo
(n=508)
PY=249.2m
 % (n) IR, per 100 PYn % (n) IR, per 100 PYn
Any
Infection
 29.1 (337) 22.81 14.0 (71) 31.43
Any
Serious
Infection
 2.2 (25) 1.32 1.4 (7) 2.84
Malignan-
cies
 1.0 (12) 0.63 0.4 (2) 0.81
  • Safety outcomes were analyzed using descriptive statistics on pooled data from all controlled and uncontrolled UC trials: participants from 32-week TOUCHSTONE trialo (phase 2), 52-week TRUE NORTH trial (phase 3), and the respective open-label extension trials9
  • Median treatment duration in weeks for ZEPOSIA 0.92 mg and placebo was 65.79 and 17.21, respectively9
  • TEAEs identified in the pooled data from all controlled and uncontrolled UC trials were consistent with the controlled UC trials9
  • mTotal patient-years equals the sum of the number of years on study contributed by each patient from time of first dose per treatment group in the pool to last date on study per treatment group in the pool. The algorithm for the last date on study is dependent on patient disposition and whether the patient enrolled into an extension study.9
  • nIncidence rate per 100 patient-years, calculated as number of patients/PY x 100 for specific SOC category or PT subcategory. Analysis was based on the treatment group to which a patient was assigned when the event occurred, including patients who were re-randomized to placebo.9
  • oTOUCHSTONE patients randomized to ZEPOSIA 0.46 mg unapproved dose were only analyzed upon entering TOUCHSTONE OLE and receiving daily ZEPOSIA 0.92 mg.9

IR=incidence rate; OLE=open-label extension; PT=preferred term; PY=patient-years; S1P=sphingosine 1-phosphate; SOC=system organ class; UC=ulcerative colitis.

Open-Label Extension Safety in TRUE NORTH Patients10

Safety From All TRUE NORTH patients in OLE (n=823)

OLE safety in TRUE NORTH patients who had up to 146 weeks of ZEPOSIA exposure

Adverse
Events
All Patients in OLE
(N=823)
% (n)
EAIR per
100
Patient-YearsPYp
TEAEs 81.7 (672) 87.6
Serious TEAEs 18.1 (149) 7.4
TEAEs Leading to Discontinuation
of ZEPOSIA		 6.7 (55) 2.5
Most Frequent TEAEs (Occurring in ≥5% of Patients)
Lymphopeniaq 15.6 (128) 6.4
Anemiaq 10.4 (86) 4.2
Nasopharyngitis 10.3 (85) 4.1
Lymphocyte Count Decreasedq 10.2 (84) 4.0
Alanine Aminotransferase Increasedq 9.0 (74) 3.6
Arthralgia 9.0 (74) 3.6
COVID-19 8.0 (66) 3.0
Headache 7.7 (63) 3.0
Upper Respiratory Tract Infection 6.8 (56) 2.7
Gamma-glutamyl Transferase Increasedq 6.6 (54) 2.6
Hypertension 6.0 (49) 2.3
UC Exacerbation 5.3 (44) 2.0
Cough 5.1 (42) 2.0
Infection (Occuring in ≥3% of Patients) 43.5 (358) 23.6
Serious Infection 5.0 (41) 1.9
Nasopharyngitis 10.3 (85) 4.1
COVID-19 8.0 (66) 3.0
Upper Respiratory Tract Infection 6.8 (56) 2.7
Herpes Zoster 3.5 (29) 1.3
Sinusitis 3.4 (28) 1.3
Bronchitis 3.0 (25) 1.2
Influenza 3.0 (25) 1.2
Malignancyr 1.6 (13) 0.6
  • Two deaths were reported during OLE: 1 sudden death and 1 due to COVID-19. Both deaths were deemed to be unrelated to ZEPOSIA treatment by the investigators.9,10

Data cutoff: January 10, 2022.10

  • pTotal PY was defined as the sum of the numbers of years on study contributed by each patient from time of first dose to last date on study; EAIRs were calculated as numbers of patients/PYx1000.10
  • qLaboratory values were flagged by the central laboratory if they fell outside the standard reference range. The investigator decided whether the laboratory value qualified as an adverse event.9
  • r Malignancies reported include 6 basal cell carcinomas and 3 colorectal neoplasms.10

EAIR=exposure-adjusted incidence rate; NR=not reported; OLE=open-label extension; SAE=serious adverse event; TEAE=treatment-emergent adverse event; UC=ulcerative colitis; ULN=upper limit of normal.

Explore the Efficacy
Data for ZEPOSIA

Understand the Study
 Design

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.
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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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