ZEPOSIA SAFETY PROFILE1

ZEPOSIA Offers Patients a Demonstrated Safety Profile1-4a

Studied in 4 clinical trials with more than 1370 ZEPOSIA-treated patients across multiple indications.1 Over 20,000 patient-years of total exposure in clinical trials (Ph 1-3 MS, Ph 2-3 UC) and post-marketing setting.2-4

ZEPOSIA 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

MS: 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-years.2-4

Adverse Reactions in Ulcerative Colitis (UC) Clinical Trials1

Adverse Reactions With an Incidence of at Least 2% in ZEPOSIA-Treated Patients and at Least 1% Greater Than Placebo in Patients With Ulcerative Colitis (Pooled UC Study 1 and Study 3)1

Induction (UC Study 1 and Study 3a)
Adverse ReactionZEPOSIA 0.92 mg
(n=496)d,e		Placebo
(n=281)e
Upper Respiratory Infectionb5%4%
Liver Test Increasedc5%0%
Headache4%3%
Pyrexia3%2%
Nausea3%2%
Arthralgia3%1%

aAdditional data from the induction period of a randomized, double-blind, placebo-controlled study [TOUCHSTONE, or, UC Study 3] included 67 patients who received ZEPOSIA 0.92 mg once daily.1

bIncludes 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

cIncludes the following terms: gamma-glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hyperbilirubinemia, liver function test increased, blood alkaline phosphatase increased, and transaminases increased.1

dZEPOSIA was initiated with a 7-day titration.1

ePercentages were calculated as the sum of each individual study percentage multiplied by its Cochran-Mantel-Haenszel weight.1

MS=multiple sclerosis; Ph=phase.

Adverse Events from TRUE NORTH Induction Period5

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)1

Maintenance (UC Study 2)
Adverse ReactionZEPOSIA 0.92 mg
(n=230)		Placebo
(n=227)
Liver Test Increaseda11%2%
Headache5%<1%

aIncludes 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 Maintenance Period5

Transaminase Elevation/LFT Elevation Observed in Clinical Trials1

UC Study 1 and Study 2
Induction
Adverse ReactionZEPOSIA 0.92 mg
(n=429)		Placebo
(n=216)
ALT ≥3x ULN2.6%0.5%
ALT ≥5x ULN0.9%0.5%
Maintenance
Adverse ReactionZEPOSIA 0.92 mg
(n=230)		Placebo
(n=227)
ALT ≥3x ULN2.3%0%
ALT ≥5x ULN0.9%0%
UC Study 1 and Study 2
InductionMaintenance
Adverse ReactionZEPOSIA 0.92 mg
(n=429)		Placebo
(n=216)		ZEPOSIA 0.92 mg
(n=230)		Placebo
(n=227)
ALT ≥3x ULN2.6%0.5%2.3%0%
ALT ≥5x ULN0.9%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; ULN=upper limit of normal.

Absolute Lymphocyte Count (ALC) profile1,6

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 Trials6

ZEPOSIA for ulcerative colitis vs placebo - alsolute lymphocyte count chart

  • 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 open-label extension study (OLE) could roll over into the TRUE NORTH OLE6
  • Reductions in ALC were observed at Week 5 (the first post-baseline assessment) and sustained through treatment6
  • 60 patients (5.3%) had ALC <0.2 x 109/L at least once during ZEPOSIA treatment6
    • 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 ZEPOSIA6

aPatients 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.6

ZEPOSIA: Low 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 one person with preexisting risk factors at baseline; it resolved after discontinuation of treatment1,7a
  • 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 studies1

aCase was associated with existing risk factors at baseline, and macular edema was resolved on discontinuation of ZEPOSIA.1

UC=ulcerative colitis.

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

Rates of Serious Infection in Clinical Trials1

 InductionaMaintenance
InfectionZEPOSIA 0.92 mg
(n=496)		Placebo
(n=281)		ZEPOSIA 0.92 mg
(n=230)		Placebo
(n=227)
Overall Rate of Infection9.9%10.7%23%12%
Serious Infections0.8%0.4%0.9%1.8%
Herpes Zoster0.4%0%2.2%0.4%
Inductiona
InfectionZEPOSIA 0.92 mg (n=496)Placebo (n=281)
Overall Rate of Infection9.9%10.7%
Serious Infections0.8%0.4%
Herpes Zoster0.4%0%
Maintenance
InfectionZEPOSIA 0.92 mg (n=230)Placebo (n=227)
Overall Rate of Infection23%12%
Serious Infections0.9%1.8%
Herpes Zoster2.2%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

aAdditional 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

S1P=sphingosine 1-phosphate; UC=ulcerative colitis.

 

Infections and Malignancies Across All UC Trials With ZEPOSIA8

 ZEPOSIA 0.92 mg
(n=1158)
PY=1922.5a		Placebo
(n=508)
PY=249.2a
% (n)IR, per 100 PYb% (n)IR, per 100 PYb
Any Infection29.1 (337)22.8114.0 (71)31.43
Any Serious Infection2.2 (25)1.321.4 (7)2.84
Malignancies1.0 (12)0.630.4 (2)0.81
ZEPOSIA 0.92 mg
(n=1158)
PY=1922.5a
% (n)IR, per 100 PYb
Any Infection29.1 (337)22.81
Any Serious Infection2.2 (25)1.32
Malignancies1.0 (12)0.63
Placebo
(n=508)
PY=249.2a
% (n)IR, per 100 PYb
Any Infection14.0 (71)31.43
Any Serious Infection1.4 (7)2.84
Malignancies0.4 (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 trialc (phase 2), 52-week TRUE NORTH trial (phase 3), and the respective open-label extension trials8
  • Median treatment duration in weeks for ZEPOSIA 0.92 mg and placebo was 65.79 and 17.21, respectively8
  • TEAEs identified in the pooled data from all controlled and uncontrolled UC trials were consistent with the controlled UC trials8

aTotal 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.8

bIncidence 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.8

cTOUCHSTONE patients randomized to ZEPOSIA 0.46 mg unapproved dose were only analyzed upon entering TOUCHSTONE OLE and receiving daily ZEPOSIA 0.92 mg.8

IR=incidence rate; OLE=open-label extension; PT=preferred term; PY=patient years; SOC=system organ class; TEAE=treatment-emergent adverse event.

OLE Safety in TRUE NORTH Patients9

This safety analysis includes patients (N=823) with UC from the TRUE NORTH parent study who entered the TRUE NORTH OLE

Data cutoff: September 30, 2020.

aAll AEs and SAEs listed were treatment emergent.9

bThe most frequent events were defined as those that occurred in at least 5% of the patients who received ozanimod in either the OLE study population or the subgroup who entered the study in clinical response.9

cLaboratory 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

dInfectious TEAEs that occurred in at least 3% of the patients who received ozanimod in either the OLE study population or the subgroup who entered the study in clinical response are listed.9

ePatients were included if their laboratory values met these cut-offs at any point in the study. The denominator shows the number of evaluable patients.9

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.

Learn about the mechanism of action for ZEPOSIA, the first and only sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active UC in adults1

MECHANISM OF ACTION
References: 1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company. 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 ECCO 2022; 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(14):1280-1291. 6. 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. 7. 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. 8. D’Haens G, Colombel JF, Lichtenstein GR, et al. Safety of ozanimod in patients with moderately to severely active ulcerative colitis over time: pooled analysis from phase 2, phase 3, and open-label extension trials. Oral presentation at: DDW 2021 Virtual Digestive Disease Week; May 21–23, 2021. 9. Data on file. BMS-REF-OZA-0020. Princeton, NJ: Bristol-Myers Squibb Company; 2022.

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.

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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Indications:

Moderately to severely active ulcerative colitis (UC) in adults
ULCERATIVE COLITIS
Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
MULTIPLE SCLEROSIS