For your patients with RMS1

For your patients with RMS1
PROTECT IT
BEFORE IT’S GONE

WITH ZEPOSIA, YOU HAVE THE POWER TO
HELP PRESERVE THEIR MOST VALUABLE RESOURCE1
Powerful efficacy
in reducing ARR, GdE lesions,
and new/enlarging T2 lesions vs Avonex®1a
Data on brain volume and cognitive processing
speed (SDMT)
in secondary, exploratory endpoints
and post hoc analysis2,3
Safety comparable to Avonex in overall incidence of
adverse events2,3b
and generally similar safety in the ongoing
long-term extension study; up to 8 years* of exposure4,5c

*From first patient randomized (October 18, 2012) through the DAYBREAK data cutoff (February 2, 2021), mean (range) continuous ozanimod 0.92 mg exposure was 67.4 (6.01-98.8) months.5

aStudy designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.181 vs. 0.350, respectively) and by 38% at 2 years (0.172 vs. 0.276, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years. 9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3

bAdverse reactions: Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year was 59.8% and 75.5%, respectively, and at 2 years was 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of at least 2% in patients treated with ZEPOSIA and at least 1% greater than Avonex, respectively, were as follows: upper respiratory infection, 26% (vs 23%); hepatic transaminase elevation, 10% (vs 5%); orthostatic hypotension, 4% (vs 3%); urinary tract infection, 4% (vs 3%); back pain, 4% (vs 3%); hypertension, 4% (vs 2%); and abdominal pain upper, 2% (vs 1%). Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. Upper respiratory infection includes nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. Hepatic transaminase elevation includes alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminase increased. Hypertension includes hypertension, essential hypertension, and orthostatic hypertension. Severe adverse reactions: The rate of severe adverse reactions at 1 year for ZEPOSIA was 1.6% vs 2.2% for Avonex and the rate at 2 years for ZEPOSIA was 3.5% vs 4.3% for Avonex. Serious adverse reactions: The rate of serious adverse reactions at 1 year for ZEPOSIA was 2.9% vs 2.5% for Avonex and the rate at 2 years for ZEPOSIA was 6.5% vs 6.4% for Avonex.2-3 Please see below for additional SUNBEAM and RADIANCE data.

cStudy design: DAYBREAK is an ongoing open-label extension (OLE) trial that enrolled participants from multiple randomized phase 1 to 3 studies including SUNBEAM and RADIANCE. This data is presented as an interim analysis with a data cutoff of February 2, 2021. Patients evaluated in this analysis included those receiving ZEPOSIA 0.92 mg (n=881) who completed the randomized phase 1 to 3 trials. Primary objective evaluated the long term safety of ZEPOSIA. Secondary objectives included ARR, new/enlarging T2 lesions, and GdE lesions. Endpoints were analyzed descriptively.4

Treatment-emergent adverse events (TEAEs): At the data cutoff (Up to 5 years), the overall incidence of TEAEs for ZEPOSIA in the DAYBREAK OLE trial was 84.7%. The most common TEAEs with an incidence of at least 4% in patients treated with ZEPOSIA, sorted by decreasing incidence, were as follows: nasopharyngitis, 19.3%; headache, 15.6%; upper respiratory tract infection, 10.9%; ALC decreased, 8.9%; lymphopenia, 8.7%; back pain, 8.1%; GGT increased, 5.9%; bronchitis, 5.8%; urinary tract infection, 5.8%; hypertension, 5.4%; respiratory tract infection, 5.4%; viral respiratory tract infection, 5.0%; and depression-related TEAEs, 4.9%. The rate of TEAEs leading to permanent treatment discontinuation was 2.7%. Severe TEAEs: The rate of severe TEAEs was 6.0%. Serious TEAEs: The rate of serious TEAEs was 11.7%.4

RMS=relapsing forms of multiple sclerosis; ARR=annualized relapse rate; GdE=gadolinium enhancing; SDMT=Symbol Digit Modalities Test.

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Up to 8 Years* of Patient Exposure From Phase 1 Trials Through Ongoing Open-Label Extension Study1-4
The Largest Number of Patients With RMS Studied in Pivotal Head-to-Head Trials With an Active Comparator (N=2659)2,3a

Study Endpoints1

PRIMARY

  • Annualized Relapse Rate

KEY SECONDARY

  • GdE Lesions
  • New/Enlarging T2 Lesions
  • Confirmed Disability Progression

Study Endpoints4,6

PRIMARY

  • Long-Term Safety

KEY SECONDARY

  • Annualized Relapse Rate
  • GdE Lesions
  • New/Enlarging T2 Lesions

The patient population evaluated in this analysis included those who received ZEPOSIA 0.92 mg (n=881) and completed the randomized Phase 1, 2, or 3 trials4

Endpoints were analyzed descriptively in the DAYBREAK study5

a2659 patients includes all 3 arms of the study: the 0.92-mg dose of ZEPOSIA, the 0.46-mg dose of ZEPOSIA (not approved for maintenance dose), and the 30-μg dose of Avonex.2,3

bAt data cutoff, mean (range) continuous ozanimod 0.92 mg exposure in DAYBREAK was 47.6 (0.43-62.7) months.7

cDAYBREAK is an ongoing open-label extension (OLE) trial that enrolled participants from multiple randomized phase 1 to 3 studies, including SUNBEAM and RADIANCE, and is presented as an interim analysis with a data cutoff of February 2, 2021.

*From the start of Phase 1 through the DAYBREAK data cutoff, mean (range) continuous ozanimod 0.92 mg exposure was 67.4 (6.01-98.8) months.5

RMS=relapsing multiple sclerosis.

ZEPOSIA Delivered Powerful Efficacy in Reducing ARR vs Avonex in Pivotal Trials1

In the ongoing open-label extension study, patients continuously treated with ZEPOSIA up to 5 yearsa had an ARR of 0.0954,6

A relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3

*DAYBREAK is an ongoing OLE trial that enrolled participants from multiple randomized Phase 1, 2, or 3 studies, including SUNBEAM and RADIANCE, and is
presented as an interim analysis with a data cutoff of February 2, 2021. Endpoints were analyzed descriptively.7

aAt data cutoff, mean (range) continuous ZEPOSIA 0.92 mg exposure in DAYBREAK was 47.6 (0.43-62.7) months.5

bStudy period includes DAYBREAK Day 1 through last treatment date or the data-cutoff date of December 20, 2019.4,6

cAt data-cutoff date of February 2, 20121.4

Proven Superior vs Avonex in Reducing Lesions Across All
Secondary Measures of MRI Activity1
In the 1-year SUNBEAM study, brain MRIs were performed at baseline, Month 6, and Month 12. In the 2-year RADIANCE study, brain MRIs were performed at baseline, Month 12, and Month 24.2,3
9 of 10 Patients Showed No Confirmed 3-Month Disability Progression1

Statistical significance was not reached for the pooled CDP.

EDSS=Expanded Disability Status Scale; NS=nonsignificant.
Statistical significance was not reached for the pooled CDP.
7.6% of patients treated with ZEPOSIA (n=67/880) experienced 3-month confirmed disability progression (CDP), as measured by EDSS, similar to Avonex (7.8%; n=69/889) (P=NS)1,3
CDP was defined as at least a 1-point increase from baseline EDSS confirmed after 3 months and after 6 months. CDP was prospectively evaluated in a pooled analysis from the SUNBEAM and RADIANCE studies.
EDSS=Expanded Disability Status Scale; NS=nonsignificant.
Compelling Efficacy in Brain Volume Loss Data in Pivotal Trials2,3
Volume loss endpoints were not part of the statistical analysis hierarchy.

In the 1-year SUNBEAM study, brain MRIs were performed at baseline, Month 6, and Month 12.2

In the 2-year RADIANCE study, brain MRIs were performed at baseline, Month 12, and Month 24.3

Post Hoc Analysis: SDMT—Cognitive Processing Speed Data
(SUNBEAM and OLE)8,9
Chart of SDMT Scores from SUNBEAM (1 year)

ZEPOSIA: n=427 at Month 12 for SDMT; Avonex: n=426 at Month 12 for SDMT

This endpoint was not part of the statistical analysis hierarchy for SUNBEAM and was analyzed descriptively in DAYBREAK.

The MSFC was a secondary endpoint made up of 3 components: 9-hole peg test (arm/hand function), timed 25-foot walk (ambulation), and SDMT (cognitive function).2,8,10

Chart of SDMT Scores from DAYBREAK (OLE)

ZEPOSIA: n=376 at Month 42 for SDMT

ZEPOSIA: n=376 at Month 42 for SDMT

This endpoint was not part of the statistical analysis hierarchy for SUNBEAM and was analyzed descriptively in DAYBREAK.

The MSFC was a secondary endpoint made up of 3 components: 9-hole peg test (arm/hand function), timed 25-foot walk (ambulation), and SDMT (cognitive function).2,8,10

SDMT is a tool that measures cognitive processing speed.11

aData cutoff for this interim analysis was December 20, 2019.
MSFC=Multiple Sclerosis Functional Composite.

WELL-ESTABLISHED SAFETY PROFILE ACROSS MULTIPLE INDICATIONSa

Multiple Sclerosis: Includes Phase 1, Phase 2, SUNBEAM, RADIANCE, and DAYBREAK (data cutoff: February 2, 2021). Ulcerative Colitis: 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: 2631 patients and 11,938 patient years. Exposure for patients with UC in clinical trials: 1158 patients and 2108 patient years. Exposure for patients in the post-marketing setting across indications: 9738 patients and 6455 patient years.

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.

*From first patient randomized (October 18, 2012) through the DAYBREAK data cutoff (February 2, 2021), mean (range) continuous ozanimod 0.92 mg exposure was 67.4 (6.01-98.8) months.5

ZEPOSIA has been studied across multiple indications in 5 Phase 3 clinical trials, including TRUE NORTH (NCT02435992), a multicenter, randomized, double-blind, placebo-controlled clinical trial; TRUE NORTH OLE (NCT02531126), a Phase 3, multicenter, open-label extension trial for moderate to severe ulcerative colitis; SUNBEAM (NCT02294058); RADIANCE (NCT02047734); and DAYBREAK (NCT02576717).1,5

Safety Comparable to Avonex in Overall Incidence of AEs, and Generally Similar Safety in Ongoing Long-Term Extension Study; Up to 8 Years* of Exposure2,4

IN PIVOTAL TRIALS: Incidence of Adverse Reactions1-3

SUNBEAM
(1 Year)
RADIANCE
(2 Years)
 SUNBEAM (1 Year)RADIANCE(2 Years)
Summary of Adverse EventsAvonex
(n=445)
ZEPOSIA
(n=448)
Avonex
(n=440)
ZEPOSIA
(n=434)
Overall incidence of adverse reactions75.5%59.8%83.0%74.7%
Severe adverse reactions2.2%1.6%4.3%3.5%
Serious adverse reactions2.5%2.9%6.4%6.5%
SUNBEAM
(1 Year)
  
Summary of Adverse EventsAvonex
(n=445)
ZEPOSIA
(n=448)
Overall incidence of adverse reactions75.5%59.8%
Severe adverse reactions2.2%1.6%
Serious adverse reactions2.5%2.9%
RADIANCE
(2 Years)
  
Summary of Adverse EventsAvonex
(n=440)
ZEPOSIA
(n=434)
Overall incidence of adverse reactions83.0%74.7%
Severe adverse reactions4.3%3.5%
Serious adverse reactions6.4%6.5%

Adverse Reactions With an Incidence of at Least 2% in Patients
Treated With ZEPOSIA and at Least 1% Greater Than Avonex1a

SUNBEAM and RADIANCE: POOLED DATA   
Adverse ReactionsAvonex 
(n=885)
ZEPOSIA 
(n=822)
Upper respiratory infectionb23%26%
Hepatic transaminase elevationc
5%10%
Orthostatic hypotension3%4%
Urinary tract infection
3%4%
Back pain3%4%
Hypertensiond2%4%
Abdominal pain upper1%2%
Adverse reactions are sorted by decreasing incidence in patients treated with ZEPOSIA. For adverse reactions pertaining to liver function tests, increases were transient and generally resolved without discontinuation.1

Elevations of 3-fold the ULN or greater occurred in 5.5% of patients taking ZEPOSIA and in 3.1% of patients taking Avonex. The majority (79%) continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2 to 4 weeks.1

IN OLE STUDY: Incidence of Adverse Events4

DAYBREAK (UP TO 5 YEARSe) 
Summary of TEAEs (DAYBREAK OLE primary endpoint)
ZEPOSIA
(n=881)
Any TEAE84.7%
Severe TEAEs6.0%
Serious TEAEs11.7%
TEAEs leading to permanent treatment discontinuation2.7%

TEAEs With Incidence of at Least 4% in Patients Treated With ZEPOSIA 
TEAEs
ZEPOSIA
(n=881)
Nasopharyngitis19.3%
Headache15.6%
Upper respiratory tract infection10.9%
ALC decreased8.9%
Lymphopenia8.7%
Back pain8.1%
GGT increased5.9%
Bronchitis5.8%
Urinary tract infection5.8%
Hypertensionf5.4%
Respiratory tract infection5.4%
Viral respiratory tract infection5.0%
Depression-related TEAEsg4.9%

  • TEAEs are sorted by decreasing incidence in patients treated with ZEPOSIA

aData are not an adequate basis for comparison of rates between ZEPOSIA and the active control.

bIncludes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis.

cIncludes the following terms: alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased.

dIncludes hypertension, essential hypertension, and orthostatic hypertension.

eAt data cutoff, mean (range) continuous ozanimod 0.92 mg exposure in DAYBREAK was 47.6 (0.43-62.7) months.6

fIncludes preferred terms of hypertension, essential hypertension, labile hypertension, systolic hypertension, and hypertensive crisis.

gIncludes preferred terms of depression, depressed mood, and depressive symptoms.

*From first patient randomized (October 18, 2012) through the DAYBREAK data cutoff (February 2, 2021), mean (range) continuous ozanimod 0.92 mg exposure was 67.4 (6.01-98.8) months.5

Demonstrated Tolerability Profile With Low Discontinuation Rates Due to Adverse Events1-4
Rates of Serious Infections and Malignancies Consistent vs Avonex
Rates of Serious Infections and Malignancies Consistent vs Avonex

The rate of serious infections at 1 year for ZEPOSIA was 1.1% vs 0.7% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.9% for Avonex. The rate of malignancies at 1 year for ZEPOSIA was 0.2% vs 0% for Avonex and the rate at 2 years for ZEPOSIA was 0.9% vs 0.5% for Avonex.2,3

  • Overall Infections

    In SUNBEAM and RADIANCE, the overall rate of infections with ZEPOSIA (35%) was similar to Avonex (34%).1 ZEPOSIA causes a reduction in peripheral blood lymphocyte count and may increase the risk of infection.1

Controlled Lymphocyte Reductions
Controlled Lymphocyte Reductions

ALC was consistently maintained near the lower limit of normal across both pivotal trials, and the mean ALC for both SUNBEAM and RADIANCE was ≈0.8 × 109/L.2,3,14

Herpetic Infections: In active-controlled MS trials, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients taking Avonex.1

One Capsule, Once a Day, From the Start With Minimal Pre-Initiation Requirements1
ZEPOSIA May Be Taken With or Without Food1

An up-titration schedule should be used to reach the maintenance dose, as a transient decrease in heart rate and AV conduction delays may occur1

Full Prescribing Information for ZEPOSIA Has

  • No genetic testing
  • No ophthalmic testing for most patients1,15a
  • No first-dose observation required

Minimal Pre-Initiation Requirements

Before Initiating Treatment With ZEPOSIA...

  • Obtain a CBC (within 6 months or after discontinuation of prior MS therapy), including lymphocyte count
  • Obtain an ECG to determine whether preexisting conduction abnormalities are present
  • Obtain transaminase and bilirubin levels (within 6 months)
  • Evaluate current and prior medications1
  • Patients without a confirmed history of VZV or without documented VZV vaccination should be tested for antibodies. If VZV or other live attenuated immunizations are required, administer at least 1 month prior to initiation1

aDiabetes mellitus and uveitis increase the risk of macular edema; patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation.
A prompt ophthalmic evaluation is recommended if there is any change in vision while taking ZEPOSIA.1

AV=atrioventricular; CBC=complete blood count; ECG=electrocardiogram; VZV=varicella-zoster virus.

NATIONWIDE, 91% OF PATIENTS WITH COMMERCIAL COVERAGE HAVE ACCESS TO ZEPOSIAa

aBased on Weekly Field Intelligence Input and MMIT, as of November 2021.

Interested in ZEPOSIA coverage in your area? Use the formulary lookup tool.

References

  1. ZEPOSIA. Prescribing Information, Celgene Corporation, a Bristol Myers Squibb company.
  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. Data on file. BMS-REF-OZA-0004. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  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.
  7. Data on file. BMS-REF-OZA-0005. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
  8. DeLuca J, Schippling S, Montalban X, et al. Effect of ozanimod on Symbol Digit Modalities Test performance in relapsing MS. Mult Scler Relat Disord. 2021;48:102673. doi:10.1016/j.msard.2020.102673
  9. Deluca J, Cohen JA, Cree BAC, et al. Effects of ozanimod on information processing speed: findings from the phase 3 SUNBEAM and DAYBREAK extension trials. Poster presented on: American Academy of Neurology (2020) Virtual Platform. Poster 1-017.
  10. Drake AS, Weinstock-Guttman B, Morrow SA, Hojnacki D, Munschauer FE, Benedict RHB. Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test. Mult Scler. 2010;16(2):228-237. doi:10.1177/1352458509354552
  11. Benedict RHB, DeLuca J, Phillips G, et al. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23(5):721-733. doi:10.1177/1352458517690821
  12. Data on file. BMS-REF-OZA-0016. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  13. Data on file. BMS-REF-OZA-0017. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
  14. Lymphocytopenia. National Heart, Lung, and Blood Institute (NHLBI). Accessed August 23, 2021. www.nhlbi.nih.gov/health-topics/lymphocytopenia
  15. Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat Rev Neurol. 2017;13(6):375-382. doi:10.1038/nrneurol.2017.33

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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This information is intended for U.S. Healthcare Professionals.