Safety Profile of ZEPOSIA


ZEPOSIA—A SAFETY PROFILE COMPARABLE TO AVONEX IN OVERALL INCIDENCE OF ADVERSE REACTIONS

Overall Incidence of Adverse Reactions Was Similar Across 2 Pivotal Head-to-Head Trials (N=2659)1,2

Overall Incidence of Adverse Reactions

  • SUNBEAM: Avonex 75.5% | ZEPOSIA 59.8%
  • RADIANCE: Avonex 83.0% | ZEPOSIA 74.7%

Adverse Reactions With an Incidence of at Least 2% in Patients Treated With ZEPOSIA and at Least 1% Greater Than Avonex3a

SUNBEAM AND RADIANCE: POOLED DATA  
Adverse ReactionsAvonex
n=885
ZEPOSIA
n=882
Upper respiratory infectionb23%26%
Hepatic transaminase elevationc5%10%
Orthostatic hypotension3%4%
Urinary tract infection3%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.4

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.3

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.

ULN=upper limit of normal.

Consistently Low Discontinuation Rates VS Avonex

Discontinuation Rates Were ≤3% in 2 Large-Scale, Double-Blind Clinical Studies1,2

Overall Discontinuation Rates3

  • SUNBEAM: Avonex 8% | ZEPOSIA 6%
  • RADIANCE: Avonex 15% | ZEPOSIA 10%

Discontinuation Rates Due to Adverse Reactions

SUNBEAM (1 Year)
3.6%
AVONEX
VS
2.9%
ZEPOSIA
RADIANCE (2 Years)
4.1%
AVONEX
VS
3.0%
ZEPOSIA

Adverse Reactions That Led to Discontinuation4a

SUNBEAM  
Adverse ReactionsAvonex
n=445 (%)
ZEPOSIA
n=448 (%)
ALT increased0 (0)2 (0.4)
Back pain1 (0.2)2 (0.4)
Headache0 (0)2 (0.4)
RADIANCE  
Adverse ReactionsAvonex
n=440 (%)
ZEPOSIA
n=434 (%)
ALT increased3 (0.7)2 (0.5)
Urticaria0 (0.0)2 (0.5)

aIncludes all adverse reactions ≥0.4% that led to discontinuation of ZEPOSIA.

ALT=alanine aminotransferase.

Consistent Rates of Serious Infections and Malignancies vs Avonex Through 2 Years

Results Were Consistent Across 2 Separate, Pivotal Head-to-Head Trials With More Than 2600 Patients1,2

Serious Infection Rates1,2

Chart showing serious infection rate in 1-year and 2-year clinical studies for Zeposia® vs Avonex
SUNBEAM (1 Year)
0.7%
AVONEX

VS
1.1%
ZEPOSIA

RADIANCE (2 Years)
0.9%
AVONEX

VS
0.9%
ZEPOSIA

Malignancy Rates at 1 and 2 Years1,2

Chart showing malignancy rates in 1-year and 2-year clinical studies for Zeposia® vs Avonex
SUNBEAM (1 Year)
0.0%
AVONEX

VS
0.2%
ZEPOSIA

RADIANCE (2 Years)
0.5%
AVONEX

VS
0.9%
ZEPOSIA

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 Avonex3

  • Overall Infections
    In SUNBEAM and RADIANCE, the overall rate of infections with ZEPOSIA (35%) was similar to Avonex (34%)3
    • ZEPOSIA causes a reduction in peripheral blood lymphocyte count and may increase the risk of infection
  • Progressive Multifocal Leukoencephalopathy (PML)
    • JCV infection resulting in PML has been observed in patients treated with other MS therapies and has been associated with some risk factors (eg, polytherapy with immunosuppressants, patients who are severely immunocompromised)3

JCV=John Cunningham virus.

ZEPOSIA CONSISTENTLY MAINTAINED ALC NEAR THE LLN

ALCs Were Consistent Across Large-Scale 1-Year and 2-Year Pivotal Trials4

Charts showing mean ALC values for Zeposia® and Avonex in 1-year and 2-year Zeposia® clinical studies

ALC=absolute lymphocyte count; BL=baseline; LLN=lower limit of normal.

Lymphocyte Numbers Can Be Restored to Normal Values by Discontinuing Therapy1-4
  • ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to 45% of baseline values because of reversible retention of lymphocytes in lymphoid tissues. ZEPOSIA may therefore increase the susceptibility to infections3
  • Mean ALC was 0.75 × 109 cells/L for both SUNBEAM and RADIANCE (at 1 year and 2 years, respectively)
  • During clinical trials, a combined total of 29 patients treated with ZEPOSIA 0.92 mg from SUNBEAM and RADIANCE had an ALC of <200 cells/μL. If ALC was <200 cells/μL after a repeated test, ZEPOSIA was temporarily discontinued, then patients were monitored weekly until ALC recovered to >500 cells/μL and restarted on therapy
  • Upon discontinuation of ZEPOSIA, median time to recovery of ALC to within a normal range was 30 days, with approximately 90% of patients recovering within 3 months

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References: 1. Comi G, Kappos L, Selmaj KW, et al; for the 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. 2. Cohen JA, Comi G, Selmaj KW, et al; for the 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. 3. ZEPOSIA® (ozanimod) [package insert]. Summit, NJ: Bristol Myers Squibb; 2020. 4. Data on file, Bristol Myers Squibb.

IMPORTANT SAFETY INFORMATION

Indication

ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

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 or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, 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 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.
  • Progressive Multifocal Leukoencephalopathy (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. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS 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
  • In 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. 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

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 sinoatrial 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

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 Disability After Stopping ZEPOSIA: 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 (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

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.