FDA Approves ZEPOSIA (Ozanimod) for the Treatment of Relapsing Forms of Multiple Sclerosis, to Include Clinically Isolated Syndrome, Relapsing-remitting Disease, and Active Secondary Progressive Disease, in Adults


On March 25, 2020, the U.S. Food and Drug Administration (FDA) approved ZEPOSIA (ozanimod) 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. The approved recommended dosage of ZEPOSIA includes a 7-day titration/treatment initiation as described below. After initial titration, the recommended maintenance dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8 and maintenance regimen.

The approved recommended ZEPOSIA dose titration regimen is as follows:

  • Days 1 to 4: 0.23 mg once daily
  • Days 5 to 7: 0.46 mg once daily
  • Day 8 and after: 0.92 once daily

Certain assessments are required prior to initiating treatment with ZEPOSIA. These assessments include obtaining complete blood count, cardiac evaluation, liver function tests, and ophthalmic assessment. Assess current or prior medications and consider possible unintended additive immunosuppressive effects, determine if patients are taking drugs that could slow heart rate or atrioventricular conduction, and test patients for antibodies to varicella zoster virus. Concomitant use of a monoamine oxidase inhibitor is contraindicated.

Additional information regarding dosage and administration, including assessments prior to the first dose of ZEPOSIA, as well as important warnings and precautions about increase risk of infections, bradyarrhythmia and atrioventricular conduction delays, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, posterior reversible encephalopathy syndrome, unintended additive immunosuppressive effects from prior treatment with immunosuppressive or immune-modulating drugs, severe exacerbation of disease, and immune system effects can be found in the full prescribing information linked below.

 

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P receptors 1 and 5.

     

  • General PK: Following ozanimod 0.92 mg once daily dose in relapsing MS patients, the steady state ozanimod and its CC112273 active metabolite mean (CV%) Cmax was 0.244 ng/mL (31.8%) and 6.98 ng/mL (42.7%), respectively. The steady state ozanimod and its major active metabolite CC112273 mean (CV%) AUC was 4.46 ng*h/mL (31.8%) and 143.77 ng*h/mL (39.2%), respectively. The Cmax and AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg. Following administration of ozanimod in healthy subjects, the time to steady state of ozanimod was 102 hours (28.2%) and accumulation ratio of ozanimod was 2.40 (21.1%). The time to steady state of CC112273 was 45 days (45%) and the accumulation ratio was 16 (101%).

     

  • Absorption: The Tmax of ozanimod is approximately 6 to 8 hours. No clinically significant differences in the Cmax and AUC of ozanimod were observed following administration of ZEPOSIA with a high-fat, high-calorie meal.

     

  • Distribution: The mean (CV%) apparent volume of distribution of ozanimod is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273, and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively.

     

  • Elimination: The mean (CV%) plasma half-life of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life of CC112273 and its direct interconverting metabolite CC1084037 is approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod is approximately 192 L/h (37%).

     

  • Metabolism: Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP101509) with similar activity and selectivity for S1P1 and S1P5. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans.

     

  • Excretion: Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37% in feces, primarily composed of inactive metabolites.

     

  • PD: 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. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months. ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing. An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions. Dose-dependent reductions in FEV1 and FVC were observed in patients treated with ZEPOSIA.

 

Drug Interactions

  • Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies: Use caution during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects. ZEPOSIA can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.

     

  • Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That may Decrease Heart Rate: If concomitant use of with Class Ia (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs is considered, seek advice from a cardiologist as these anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties because of the potential additive effects on heart rate. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, seek advice from a cardiologist.

     

  • Vaccinations: Vaccinations may be less effective during and for up to three months after discontinuation of treatment with ZEPOSIA. Avoid the use of live attenuated vaccines during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA due to the risk of infection.

     

  • Strong CYP2C8 Inhibitors: Co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod, which may increase the risk of ZEPOSIA adverse reactions.

     

  • Breast Cancer Resistance Protein (BCRP) Inhibitors: Co-administration of ZEPOSIA with inhibitors of BCRP (e.g., cyclosporine, eltrombopag) is not recommended. Co-administration of ZEPOSIA with BCRP inhibitors increases the exposure of the active metabolites of ozanimod, which may increase the risk of ZEPOSIA adverse reactions.

     

  • Strong CYP2C8 Inducers: Avoid co-administration of ZEPOSIA with strong CYP2C8 inducers. Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod, which may decrease the efficacy of ZEPOSIA.

     

  • Monoamine Oxidase (MAO) Inhibitors: Co-administration of ZEPOSIA with MAO inhibitors (e.g., selegiline, phenelzine, linezolid) is contraindicated. At least 14 days should elapse between discontinuation of ZEPOSIA and initiation of treatment with MAO inhibitors. The potential for a clinical interaction with MAO inhibitors has not been studied; however, the increased risk of nonselective MAO inhibition may lead to a hypertensive crisis. Co-administration of ZEPOSIA with MAO-B inhibitors may decrease exposure of the active metabolites of ozanimod. In addition, metabolites of ozanimod may inhibit MAO.

     

  • Adrenergic and Serotonergic Drugs: Co-administration of ZEPOSIA with drugs or over-the-counter medications that can increase norepinephrine or serotonin [e.g., opioid drugs, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), tricyclics, tyramine] is not recommended. Monitor patients for hypertension with concomitant use. Because an active metabolite of ozanimod inhibits MAO-B in vitro, there is a potential for serious adverse reactions, including hypertensive crisis. Serious, sometimes fatal reactions have been precipitated with concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, or tramadol) and MAOIs, including selective MAO-B inhibitors. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to opioids, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration. Although a small number of patients treated with ZEPOSIA were concomitantly exposed to serotonergic medications, this exposure was not adequate to rule out the possibility of an adverse reaction from co-administration. Concomitant use of ZEPOSIA with pseudoephedrine did not potentiate the effects on blood pressure. However, hypertensive crisis has occurred with administration of ZEPOSIA alone and hypertensive crisis has been reported with co-administration of other selective and nonselective MAO inhibitors (e.g., rasagiline) with sympathomimetic medications.

     

  • Tyramine: Advise patients to avoid foods containing a large amount of tyramine while taking recommended doses of ZEPOSIA. MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (tyramine reaction).

 

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex, race/ethnicity (Japanese or Caucasian), or renal impairment. The effect of age (65 years of age and older) or smoking on the pharmacokinetics of ozanimod is unknown.

 

  • Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of the ozanimod major active metabolites is unknown. Use of ZEPOSIA in patients with hepatic impairment is not recommended.

     

  • Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.

 

Efficacy and Safety

Efficacy of ZEPOSIA was demonstrated in two randomized, double-blind, double-dummy, parallel-group, active comparator-controlled clinical trials of similar design, in patients with relapsing forms of MS.  The primary endpoint was the annualized relapse rate over the treatment period and 24 months. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 4%) were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

Full prescribing information is available at https://go.usa.gov/xvYzV.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.