Tables 5 and 6 include drugs with clinically important drug and vaccine interactions when administered concomitantly with ZEPOSIA and instructions for preventing or managing them.

A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months

New York Heart Association Class III / IV heart failure

Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient's health

Other pre-existing stable cardiac conditions without clearance from a cardiologist

Severe untreated sleep apnea

A resting heart rate less than 55 beats per minute (bpm) at baseline

Reduction in Heart Rate

Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate occurred at Hour 5 on Day 1 (decrease of 1.2 bpm in MS Study 1 and Study 2, and 0.7 bpm in UC Study 1 and Study 3), returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate

[seeDosage and Administration (2.2)].

In MS Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. In UC Study 1 and Study 3, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) treated with ZEPOSIA compared to none in patients who received placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with ZEPOSIA. In UC Study 2, bradycardia was not reported.

Atrioventricular Conduction Delays

Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in MS Study 1 and Study 2 and UC Study 1 and Study 3 with dose titration, Mobitz type 2 second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA.

If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:

With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females)

With arrhythmias requiring treatment with Class Ia or Class 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 with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block

[seeContraindications (4)]

].

Because of the potential additive effects on heart rate, treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties

[see

5.3 Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays

an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA

[seeDosage and Administration (2.2)andClinical Pharmacology (12.2)]

ZEPOSIA was not studied in patients who had:

A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months

New York Heart Association Class III / IV heart failure

Other pre-existing stable cardiac conditions without clearance from a cardiologist

Severe untreated sleep apnea

A resting heart rate less than 55 beats per minute (bpm) at baseline

Reduction in Heart Rate

[seeDosage and Administration (2.2)].

Atrioventricular Conduction Delays

If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:

With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females)

With arrhythmias requiring treatment with Class Ia or Class 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 with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block

[seeContraindications (4)]

]. If treatment initiation with ZEPOSIA is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought.

A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months

New York Heart Association Class III / IV heart failure

Other pre-existing stable cardiac conditions without clearance from a cardiologist

Severe untreated sleep apnea

A resting heart rate less than 55 beats per minute (bpm) at baseline

Reduction in Heart Rate

[seeDosage and Administration (2.2)].

Atrioventricular Conduction Delays

If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:

With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females)

With arrhythmias requiring treatment with Class Ia or Class 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 with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block

[seeContraindications (4)]

]. If treatment initiation with ZEPOSIA is considered in patients on both a heart rate lowering calcium channel blocker and beta blocker, advice from a cardiologist should be sought.

Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies

Clinical Impact:

ZEPOSIA has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which had no pharmacokinetic interaction

[see

12.3 Pharmacokinetics

The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.

Table 7: Exposure Parameters of Ozanimod and its Major Metabolite^a
^aMean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. ^bIn healthy subjects. C_max,ss= maximum observed plasma concentration at steady state, AUC_tau,ss= area under the plasma concentration-time curve during a dosage interval at steady state.
Parameters	Ozanimod	CC112273
C_max,ss	0.244 ng/mL (31.8%)	6.98 ng/mL (42.7%)
AUC_tau,ss	4.46 ng*h/mL (31.8%)	143.77 ng*h/mL (39.2%)
Dose Proportionality	The C_maxand AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg.
Time to Steady State	102 hours (28.2%)^b	45 days (45%)
Accumulation Ratio	2.40 (21.1%)^b	16 (101%)

Absorption

The T_maxof ozanimod is approximately 6 to 8 hours.

Effect of Food

No clinically significant differences in the C_maxand AUC of ozanimod were observed following administration of ZEPOSIA with either a high-fat, high-calorie meal (1000 calories, 50% fat) or a low-fat, low-calorie meal (300 calories, 10% fat) compared to fasted conditions

[seeDosage and Administration (2.2)]

Distribution

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) 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 (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod was 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 RP112509) with similar activity and selectivity for S1P₁and S1P₅. Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075. RP101075 is then metabolized either by NAT-2 to form a minor active metabolite RP101442 or by MAO-B to form CC112273. CC112273 is then metabolized by CYP2C8 to form RP112509 or reduced to form CC1084037. CC1084037 is metabolized by AKR 1C1/1C2 and/or 3β- and 11β-HSD to form CC112273. The interconversion between CC112273 and CC1084037 favors CC112273. 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.

Specific Populations

Geriatric Patients

Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in UC patients over 65 years of age was approximately 3% to 4% greater than patients 45 to 65 years of age and 27% greater than adult patients under 45 years of age. There is no meaningful difference in the pharmacokinetics in elderly patients with UC

[seeUse in Specific Populations (8.5)]

Male and Female Patients

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight.

Racial or Ethnic Groups

In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (C_maxand AUC_tau) were unchanged and CC112273 exposures (C_maxand AUC_tau) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful.

Patients with Renal Impairment

In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUC_last) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8). Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273.

Patients with Hepatic Impairment

In a hepatic impairment study, following an 8-day titration regimen of once daily doses of ZEPOSIA 0.23 mg on days 1 to 4, 0.46 mg on days 5 to 7, and 0.92 mg on day 8, in subjects with mild hepatic impairment (Child-Pugh class A, N=8), mean exposures (AUC_last) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 60%, 98%, and 107%, respectively, compared to healthy controls (N=8). In subjects with moderate hepatic impairment (Child-Pugh class B, N=8) mean exposures (AUC_last) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 17%, 38%, and 61%, respectively, compared to healthy controls.

The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C)

[seeUse in Specific Populations (8.6)]

Smokers

Population PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers, although for smokers this reduction in exposure did not result in meaningful differences in absolute lymphocyte count (ALC) reduction or an apparent impact on clinical efficacy.

Drug Interaction Studies

Clinical/In Vivo Studies

Strong CYP3A and P-gp Inhibitors

No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor).

Strong CYP2C8 Inhibitors

Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively, with no change in the AUC of ozanimod

[seeDrug Interactions (7)].

BCRP Inhibitors

Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

Strong CYP2C8 Inducers

Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively. The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8

[seeDrug Interactions (7)].

Prednisone and Prednisolone

Population pharmacokinetic analyses showed that concomitant administration of prednisone or prednisolone in patients with UC did not alter the apparent clearance of the predominant active metabolite CC112273. The impact of prednisone or prednisolone on the pharmacokinetics of CC1084037 is unknown.

Monoamine Oxidase Inhibitors

No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted

[see

Drug Interactions (7)

Monoamine Oxidase Substrates

Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate.

Oral Contraceptives

No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A.

In vitro, CC112273 and CC1084037 inhibited MAO-B (IC₅₀values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A)

[seeDrug Interactions (7)]

Transporter Systems

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2-K. CC112273 and CC1084037 do not inhibit BCRP at clinically relevant concentrations.

]

Prevention or Management:

Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration

[see

5.1 Infections

Risk of Infections

ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues

[seeClinical Pharmacology (12.2)].

ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature

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.

In MS Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received interferon (IFN) beta-1a (35% vs. 34% and 1% vs. 0.8%, respectively). In UC Study 1 and Study 3, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). In UC Study 2, the overall rate of infections in patients treated with ZEPOSIA was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).

ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections

[seeAdverse Reactions (6.1)].

The proportion of patients treated with ZEPOSIA who experienced lymphocyte counts less than 0.2 × 10⁹/L was 3.3% in MS Study 1 and Study 2. The proportion of patients treated with ZEPOSIA with lymphocyte counts less than 0.2 × 10⁹/L was 2% in UC Study 1 and Study 3 and 2.3% in UC Study 2. These values generally returned to greater than 0.2 × 10⁹/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months

[seeClinical Pharmacology (12.2)].

Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection.

Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Herpes Viral Infection

Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA.

In MS Study 1 and Study 2, 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 who received IFN beta-1a.

In UC Study 1 and Study 3, herpes zoster was reported in 0.4% of patients who received ZEPOSIA and none in patients who received placebo. In UC Study 2, herpes zoster was reported in 2.2% of patients who received ZEPOSIA and 0.4% of patients who received placebo. None were serious or disseminated.

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

(see Vaccinations below).

Cryptococcal Infection

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating Therapies

In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. In UC studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ZEPOSIA

[seeClinical Studies (14.2)].

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

Vaccinations

Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against 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, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur.

No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment.

If live

attenuated

vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live

attenuated

vaccines during and for 3 months after treatment with ZEPOSIA.

]

.

When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects

[see

5.11 Unintended Additive Immunosuppressive Effects from Prior Treatment with 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, when initiating ZEPOSIA.

Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended

[seeDrug Interactions (7)].

]

Alemtuzumab

: Initiating treatment with ZEPOSIA after alemtuzumab is not recommended because of the characteristics and duration of alemtuzumab immune suppressive effects.

Beta interferon or glatiramer acetate

: 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

Clinical Impact:

ZEPOSIA has not been studied in patients taking QT prolonging drugs.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia.

Prevention or Management:

If treatment with ZEPOSIA is considered in patients on Class Ia or Class III anti-arrhythmic drugs, advice from a cardiologist should be sought

[see

5.3 Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays

an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA

[seeDosage and Administration (2.2)andClinical Pharmacology (12.2)]

ZEPOSIA was not studied in patients who had:

Combination Beta Blocker and Calcium Channel Blocker

Clinical Impact

The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker has not been studied. However, there is a potential of additive effects on heart rate.

Prevention or Management:

Treatment with ZEPOSIA should generally not be initiated in patients who are concurrently treated with both a heart rate lowering calcium channel blocker (e.g., verapamil, diltiazem) and beta blocker

[see

5.3 Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays

an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA

[seeDosage and Administration (2.2)andClinical Pharmacology (12.2)]

ZEPOSIA was not studied in patients who had:

Vaccination

Clinical Impact:

During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live

attenuated

vaccines may carry the risk of infection.

Prevention or Management:

Live

attenuated

vaccines should be avoided during ZEPOSIA treatment and for up to 3 months after discontinuation of treatment with ZEPOSIA

[see

5.1 Infections

Risk of Infections

ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues

[seeClinical Pharmacology (12.2)].

ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature

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.

ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections

[seeAdverse Reactions (6.1)].

[seeClinical Pharmacology (12.2)].

Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection.

Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Herpes Viral Infection

Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA.

In MS Study 1 and Study 2, 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 who received IFN beta-1a.

(see Vaccinations below).

Cryptococcal Infection

Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating Therapies

[seeClinical Studies (14.2)].

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment.

If live

attenuated

vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live

attenuated

vaccines during and for 3 months after treatment with ZEPOSIA.

]

Monoamine Oxidase (MAO) Inhibitors

Clinical Impact:

The effect of MAO inhibition on ozanimod and/or its metabolites has not been studied clinically. Potential effects on efficacy or safety with co-administration of MAO inhibitors because of altered exposures of ozanimod and/or its metabolites cannot be ruled out.

Prevention or Management:

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.

Strong CYP2C8 Inhibitors

Clinical Impact:

Co-administration of ZEPOSIA with strong CYP2C8 inhibitors increases the exposure of the active metabolites of ozanimod

[see

12.3 Pharmacokinetics

Table 7: Exposure Parameters of Ozanimod and its Major Metabolite^a
^aMean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. ^bIn healthy subjects. C_max,ss= maximum observed plasma concentration at steady state, AUC_tau,ss= area under the plasma concentration-time curve during a dosage interval at steady state.
Parameters	Ozanimod	CC112273
C_max,ss	0.244 ng/mL (31.8%)	6.98 ng/mL (42.7%)
AUC_tau,ss	4.46 ng*h/mL (31.8%)	143.77 ng*h/mL (39.2%)
Dose Proportionality	The C_maxand AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg.
Time to Steady State	102 hours (28.2%)^b	45 days (45%)
Accumulation Ratio	2.40 (21.1%)^b	16 (101%)

Absorption

The T_maxof ozanimod is approximately 6 to 8 hours.

Effect of Food

[seeDosage and Administration (2.2)]

Distribution

Elimination

Metabolism

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.

Specific Populations

Geriatric Patients

[seeUse in Specific Populations (8.5)]

Male and Female Patients

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight.

Racial or Ethnic Groups

Patients with Renal Impairment

Patients with Hepatic Impairment

The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C)

[seeUse in Specific Populations (8.6)]

Smokers

Drug Interaction Studies

Clinical/In Vivo Studies

Strong CYP3A and P-gp Inhibitors

Strong CYP2C8 Inhibitors

[seeDrug Interactions (7)].

BCRP Inhibitors

Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

Strong CYP2C8 Inducers

[seeDrug Interactions (7)].

Prednisone and Prednisolone

Monoamine Oxidase Inhibitors

No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted

[see

Drug Interactions (7)

Monoamine Oxidase Substrates

Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate.

Oral Contraceptives

No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A.

In vitro, CC112273 and CC1084037 inhibited MAO-B (IC₅₀values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A)

[seeDrug Interactions (7)]

Transporter Systems

]

, which may increase the risk of ZEPOSIA adverse reactions.

Prevention or Management:

Co-administration of ZEPOSIA with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended.

Strong CYP2C8 Inducers

Clinical Impact:

Co-administration of ZEPOSIA with strong CYP2C8 inducers (e.g., rifampin) reduces the exposure of the major active metabolites of ozanimod

[see

12.3 Pharmacokinetics

Table 7: Exposure Parameters of Ozanimod and its Major Metabolite^a
^aMean [coefficient of variation (CV%)] following ozanimod 0.92 mg once daily dose in relapsing MS patients, unless otherwise specified. ^bIn healthy subjects. C_max,ss= maximum observed plasma concentration at steady state, AUC_tau,ss= area under the plasma concentration-time curve during a dosage interval at steady state.
Parameters	Ozanimod	CC112273
C_max,ss	0.244 ng/mL (31.8%)	6.98 ng/mL (42.7%)
AUC_tau,ss	4.46 ng*h/mL (31.8%)	143.77 ng*h/mL (39.2%)
Dose Proportionality	The C_maxand AUC increases proportionally over the ozanimod dose range from 0.46 mg to 0.92 mg.
Time to Steady State	102 hours (28.2%)^b	45 days (45%)
Accumulation Ratio	2.40 (21.1%)^b	16 (101%)

Absorption

The T_maxof ozanimod is approximately 6 to 8 hours.

Effect of Food

[seeDosage and Administration (2.2)]

Distribution

Elimination

Metabolism

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.

Specific Populations

Geriatric Patients

[seeUse in Specific Populations (8.5)]

Male and Female Patients

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight.

Racial or Ethnic Groups

Patients with Renal Impairment

Patients with Hepatic Impairment

The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C)

[seeUse in Specific Populations (8.6)]

Smokers

Drug Interaction Studies

Clinical/In Vivo Studies

Strong CYP3A and P-gp Inhibitors

Strong CYP2C8 Inhibitors

[seeDrug Interactions (7)].

BCRP Inhibitors

Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

Strong CYP2C8 Inducers

[seeDrug Interactions (7)].

Prednisone and Prednisolone

Monoamine Oxidase Inhibitors

No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted

[see

Drug Interactions (7)

Monoamine Oxidase Substrates

Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate.

Oral Contraceptives

No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A.

In vitro, CC112273 and CC1084037 inhibited MAO-B (IC₅₀values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A)

[seeDrug Interactions (7)]

Transporter Systems

]

, which may decrease the efficacy of ZEPOSIA.

Prevention or Management:

Co-administration of ZEPOSIA with strong CYP2C8 inducers should be avoided.

Zeposia | University of Colorado Hemophilia Pharmacy