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Ozanimod: Drug information

Ozanimod: Drug information
(For additional information see "Ozanimod: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Zeposia;
  • Zeposia 7-Day Starter Pack;
  • Zeposia Starter Kit
Brand Names: Canada
  • Zeposia;
  • Zeposia Initiation Pack
Pharmacologic Category
  • Sphingosine 1-Phosphate (S1P) Receptor Modulator
Dosing: Adult

Note: If live attenuated vaccine immunizations are required prior to administration, initiate ozanimod therapy at least 1 month following immunizations. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).

Multiple sclerosis, relapsing: Oral: Initial: 0.23 mg once daily on days 1 through 4; then 0.46 mg once daily on days 5 through 7; maintenance dose: 0.92 mg once daily starting on day 8.

Ulcerative colitis: Oral: Initial: 0.23 mg once daily on days 1 through 4; then 0.46 mg once daily on days 5 through 7; maintenance dose: 0.92 mg once daily starting on day 8.

Missed doses: If a dose is missed during the first 2 weeks of treatment, reinitiate the titration regimen with 0.23 mg once daily. If a dose is missed after the first 2 weeks of treatment, continue with treatment as planned.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to initiation of treatment:

Mild to severe impairment: Use not recommended.

Hepatic impairment during treatment:

Significant liver injury: Discontinue ozanimod if significant liver injury is confirmed.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Zeposia: 0.92 mg

Capsule Therapy Pack, Oral, as hydrochloride:

Zeposia 7-Day Starter Pack: Ozanimod 0.23 mg (4 capsules) and ozanimod 0.46 mg (3 capsules) (7 ea)

Zeposia Starter Kit: Ozanimod 0.23 mg (4 capsules), ozanimod 0.46 mg (3 capsules), and ozanimod 0.92 mg (30 capsules) (37 ea)

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Zeposia: 0.92 mg

Capsule Therapy Pack, Oral, as hydrochloride:

Zeposia Initiation Pack: Ozanimod 0.23 mg (4 capsules) and ozanimod 0.46 mg (3 capsules) (7 ea)

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Zeposia: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209899s003lbl.pdf#page=25

Administration: Adult

Oral: Swallow capsules whole, with or without food.

Use: Labeled Indications

Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults.

Medication Safety Issues
Sound-alike/look-alike issues:

Ozanimod may be confused with fingolimod.

Adverse Reactions (Significant): Considerations
Cardiovascular effects

Transient, dose-dependent decreases in heart rate (≤1.2 bpm) and bradycardia have been observed following the first dose of ozanimod and with dose titration. Transient atrioventricular (AV) conduction delays may also occur with initiation; concern stems from AV block (first and second degree) observed rarely in studies with higher than recommended doses and without appropriate dose titration (Ref). Orthostatic hypotension is frequently observed upon initiation and dose titration, but in a cardiac safety trial, these events were described as transient and asymptomatic (Ref). During therapy, hypertension frequently develops. Hypertensive crisis has also been reported.

Mechanism: Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator; S1P receptors play a role in regulating vascular tone, heart rate, and cardiac repolarization (Ref).

Bradycardia: Dose-related; S1P modulators have been associated with negative chronotropic effects; however, these effects may attenuate over time secondary to S1P desensitization on atrial myocytes (Ref).

Onset:

Bradycardia/decreased heart rate: Rapid; ~5 hours after the first dose with a return to baseline at approximately hour 6. With continued up-titration, additional transient decreases in heart rate occur, with maximum heart rate effects seen by day 8.

Hypertension: Delayed; increased BP occurred ~3 months after initiation of therapy and persisted throughout the duration of therapy.

Orthostatic hypotension: Rapid; ~3 to 6 hours after initial dose and first up-titration of dose (Ref).

Risk factors:

Bradycardia/atrioventricular conduction delays:

• Preexisting conditions that may increase the risk for bradycardia or AV block. Of note, contraindications related to these risk factors exist.

Hypertension:

• Concomitant ingestion of tyramine-containing foods (>150 mg)

Hepatotoxicity

Increased serum transaminases commonly occur with ozanimod therapy, primarily as increased serum alanine aminotransferase (ALT), including increases up to 5 x ULN. The majority of increased serum transaminases were transient and did not require therapy discontinuation (Ref). For most patients, ALT returned to <3 times ULN within 2 to 4 weeks while remaining on ozanimod.

Onset: Delayed; median time to development of ALT ≥3 times ULN was 6 months.

Risk factors:

• History of significant liver disease (potential risk factor)

Lymphocytopenia/Infection

Reversible lymphocytopenia occurs during ozanimod therapy. Infection is commonly observed with use, typically upper respiratory tract infection and less commonly urinary tract infection; viral infections (eg, herpes zoster infection) have also been observed. Infections may be serious, life-threatening, and potentially fatal. Fatal cryptococcal meningitis, disseminated cryptococcal infection, and progressive multifocal leukoencephalopathy cases have been reported with other sphingosine 1-phosphate (S1P) receptor modulators.

Mechanism: Dose-related; as an antagonist of the sphingosine 1-phosphate 1 receptor (S1P1R), ozanimod results in the blocking of S1P1R receptors on lymphocytes, a necessary signal for their release from peripheral lymphoid organs, causing a reduction in number of circulating lymphocytes. Sequestered lymphocytes remain in peripheral lymphoid organs preventing their movement to sites of inflammation where they would typically contribute to immune-mediated pathology (Ref).

Onset: Rapid; a single oral dose reduced circulating lymphocytes in a rapidly reversible manner (Ref).

Macular edema

Macular edema has occurred with ozanimod therapy. Though the incidence is rare, macular edema is also associated with other sphingosine 1-phosphate (S1P) receptor modulators.

Risk factors:

• Diabetes

• Prior history of uveitis

Respiratory effects

Decrease in forced vital capacity (FVC) and reduced forced expiratory volume over 1 second (FEV1) have occurred with ozanimod therapy. There is insufficient evidence to determine whether changes in FEV1 or FVC are reversible with drug discontinuation.

Mechanism: Dose-related; mechanism is unknown.

Onset: Varied; may occur as early as 3 months after therapy initiation.

Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) has been observed rarely in patients taking sphingosine 1-phosphate receptor modulators, including ozanimod. Symptoms are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Permanent neurological sequelae may result from delayed diagnosis and treatment.

Onset: Delayed; in the single case report of RPLS with ozanimod, onset was 10 months after starting therapy (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Infection: Infection (35%; serious infection: 1%) (table 1)

Ozanimod: Adverse Reaction: Infection

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

Comments

35%

34%

882

885

N/A

1%

0.8%

882

885

Serious infection

Respiratory: Upper respiratory tract infection (26%) (table 2)

Ozanimod: Adverse Reaction: Upper Respiratory Tract Infection

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

26%

23%

882

885

1% to 10%:

Cardiovascular: Hypertension (4%) (table 3), orthostatic hypotension (4%) (table 4)

Ozanimod: Adverse Reaction: Hypertension

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

4%

2%

882

885

Ozanimod: Adverse Reaction: Orthostatic Hypotension

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Comparator Dose

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

4%

3%

30 mcg once weekly

882

885

Gastrointestinal: Upper abdominal pain (2%)

Genitourinary: Urinary tract infection (4%) (table 5)

Ozanimod: Adverse Reaction: Urinary Tract Infection

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

4%

3%

882

885

Hematologic & oncologic: Lymphocytopenia (3%)

Hepatic: Increased serum alanine aminotransferase (3 x ULN: 6%; 5 x ULN: 2%) (table 6), increased serum transaminases (10%) (table 7)

Ozanimod: Adverse Reaction: Increased Serum Alanine Aminotransferase (ALT)

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

3 x ULN: 6%

3%

882

885

5 x ULN: 2%

1%

882

885

Ozanimod: Adverse Reaction: Increased Serum Transaminases

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

10%

5%

882

885

Neuromuscular & skeletal: Back pain (4%)

<1%:

Cardiovascular: Bradycardia (table 8), hypertensive crisis

Ozanimod: Adverse Reaction: Bradycardia

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

Comments

0.8%

0.7%

882

885

After day 1 of treatment

0.6%

0%

882

885

Reported on the day of treatment

Infection: Herpes zoster infection (table 9)

Ozanimod: Adverse Reaction: Herpes Zoster Infection

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

0.6%

0.2%

882

885

Ophthalmic: Macular edema (increased risk in patients with a history of uveitis or diabetes mellitus) (table 10)

Ozanimod: Adverse Reaction: Macular Edema

Drug (Ozanimod)

Comparator (Interferon Beta-1a)

Number of Patients (Ozanimod)

Number of Patients (Interferon Beta-1a)

0.3%

0.3%

882

885

Nervous system: Reversible posterior leukoencephalopathy syndrome

Frequency not defined:

Hematologic & oncologic: Basal cell carcinoma of skin, malignant melanoma, malignant neoplasm (including seminoma), malignant neoplasm of breast

Hypersensitivity: Hypersensitivity reaction

Respiratory: Decrease in forced vital capacity, reduced forced expiratory volume

Contraindications

Myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or class III or IV heart failure in the last 6 months; Mobitz type II second- or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block, unless the patient has a functioning pacemaker; severe untreated sleep apnea; concomitant use of a monoamine oxidase inhibitor.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ozanimod or any component of the formulation; patients at increased risk of opportunistic infections, including those who are immunocompromised due to treatment (eg, antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation, bone marrow transplantation) or disease (eg, immunodeficiency syndrome); severe active infections, including active chronic bacterial, fungal, or viral infections (eg, hepatitis, tuberculosis); known active malignancy (excluding basal cell carcinoma); pregnancy and women in childbearing years not using effective contraception.

Warnings/Precautions

Concerns related to adverse effects:

• Infections: Delay initiation of ozanimod in patients with active infections.

• Progressive multifocal leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML) due to the John Cunningham virus have been reported in patients taking sphingosine 1-phosphate receptor modulators. Risk factors for development of PML include HIV, AIDS, cancer history, rheumatologic disease history, persistent lymphocytopenia, sarcoidosis, and prior immunosuppressant use (Jamilloux 2014; Tan 2010). At the first sign or symptom suggestive of PML, suspend therapy and perform a diagnostic evaluation; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Discontinue therapy in patients with confirmed PML.

• Varicella zoster infections: Test for antibodies to varicella zoster virus (VZV) in patients without a health care professional–confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV. In antibody-negative patients who require VZV vaccination, wait ≥1 month after a full vaccination course has been completed before initiating ozanimod treatment.

Disease-related concerns:

• Cardiovascular: Consult with a cardiologist before initiating ozanimod in individuals with significant QTc prolongation (QTcF >450 msec in males and >470 msec in females), with arrhythmias requiring treatment with class Ia or class III antiarrhythmic drugs, with ischemic heart disease, heart failure, cerebrovascular disease or uncontrolled hypertension, or those with a history of cardiac arrest, myocardial infarction, second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block.

• Hepatic impairment: Use is not recommended in patients with liver disease because the effects of hepatic impairment on the pharmacokinetics of ozanimod metabolites are unknown.

Other warnings/precautions:

• Discontinuation of therapy: In patients with multiple sclerosis, cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported after stopping treatment with a sphingosine 1-phosphate receptor modulator. Monitor for development of severe increase in disability and begin appropriate treatment as needed. Rebound symptoms have included back and extremity pain, confusion, constipation, diplopia, facial muscle spasms, fatigue, increased leg weakness, nausea, paraparesis and paresthesias (Hatcher 2016; Willis 2017). Due to residual pharmacodynamic effects following treatment discontinuation (eg, decreased peripheral lymphocyte counts), use caution for 4 weeks after the last dose of therapy.

• Immunizations: Administer live-attenuated vaccines at least 1 month prior to administration of ozanimod. Avoid live-attenuated vaccines in patients who currently receive or have discontinued ozanimod in the past 3 months; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]).

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, CYP2C8 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

Alemtuzumab: May enhance the immunosuppressive effect of Ozanimod. Risk X: Avoid combination

Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Bradycardia-Causing Agents: Ozanimod may enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

BuPROPion: Ozanimod may enhance the hypertensive effect of BuPROPion. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification

Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

CYP2C8 Inducers (Moderate): May decrease serum concentrations of the active metabolite(s) of Ozanimod. CYP2C8 Inducers (Moderate) may decrease the serum concentration of Ozanimod. Risk X: Avoid combination

CYP2C8 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of Ozanimod. Risk C: Monitor therapy

CYP2C8 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Ozanimod. Risk X: Avoid combination

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: Consider therapy modification

Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination

Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

Immunosuppressants (Cytotoxic Chemotherapy): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy

Immunosuppressants (Miscellaneous Oncologic Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy

Immunosuppressants (Therapeutic Immunosuppressant Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy

Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Methotrexate: May enhance the immunosuppressive effect of Sphingosine 1-Phosphate (S1P) Receptor Modulator. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: Ozanimod may enhance the hypertensive effect of Monoamine Oxidase Inhibitors. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Selective Norepinephrine Reuptake Inhibitors: Ozanimod may enhance the hypertensive effect of Selective Norepinephrine Reuptake Inhibitors. Risk C: Monitor therapy

Serotonergic Agents (High Risk): Ozanimod may enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification

Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sympathomimetics: Ozanimod may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tobacco (Smoked): May decrease the serum concentration of Ozanimod. Risk C: Monitor therapy

Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

Varicella Virus-Containing Vaccines: Ozanimod may enhance the adverse/toxic effect of Varicella Virus-Containing Vaccines. The risk of developing a clinical infection from the live vaccine may be increased. Ozanimod may diminish the therapeutic effect of Varicella Virus-Containing Vaccines. Risk X: Avoid combination

Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Food Interactions

Concurrent ingestion of foods and beverages with very high amounts of tyramine (ie, >150 mg) may cause sudden and severe high BP (hypertensive crisis). Management: Avoid foods with very high tyramine content.

Reproductive Considerations

Evaluate pregnancy status prior to use in patients who may become pregnant. Elimination of ozanimod takes ~3 months; to avoid potential fetal harm, patients should use effective contraception to avoid becoming pregnant during therapy and for 3 months after discontinuing treatment.

In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). Consider other agents in patients at high risk of disease reactivation who are planning to become pregnant. Delaying pregnancy is recommended for patients with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

Agents other than ozanimod may be preferred to treat inflammatory bowel disease in patients planning to become pregnant. Disease management should be optimized prior to pregnancy (Mahadevan 2019).

Pregnancy Considerations

Based on data from animal reproduction studies, in utero exposure to ozanimod may cause fetal harm.

In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

Pregnancy outcome information following use of ozanimod in patients with ulcerative colitis is limited (Sandborn 2021). Inflammatory bowel disease is associated with adverse pregnancy outcomes, including an increased risk of miscarriage, premature delivery, delivery of a low birth weight infant, and poor maternal weight gain. Management of maternal disease should be optimized prior to pregnancy. When treatment for inflammatory bowel disease is needed in pregnant patients, agents other than ozanimod may be preferred (Mahadevan 2019).

Breastfeeding Considerations

It is not known if ozanimod is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring Parameters

CBC, including lymphocyte counts (baseline [within 6 months], then as clinically necessary, and for 3 months after stopping therapy).

Hepatic monitoring: Baseline bilirubin and transaminase levels in all patients prior to therapy initiation (within 6 months); monitor bilirubin and liver enzymes in patients who develop symptoms of hepatic injury (eg, unexplained nausea/vomiting, right abdominal pain, fatigue, anorexia, jaundice, dark urine).

ECG (baseline); heart rate; BP; signs and symptoms of bradycardia.

Ophthalmologic exam (baseline evaluation of the fundus, including the macula; repeat as clinically indicated, especially if vision changes; monitor more frequently in patients with diabetes or a history of uveitis), blurred vision, decreased visual acuity; respiratory function (spirometry, including FEV1 and forced vital capacity) if clinically indicated; varicella zoster virus (VZV) antibodies (prior to starting treatment; in patients with no health care professional-confirmed history of chickenpox or without documented previous full series VZV vaccination); latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline); brain MRI for PML signs; severe increase in disability following discontinuation of therapy; signs/symptoms of PRES (eg, behavioral changes, cognitive deficits, cortical visual disturbances, any other neurological cortical symptom/sign, symptoms/signs suggestive of increased intracranial pressure). Monitor for signs and symptoms of infection during treatment and at least 4 weeks after discontinuation. Promptly evaluate and treat patients with symptoms and signs of an infection, such as opportunistic ones (eg, Cryptococcal meningitis, disseminated infections).

Mechanism of Action

Ozanimod has a high affinity to sphingosine 1-phosphate receptors 1 and 5. Ozanimod blocks the lymphocytes' ability to emerge from lymph nodes; therefore, the amount of lymphocytes available to the CNS and intestine is decreased.

Pharmacokinetics

Distribution: Vd: 5,590 L.

Protein binding: Ozanimod: ~98.2%; CC112273 (active metabolite): ~99.8%; CC1084037 (active metabolite): ~99.3%.

Metabolism: By multiple enzymes to form circulating major active metabolites CC112273 and CC1084037 and minor active metabolites RP101988, RP101075, and RP112509 with similar activity and selectivity for S1P1 and S1P5. ~94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans.

Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075.

RP101075 is metabolized by NAT-2 to form RP101442 or by MAO-B to form CC112273.

CC112273 is 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.

Half-life elimination: Ozanimod: ~21 hours; CC112273 and CC1084037 (active metabolites): ~11 days.

Time to peak: ~6 to 8 hours.

Excretion: Urine: ~26% (inactive metabolites); feces: 37% (inactive metabolites).

Pharmacokinetics: Additional Considerations

Elderly: CC112273 steady state AUC in ulcerative colitis patients >65 years of age was ~3% to 4% greater than patients 45 to 65 years of age and 27% greater than patients <45 years of age.

Smoking: CC112273 steady-state AUC was ~50% lower in smokers compared to nonsmokers; the clinical impact of this difference is not significant.

Pricing: US

Capsule Therapy Pack (Zeposia 7-Day Starter Pack Oral)

4 x 0.23MG &3 x 0.46MG (per each): $308.76

Capsule Therapy Pack (Zeposia Starter Kit Oral)

0.23MG & 0.46MG& 0.92MG (per each): $308.76

Capsules (Zeposia Oral)

0.92 mg (per each): $308.76

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Zeposia (AT, AU, CZ, DE, DK, EE, GB, HR, HU, LT, LV, NL, NO, PT, SK)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. Cohan S, Lucassen E, Smoot K, Brink J, Chen C. Sphingosine-1-phosphate: its pharmacological regulation and the treatment of multiple sclerosis: a review article. Biomedicines. 2020;8(7):227. doi:10.3390/biomedicines8070227 [PubMed 32708516]
  2. Cohen JA, Comi G, Arnold DL, et al. Efficacy and safety of ozanimod in multiple sclerosis: dose-blinded extension of a randomized phase II study. Mult Scler. 2019;25(9):1255-1262. doi:10.1177/1352458518789884 [PubMed 30043658]
  3. Farez MF, Correale J, Armstrong MJ, et al. Practice guideline update summary: vaccine-preventable infections and immunization in multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2019;93(13):584-594. doi:10.1212/WNL.0000000000008157 [PubMed 31462584]
  4. Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 2016;73(7):790‐794. doi:10.1001/jamaneurol.2016.0826 [PubMed 27135594]
  5. Jamilloux Y, Néel A, Lecouffe-Desprets M, et al. Progressive multifocal leukoencephalopathy in patients with sarcoidosis. Neurology. 2014;82(15):1307‐1313. doi:10.1212/WNL.0000000000000318 [PubMed 24610328]
  6. Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD parenthood project working group. Gastroenterology. 2019;156(5):1508-1524. doi:10.1053/j.gastro.2018.12.022 [PubMed 30658060]
  7. Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Eur J Neurol. 2018;25(2):215‐237. doi:10.1111/ene.13536 [PubMed 29352526]
  8. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777‐788. doi:10.1212/WNL.0000000000005347 [PubMed 29686116]
  9. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderate-to-severe ulcerative colitis: results from the open-label extension of the randomized, phase 2 touchstone study. J Crohns Colitis. 2021:jjab012. doi:10.1093/ecco-jcc/jjab012 [PubMed 33438008]
  10. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778-1792. doi:10.1111/bph.13476 [PubMed 26990079]
  11. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010;9(4):425‐437. doi:10.1016/S1474-4422(10)70040-5 [PubMed 20298966]
  12. Tran JQ, Hartung JP, Olson AD, et al. Cardiac safety of ozanimod, a novel sphingosine-1-phosphate receptor modulator: results of a thorough QT/QTc study. Clin Pharmacol Drug Dev. 2018;7(3):263-276. doi:10.1002/cpdd.383 [PubMed 28783871]
  13. Willis M, Pearson O, Illes Z, et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e320. doi:10.1212/NXI.0000000000000320 [PubMed 28101520]
  14. Zeposia (ozanimod) [prescribing information]. Summit, NJ: Celgene Corporation; December 2021.
  15. Zeposia (ozanimod) [product monograph]. Saint-Laurent, Quebec, Canada: Celgene Inc; October 2021.
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