Chemical formula: C₂₃H₂₄N₄O₃ Molecular mass: 404.47 g/mol PubChem compound: 52938427
Ozanimod interacts in the following cases:
The coadministration of gemfibrozil (a strong inhibitor of CYP2C8) 600 mg twice daily at steady state and a single dose of ozanimod 0.46 mg increased exposure (AUC) of the major active metabolites by approximately 47% to 69%. Caution should be exercised for concomitant use of ozanimod with strong CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel).
The coadministration of rifampicin (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 ozanimod 0.92 mg reduced exposure (AUC) of major active metabolites by approximately 60% via CYP2C8 induction which may result in reduced clinical response. The coadministration of CYP2C8 inducers (i.e. rifampicin) with ozanimod is not recommended.
The potential for clinical interaction with MAO inhibitors has not been studied. However, the coadministration with MAO-B inhibitors may decrease exposure of the major active metabolites and may result in reduced clinical response. The coadministration of MAO inhibitors (e.g., selegiline, phenelzine) with ozanimod is not recommended.
During and for up to 3 months after treatment with ozanimod, vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should, therefore, be avoided during and for up to 3 months after treatment with ozanimod.
If live attenuated vaccine immunizations are required, these should be administered at least 1 month prior to initiation of ozanimod. Varicella Zoster Virus (VZV) vaccination of patients without documented immunity to VZV is recommended prior to initiating treatment with ozanimod.
In healthy subjects, a single dose of ozanimod 0.23 mg with steady state propranolol long acting 80 mg once daily or diltiazem 240 mg once daily did not result in any additional clinically meaningful changes in HR and PR interval compared to either propranolol or diltiazem alone. Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta-blocker or a calciumchannel blocker. Patients on other bradycardic medicinal products and on antiarrhythmic medicinal products (which have been associated with cases of torsades de pointes in patients with bradycardia) have not been studied with ozanimod.
Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies should not be coadministered due to the risk of additive immune system effects.
In MS and UC clinical studies, patients who received ozanimod were not to receive concomitant antineoplastic, non-corticosteroid immunosuppressive (e.g. azathioprine and 6-mercaptopurine in UC), or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ozanimod with any of these therapies would be expected to increase the risk of immunosuppression and should be avoided.
In UC clinical studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ozanimod, however, long-term data on concomitant use of ozanimod and corticosteroids are still limited. When switching to ozanimod from immunosuppressive medicinal products, the half-life and mode of action must be considered to avoid an additive immune effect whilst at the same time minimizing the risk of disease reactivation.
Ozanimod can generally be started immediately after discontinuation of interferon (IFN) or glatiramer.
Patients with a history of uveitis or diabetes mellitus or underlying/co existing retinal disease are at increased risk of macular oedema. It is recommended that patients with diabetes mellitus, uveitis or a history of retinal disease undergo an ophthalmological evaluation prior to treatment initiation with ozanimod and have follow up evaluations while receiving therapy.
Since there is a potential risk of malignant skin growths, patients treated with ozanimod should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.
Ozanimod should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease.
There are no or limited amount of data from the use of ozanimod in pregnant women. Studies in animals have shown reproductive toxicity including foetal loss and anomalies, notably malformations of blood vessels, generalised oedema (anasarca), and malpositioned testes and vertebrae. Sphingosine 1-phosphate is known to be involved in vascular formation during embryogenesis.
Consequently, ozanimod is contraindicated during pregnancy. Ozanimod should be stopped 3 months before planning a pregnancy. If a woman becomes pregnant during treatment, ozanimod must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed.
Ozanimod/metabolites are excreted in milk of treated animals during lactation. Due to the potential for serious adverse reactions to ozanimod/metabolites in nursing infants, women receiving ozanimod should not breastfeed.
Ozanimod is contraindicated in women of childbearing potential not using effective contraception. Therefore, before initiation of treatment in women of childbearing potential, a negative pregnancy test result must be available and counselling should be provided regarding the risk to the foetus. Women of childbearing potential must use effective contraception during ozanimod treatment and for 3 months after treatment discontinuation.
Specific measures are also included in the Healthcare Professional checklist. These measures must be implemented before ozanimod is prescribed to female patients and during treatment.
When stopping ozanimod therapy for planning a pregnancy the possible return of disease activity should be considered.
No fertility data are available in humans. In animal studies, no adverse effects on fertility were observed.
Ozanimod has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reactions (>5%) in controlled periods of the adult MS and UC clinical studies are nasopharyngitis, alanine aminotransferase (ALT) increased, and gamma-glutamyl transferase (GGT) increased.
The most common adverse reactions leading to discontinuation were related to liver enzyme elevations (1.1%) in the MS clinical studies. Liver enzyme elevations leading to discontinuation occurred in 0.4% of patients, in UC controlled clinical studies. The overall safety profile was similar for patients with multiple sclerosis and ulcerative colitis.
The adverse reactions observed in patients treated with ozanimod in MS and UC clinical studies and from post-marketing experience including spontaneous case reports are listed below by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000).
Summary of adverse reactions reported:
| SOC | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Very common | Nasopharyngitis |
| Common | Pharyngitis, respiratory tract infection viral, urinary tract infection*, herpes zoster, herpes simplex | |
| Rare | Progressive multifocal leukoencephalopathy | |
| Blood and lymphatic system disorders | Very common | Lymphopenia |
| Hepatobiliary disorders | Common | Alanine aminotransferase increased, gamma-glutamyl transferase increased, blood bilirubin increased |
| Rare | Liver injury**** | |
| Immune system disorders | Uncommon | Hypersensitivity (including rash and urticaria*) |
| Nervous system disorders | Common | Headache |
| Eye disorders | Uncommon | Macular oedema** |
| Cardiac disorders | Common | Bradycardia* |
| Vascular disorders | Common | Hypertension*†, orthostatic hypotension |
| General disorders and administration site conditions | Common | Peripheral oedema |
| Investigations | Common | Pulmonary function test abnormal*** |
* At least one of these adverse reactions was reported as serious
† Includes hypertension, essential hypertension, and blood pressure increased.
** for patients with pre-existing factors
*** including pulmonary function test decreased, spirometry abnormal, forced vital capacity decreased, carbon monoxide diffusing capacity decreased, forced expiratory volume decreased
**** Adverse reactions from post-marketing reports
In MS clinical studies, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ozanimod 0.92 mg and 1.3% of patients on IFN β-1a IM. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients on ozanimod and 3.1% of patients on IFN β-1a IM. The median time to elevation 3-fold the ULN was 6 months. The majority (79%) continued treatment with ozanimod with values returning to <3-fold the ULN within approximately 2-4 weeks. Ozanimod was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was 1.1% of MS patients on ozanimod 0.92 mg and 0.8% of patients on IFN beta-1a IM.
In UC clinical studies, during the induction period, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 0.9% and no patients, respectively. In the induction period, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ozanimod 0.92 mg and 0.5% of patients who received placebo, and in the maintenance period elevations occurred in 2.3% and no patients, respectively. In controlled and uncontrolled UC clinical studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ozanimod with values returning to less than 3-fold the ULN within approximately 2 to 4 weeks.
Overall, the discontinuation rate due to elevations in hepatic enzymes was 0.4% of patients treated with ozanimod 0.92 mg, and none in patients who received placebo in the controlled UC clinical studies.
Severe liver injury has been reported in a post-marketing setting.
After the initial dose of ozanimod 0.23 mg, the greatest mean reduction from baseline in sitting/supine HR occurred at Hour 5 on day 1 (decrease of 1.2 bpm in MS clinical studies and 0.7 bpm in the UC clinical studies), returning towards baseline at Hour 6. With continued dose escalation, there were no clinically relevant HR decreases.
In MS clinical studies, bradycardia was reported in 0.5% of patients treated with ozanimod versus 0% of patients treated with IFN β-1a IM on the day of treatment initiation (Day 1). After Day 1, the incidence of bradycardia was 0.8% on ozanimod versus 0.7% on IFN β-1a IM. Patients who experienced bradycardia were generally asymptomatic. Heart rates below 40 beats per minute were not observed.
In MS clinical studies, first-degree atrioventricular block was reported in 0.6% (5/882) of patients treated with ozanimod versus 0.2% (2/885) treated with IFN β-1a IM. Of the cases reported with ozanimod, 0.2% were reported on Day 1 and 0.3% were reported after Day 1.
In UC clinical studies, during the induction period, bradycardia was reported on the day of treatment initiation (Day 1), in 0.2% of patients treated with ozanimod and none in patients treated with placebo. After Day 1 bradycardia was reported in 0.2% of patients treated with ozanimod. During the maintenance period, bradycardia was not reported.
In MS clinical studies, patients treated with ozanimod had an average increase of approximately 1-2 mm Hg in systolic pressure over IFN β-1a IM, and approximately 1 mm Hg in diastolic pressure over IFN β-1a IM. The increase in systolic pressure was first detected after approximately 3 months of treatment initiation and remained stable throughout treatment.
Hypertension-related events (hypertension, essential hypertension, and blood pressure increased) were reported as an adverse reaction in 4.5% of patients treated with ozanimod 0.92 mg and in 2.3% of patients treated with IFN β-1a IM.
In UC clinical studies, during the induction period, patients treated with ozanimod had an average increase of 1.4 mm Hg in systolic pressure over placebo (3.7 vs 2.3 mm Hg) and 1.7 mm Hg in diastolic pressure over placebo (2.3 vs 0.6 mm Hg). During the maintenance period, patients treated with ozanimod had an average increase of 3.6 mm Hg in systolic pressure over placebo (5.1 vs 1.5 mm Hg) and 1.4 mm Hg in diastolic pressure over placebo (2.2 vs 0.8 mm Hg).
Hypertension was reported as an adverse reaction in 1.2% of patients treated with ozanimod 0.92 mg and none in patients treated with placebo in the induction period. In the maintenance period, hypertension was reported in 2.2% of patients in each treatment arm. Hypertensive crisis was reported in two patients receiving ozanimod, who recovered without treatment interruption, and one patient receiving placebo.
In MS clinical studies, 3.3% of patients and in UC controlled clinical studies, 3% of patients experienced lymphocyte counts less than 0.2 × 109/L with values generally resolving to greater than 0.2 × 109/L while remaining on treatment with ozanimod.
In MS clinical studies, the overall rate of infections (35%) with ozanimod 0.92 mg was similar to IFN β-1a IM. The overall rate of serious infections was similar between ozanimod (1%) and IFN β-1a IM (0.8%) in MS clinical studies.
In UC clinical studies, during the induction period, the overall rate of infections and rate of serious infections in patients treated with ozanimod or placebo were similar (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). During the maintenance period, the overall rate of infections in patients treated with ozanimod was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).
Ozanimod increased the risk of herpes infections, upper respiratory tract infections and urinary tract infections.
In MS clinical studies, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ozanimod 0.92 mg and in 0.2% of patients on IFN β-1a IM.
In UC clinical studies, herpes zoster was reported in 0.4% of patients who received ozanimod 0.92 mg and none in patients who received placebo in the induction period. In the maintenance period, herpes zoster was reported in 2.2% of patients who received ozanimod 0.92 mg and in 0.4% of patients who received placebo. None were serious or disseminated.
Minor dose-dependent reductions in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were observed with ozanimod treatment. At months 3 and 12 of treatment in MS clinical studies, median changes from baseline in FEV1 (FVC) in the ozanimod 0.92 mg group were -0.07 L and -0.1 L (-0.05 L and –0.065 L), respectively, with smaller changes from baseline in the IFN β-1a group (FEV1: -0.01 L and -0.04 L, FVC: 0.00 L and -0.02 L).
Similar to MS clinical studies, small mean reductions in pulmonary function tests were observed with ozanimod relative to placebo (FEV1 and FVC) during UC clinical studies, in the induction period. There were no further reductions with longer term treatment with ozanimod in the maintenance period and these small changes in pulmonary function tests were reversible in patients re-randomised to placebo.
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