Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Prior to treatment initiation with ozanimod, an ECG in all patients should be obtained to determine whether any pre-existing cardiac abnormalities are present. In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below).
Initiation of ozanimod may result in transient reductions in heart rate (HR) (see sections 4.8 and 5.1), and, therefore the initial dose escalation regimen to reach the maintenance dose (0.92 mg) on day 8 should be followed (see section 4.2).
After the initial dose of ozanimod 0.23 mg, the HR decrease started at Hour 4, with the greatest mean reduction at Hour 5, returning towards baseline at Hour 6. With continued dose escalation, there were no clinically relevant HR decreases. Heart rates below 40 beats per minute were not observed. If necessary, the decrease in HR induced by ozanimod can be reversed by parenteral doses of atropine or isoprenaline.
Caution should be applied when ozanimod is initiated in patients receiving treatment with a beta-blocker or a calcium-channel blocker (e.g. diltiazem and verapamil) because of the potential for additive effects on lowering HR. Beta-blockers and calcium-channel blockers treatment can be initiated in patients receiving stable doses of ozanimod.
The co-administration of ozanimod in patients on a beta-blocker in combination with a calcium channel blocker has not been studied (see section 4.5).
Due to the risk of transient decreases in HR with the initiation of ozanimod, first-dose, 6-hour monitoring for signs and symptoms of symptomatic bradycardia is recommended in patients with resting HR <55 bpm, second-degree [Mobitz type I] AV block or a history of myocardial infarction or heart failure (see section 4.3).
Patients should be monitored with hourly pulse and blood pressure measurement during this 6-hour period. An ECG prior to and at the end of this 6-hour period is recommended.
Additional monitoring is recommended in patients if at hour 6 post-dose:
In these cases, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If medical treatment is required, monitoring should be continued overnight, and a 6-hour monitoring period should be repeated after the second dose of ozanimod.
Cardiologist advice should be obtained before initiation of ozanimod in the following patients to decide if ozanimod can safely be initiated and to determine the most appropriate monitoring strategy
Elevations of aminotransferases, gamma-glutamyl transferase (GGT) and bilirubin have been reported in patients treated with ozanimod (see section 4.8).
Clinically significant liver injury has occurred in patients treated with ozanimod in the post marketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. Severe liver injury may result in the need for a liver transplant (see section 4.8).
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with ozanimod. In the absence of clinical symptoms, liver transaminases and bilirubin levels should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter. If liver transaminases rise above 5 times the ULN, more frequent monitoring including serum bilirubin and alkaline phosphatase (ALP) should be instituted. If liver transaminases above 5 times the ULN are confirmed, or at least 3 times the ULN associated with increase of serum bilirubin more than 2 times the ULN, treatment with ozanimod should be interrupted and only re-commenced once liver transaminase values have normalised (including if an alternative cause of the hepatic dysfunction is discovered).
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked and ozanimod should be discontinued if significant liver injury is confirmed.
Resumption of therapy will be dependent on whether another cause of liver injury is determined and on the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction. Patients with pre-existing liver disease may be at increased risk of developing elevated hepatic enzymes when taking ozanimod (see section 4.2).
Ozanimod has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and must not be used in these patients (see section 4.3).
Ozanimod has an immunosuppressive effect that predisposes patients to a risk of infection, including opportunistic infections, and may increase the risk of developing malignancies, including those of the skin. Physicians should carefully monitor patients, especially those with concurrent conditions or known factors, such as previous immunosuppressive therapy. If this risk is suspected, discontinuation of treatment should be considered by the physician on a case-by-case basis (see section 4.3).
Ozanimod causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible retention of lymphocytes in the lymphoid tissues. Ozanimod may, therefore, increase the susceptibility to infections (see section 4.8).
A recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood cell count (CBC) should be obtained, including lymphocyte count, before initiation of ozanimod.
Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 × 109/L, if confirmed, should lead to interruption of ozanimod therapy until the level reaches >0.5 × 109/L when re-initiation of ozanimod can be considered.
The initiation of ozanimod administration in patients with any active infection should be delayed until the infection is resolved.
Patients should be instructed to report promptly symptoms of infection to their physician. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. If a patient develops a serious infection, treatment interruption with ozanimod should be considered.
Because the elimination of ozanimod after discontinuation may take up to 3 months, monitoring for infections should be continued throughout this period.
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.
PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that typically occurs in patients who are immunocompromised and may lead to death or severe disability. PML has been reported in patients treated with S1P receptor modulators, including ozanimod, and other therapies for MS and UC. JCV infection resulting in PML has been associated with some risk factors (e.g., polytherapy with immunosuppressants, severely immunocompromised patients). Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ozanimod should be suspended until PML has been excluded. If confirmed, treatment with ozanimod should be discontinued.
No clinical data are available on the efficacy and safety of vaccinations in patients taking ozanimod. The use of live attenuated vaccines should be avoided during and for 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.
Half of the neoplasms reported with ozanimod in the MS controlled Phase 3 studies consisted of non-melanoma skin malignancies, with basal cell carcinoma presenting as the most common skin neoplasm and reported with similar incidence rates in the combined ozanimod (0.2%, 3 patients) and IFN β-1a (0.1%, 1 patient) groups.
In patients treated with ozanimod in UC controlled clinical studies one patient (0.2%) had squamous cell carcinoma of the skin, in the induction period, and one patient (0.4%) had basal cell carcinoma, in the maintenance period. There were no cases in patients who received placebo.
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.
Macular oedema with or without visual symptoms was observed with ozanimod (see section 4.8) in patients with pre-existing risk factors or comorbid conditions.
Patients with a history of uveitis or diabetes mellitus or underlying/co existing retinal disease are at increased risk of macular oedema (see section 4.8). 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.
Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with ozanimod should be discontinued. A decision on whether ozanimod should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient.
PRES is a syndrome characterised by sudden onset of severe headache, confusion, seizures and visual loss. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral haemorrhage. In MS controlled clinical trials with ozanimod, one case of PRES was reported in a patient with Guillain-Barré syndrome. If PRES is suspected, treatment with ozanimod should be discontinued.
In MS and UC controlled clinical studies, hypertension was more frequently reported in patients treated with ozanimod than in patients treated with IFN β-1a IM (MS) or placebo (UC) and in patients receiving concomitant ozanimod and SSRIs or SNRIs (see section 4.8). Blood pressure should be regularly monitored during treatment with ozanimod.
Ozanimod should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease.
The coadministration with inhibitors of monoamine oxidase (MAO), or CYP2C8 inducer (rifampicin) with ozanimod is not recommended (see section 4.5).
Due to risk to the foetus, ozanimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment, and for 3 months after treatment discontinuation (see sections 4.3 and 4.6 and the information contained in the Healthcare Professional checklist).
Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of another S1P receptor modulator. In the ozanimod long-term extension study, following permanent discontinuation of ozanimod, clinical relapses were reported in 3.3% of patients, none with severe exacerbation of disease or severe increase in disability. Patients should be observed for return of disease activity upon ozanimod discontinuation and appropriate treatment should be instituted as required.
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
Coadministration of ozanimod with ciclosporin, a strong BCRP inhibitor, had no effect on the exposure of ozanimod and its major active metabolites (CC112273 and CC1084037).
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 (see section 4.4).
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 (see section 4.4).
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 calcium- channel blocker (see section 4.4). 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.
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 (see section 4.4).
Anti-neoplastic, immunomodulatory or non-corticosteroid immunosuppressive therapies should not be coadministered due to the risk of additive immune system effects (see sections 4.3 and 4.4).
Interaction studies have only been performed in adults.
Zeposia is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). 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 (see section 4.4).
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 (see section 4.4).
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 (see section 5.3). Sphingosine 1-phosphate is known to be involved in vascular formation during embryogenesis (see section 5.3).
Consequently, Zeposia is contraindicated during pregnancy (see section 4.3). Zeposia should be stopped 3 months before planning a pregnancy (see section 4.4). If a woman becomes pregnant during treatment, Zeposia 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 (see section 5.3). Due to the potential for serious adverse reactions to ozanimod/metabolites in nursing infants, women receiving ozanimod should not breastfeed.
No fertility data are available in humans. In animal studies, no adverse effects on fertility were observed (see section 5.3).
Zeposia 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).
Table 2. 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 (see section 4.4).
** for patients with pre-existing factors (see section 4.4)
*** 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 (see section 4.4).
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. (see section 5.1). 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 (FEV~1~ 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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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