Ozanimod-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OZANIMOD-VISTA (OZANIMOD-VISTA)

Composition:

Active substance: ozanimod;

1 capsule contains 0.23 mg, 0.46 mg, or 0.92 mg of ozanimod as ozanimod hydrochloride;

Excipients: microcrystalline cellulose 102, sodium croscarmellose, magnesium stearate.

Capsule shell of the 0.23 mg dosage strength: gelatin, titanium dioxide, black iron oxide (E 172);

Capsule shell of the 0.46 mg dosage strength: gelatin, titanium dioxide, black iron oxide (E 172), yellow iron oxide (E 172), red iron oxide (E 172);

Capsule shell of the 0.92 mg dosage strength: gelatin, titanium dioxide, yellow iron oxide (E 172), red iron oxide (E 172).

Dosage form. Hard capsules.

Main physicochemical properties:

0.23 mg capsules: hard gelatin capsule size № 4 with light grey body and cap, with radial black print on the cap “O7ZM L”;

0.46 mg capsules: hard gelatin capsule size № 4 with light grey body and orange cap, with radial black print on the cap “O7ZM M”;

0.92 mg capsules: hard gelatin capsule size № 4 with orange body and cap, with radial black print on the cap “O7ZM H”.

Pharmacotherapeutic group. Antineoplastic agents and immunomodulators. Immunosuppressants. Sphingosine-1-phosphate (S1P) receptor modulators. Ozanimod.

ATC code L04AE02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Ozanimod is a potent modulator of sphingosine-1-phosphate (S1P) receptors, binding with high affinity to sphingosine-1-phosphate receptors 1 and 5. Ozanimod has minimal or no activity at S1P2, S1P3, and S1P4. In vitro, ozanimod and its major active metabolites demonstrated similar activity and selectivity for S1P1 and S1P5. The mechanism by which ozanimod exerts its therapeutic effect in multiple sclerosis and ulcerative colitis is unknown, but may involve reduction of lymphocyte migration into the central nervous system (CNS) and gastrointestinal tract.

The reduction in lymphocyte count in the peripheral circulation caused by ozanimod has a differential effect on leukocyte subpopulations, with a greater decrease in cells involved in adaptive immune responses. Ozanimod has minimal effect on cells involved in innate immune responses, thus preserving immune surveillance.

Ozanimod is extensively metabolized in humans, forming a number of circulating active metabolites, including two major metabolites (CC112273 and CC1084037). In humans, approximately 94% of total exposure to circulating active substances is represented by ozanimod (6%), and the two major metabolites CC112273 (73%) and CC1084037 (15%).

Pharmacokinetics

Ozanimod is extensively metabolized in humans, forming several circulating active metabolites, including two major active metabolites CC112273 and CC1084037, which exhibit activity and selectivity for S1P1 and S1P5 similar to the parent drug. The maximum plasma concentration (Cmax) and area under the curve (AUC) for ozanimod, CC112273, and CC1084037 increased proportionally over the dose range of ozanimod from 0.46 mg to 0.92 mg (0.5 to 1 of the recommended dose). After multiple dosing, approximately 94% of circulating active substances are represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%). At a dose of 0.92 mg orally once daily in patients with relapsing-remitting multiple sclerosis, the geometric mean [coefficient of variation (CV%)] steady-state Cmax and AUC0–24h were 231.6 pg/mL (37.2%) and 4223 pg⁎h/mL (37.7%), respectively, for ozanimod, and 6378 pg/mL (48.4%) and 132,861 pg⁎h/mL (45.6%), respectively, for CC112273. Cmax and AUC0–24h for CC1084037 are approximately 20% of those for CC112273. Factors affecting CC112273 are applicable to CC1084037, as they are metabolites that interconvert. Population pharmacokinetic analysis showed no substantial differences in these pharmacokinetic parameters in patients with relapsing multiple sclerosis or ulcerative colitis.

Absorption

The Tmax of ozanimod is approximately 6–8 hours. The Tmax for CC112273 is approximately 10 hours. Administration of ozanimod with a high-fat, high-calorie meal did not affect the exposure of ozanimod (Cmax and AUC). Therefore, ozanimod can be taken independently of food intake.

Distribution

The mean (CV%) apparent volume of distribution (Vz/F) of ozanimod is 5590 L (27%), indicating extensive tissue distribution. Plasma protein binding of ozanimod in humans is approximately 98.2%. Plasma protein binding of CC112273 and CC1084037 in humans is approximately 99.8% and 99.3%, respectively.

Biotransformation

Ozanimod is extensively metabolized via multiple biotransformation pathways, including aldehyde dehydrogenase and alcohol dehydrogenase (ALDH/ADH), cytochrome P450 (CYP) isoenzymes 3A4 and 1A1, and gut microbiota, although no single enzymatic system dominates overall metabolism. After repeated dosing, the AUC of the two major active metabolites CC112273 and CC1084037 exceeds that of ozanimod by 13-fold and 2.5-fold, respectively. In vitro studies showed that monoamine oxidase B (MAO-B) is responsible for the formation of CC112273 (via the intermediate minor active metabolite RP101075), while CYP2C8 and reductases are involved in the metabolism of CC112273. CC1084037 is formed directly from CC112273 and undergoes reversible metabolism back to CC112273. Interconversion between these two active metabolites occurs via carbonyl reductases, aldo-keto reductase 1C1/1C2, and/or 3β- and 11β-hydroxysteroid dehydrogenases.

Elimination

The mean apparent oral clearance of ozanimod is approximately 192 L/h (37%). The mean plasma elimination half-life (t1/2) of ozanimod is approximately 21 hours (15%). Steady-state levels of ozanimod are achieved within 7 days, with a calculated accumulation ratio after repeated oral administration of 0.92 mg once daily of approximately 2.

Based on modeling, the mean (CV%) effective half-life (t1/2) of CC112273 is approximately 11 days (104%) in patients with relapsing multiple sclerosis, with a mean (CV%) time to steady-state of approximately 45 days (45%) and an accumulation ratio of approximately 16 (101%), indicating predominant exposure to CC112273 over ozanimod. Plasma levels of CC112273 and its directly interconverting metabolite CC1084037 decline in parallel during the terminal phase, resulting in similar t1/2 values for both metabolites. Steady-state achievement and accumulation ratio for CC1084037 are expected to be similar to those of CC112273.

After a single oral dose of [14C]-ozanimod 0.92 mg, approximately 26% and 37% of radioactivity was excreted in urine and feces, respectively, with inactive metabolites predominating. Concentrations of ozanimod, CC112273, and CC1084037 in urine were negligible, indicating that renal clearance is not a significant elimination pathway for ozanimod, CC112273, or CC1084037.

Pharmacokinetics in Specific Patient Populations

Renal impairment. In a dedicated study in patients with renal impairment, after a single oral dose of ozanimod 0.23 mg, exposure (AUClast) for ozanimod and CC112273 was approximately 27% higher and 23% lower, respectively, in patients with end-stage renal disease (N = 8) compared to patients with normal renal function (n = 8). According to data from this study, renal impairment had no clinically significant effect on the pharmacokinetics of ozanimod or CC112273. Dose adjustment is not required in patients with renal impairment.

Hepatic impairment. In single- and multiple-dose studies in subjects with chronic liver disease, no significant effect of mild or moderate chronic hepatic impairment (Child-Pugh class A or B) on the pharmacokinetics of ozanimod or the major metabolite CC112273 was observed on day 1, day 5, or day 8 of administration. After dose escalation in a second study, administration of ozanimod 0.92 mg led to an increase in the mean AUC0–last of unbound CC112273 and CC1084037 (measured over 64 days after dose administration) in subjects with mild or moderate chronic hepatic impairment by 99.64–129.74% compared to healthy control subjects. In patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B), it is recommended to complete the 7-day dose-escalation regimen, followed by 0.92 mg once every other day.

Pharmacokinetics of ozanimod has not been evaluated in patients with severe hepatic impairment. Use in patients with severe hepatic impairment (Child-Pugh class C) is contraindicated.

Elderly patients. Population pharmacokinetic analysis showed that steady-state exposure (AUC) of CC112273 in patients over 65 years of age was approximately 3–4% higher than in patients aged 45–65 years and 27% higher than in adult patients under 45 years of age. There is no substantial difference in pharmacokinetics in elderly patients.

Pediatric population. There are no data on the use of ozanimod in children or adolescents (under 18 years of age).

Clinical Characteristics

Indications

• Multiple sclerosis.

Administer for the treatment of adult patients with active relapsing-remitting multiple sclerosis (MS), defined by clinical characteristics or results of imaging studies.

• Ulcerative colitis.

Administer for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had inadequate response, loss of response, or intolerance to conventional therapy or biological agents.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Immunodeficiency increasing the risk of developing systemic opportunistic infections.
• Contraindicated in patients who within the past 6 months have experienced myocardial infarction (MI), unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or New York Heart Association (NYHA) class III/IV heart failure.
• Contraindicated in patients with second-degree atrioventricular (AV) block type II or third-degree AV block, history of sick sinus syndrome, or second-degree AV block if the patient does not have a functioning pacemaker.
• Severe active infections, active chronic infections such as hepatitis or tuberculosis.
• Active malignancies.
• Severe hepatic impairment (Child–Pugh class C).
• Contraindicated in pregnant women and women of childbearing potential who are not using effective contraception.

Interaction with other medicinal products and other forms of interaction

Antineoplastic, immunomodulatory, or non-corticosteroid immunosuppressive therapy

Antineoplastic, immunomodulatory, or non-corticosteroid immunosuppressive therapy should not be used concomitantly with ozanimod due to the risk of additive effects on the immune system.

Vaccination

Vaccination may be less effective during treatment and for 3 months after treatment with ozanimod. The use of live attenuated vaccines may carry a risk of infection and should therefore be avoided during treatment with ozanimod and for 3 months following discontinuation.

Effect of monoamine oxidase inhibitors on ozanimod

The potential for clinical interaction with monoamine oxidase inhibitors (MAO) has not been studied. However, concomitant use with MAO type B inhibitors may reduce exposure to the main active metabolites and could lead to reduced clinical response. Concomitant use of MAO inhibitors (e.g., selegiline, phenelzine) with ozanimod is not recommended.

Effect of CYP2C8 inducers on ozanimod

Concomitant administration of rifampicin (a strong CYP3A and P-gp inducer and moderate CYP2C8 inducer) at a dose of 600 mg once daily at steady state and a single 0.92 mg dose of ozanimod decreased the AUC exposure of the main active metabolites by approximately 60% due to CYP2C8 induction, which may lead to reduced clinical response. Concomitant use of CYP2C8 inducers (e.g., rifampicin) with ozanimod is not recommended.

Effect of ozanimod on medicinal products that slow heart rate or atrioventricular conduction (e.g., beta-blockers or calcium channel blockers)

In healthy volunteers, administration of a single 0.23 mg dose of ozanimod with steady-state doses of 80 mg once daily extended-release propranolol or 240 mg once daily diltiazem did not result in any additional clinically significant changes in heart rate (HR) or PR interval on electrocardiogram (ECG) compared to monotherapy with propranolol or diltiazem. Caution should be exercised when initiating ozanimod treatment in patients receiving beta-blockers or calcium channel blockers.

Interaction of ozanimod in patients taking medications for bradycardia or antiarrhythmic drugs (which have been associated with cases of torsades de pointes in patients with bradycardia) has not been studied.

Effect of CYP2C8 inhibitors on ozanimod

Concomitant administration of gemfibrozil (a strong CYP2C8 inhibitor) at a dose of 600 mg twice daily at steady state and a single 0.46 mg dose of ozanimod increased exposure (AUC) of the main active metabolites by approximately 47–69%. Ozanimod should be used cautiously with strong CYP2C8 inhibitors (e.g., gemfibrozil, clopidogrel).

Effect of breast cancer resistance protein inhibitors on ozanimod

Concomitant administration of ozanimod with cyclosporine, a strong breast cancer resistance protein inhibitor, did not affect the exposure of ozanimod or its main active metabolites (CC112273 and CC1084037).

Special precautions for use

Bradycardia

Initiation of ozanimod treatment

Prior to initiating ozanimod treatment, all patients should undergo an electrocardiogram (ECG) to identify potential cardiac abnormalities. Patients with certain pre-existing conditions should undergo cardiac monitoring after the first dose.

Transient reduction in heart rate (HR) may occur at the initiation of ozanimod therapy; therefore, the recommended dose-escalation regimen should be followed to reach the maintenance dose (0.92 mg) on day 8 of treatment.

Following administration of the initial 0.23 mg dose of ozanimod, HR reduction was observed at 4 hours, with the greatest mean reduction at 5 hours and return to baseline by 6 hours. With prolonged dose titration, no clinically significant reduction in HR was observed. Heart rates below 40 beats per minute were not observed. If necessary, ozanimod-induced bradycardia can be reversed by parenteral administration of appropriate doses of atropine or isoprenaline.

Caution should be exercised when initiating ozanimod in patients receiving treatment with beta-blockers or calcium channel blockers (e.g., diltiazem and verapamil), due to the potential for additive HR reduction. Treatment with beta-blockers and calcium channel blockers may be initiated in patients already receiving stable doses of ozanimod.

Concomitant use of ozanimod in patients receiving beta-blockers in combination with calcium channel blockers has not been studied.

Cardiac monitoring after the first dose of ozanimod in patients with certain cardiac conditions

Due to the risk of transient HR reduction at the initiation of ozanimod treatment, patients with a resting HR < 55 beats per minute are recommended to undergo a 6-hour monitoring period for signs and symptoms of symptomatic bradycardia, second-degree atrioventricular (AV) block type I (Mobitz-I), history of myocardial infarction, or heart failure.

During this 6-hour period, patients should have their pulse and blood pressure measured hourly. An ECG is recommended before and at the end of the 6-hour monitoring period.

Additional cardiac monitoring is recommended if, 6 hours after dosing:

• HR is less than 45 beats per minute;
• HR is still at its lowest point after dosing, indicating that maximal HR reduction has not yet occurred;
• the 6-hour post-dose ECG shows evidence of new-onset second-degree or higher AV block;
• QTc interval ≥ 500 ms.

In such cases, appropriate treatment should be initiated and observation continued until symptoms/resolution occur. If pharmacological intervention is required, monitoring should continue overnight, and the 6-hour monitoring period should be repeated after the second dose of ozanimod.

In the following situations, cardiology consultation should be obtained prior to initiating ozanimod therapy to determine whether treatment can be safely initiated and to establish the most appropriate monitoring strategy:

• History of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, severe untreated sleep apnea, recurrent syncope, or symptomatic bradycardia;
• Presence of significant QT prolongation (QTc > 500 ms) or other risk factors for QT prolongation, and concomitant use of medications other than beta-blockers or calcium channel blockers that may potentiate bradycardia.

The use of ozanimod has not been studied in patients receiving class Ia antiarrhythmic agents (e.g., quinidine, disopyramide) or class III antiarrhythmics (e.g., amiodarone, sotalol), which have been associated with cases of torsades de pointes in patients with bradycardia.

Hepatic impairment

Elevations in aminotransferases, gamma-glutamyl transferase (GGT), and bilirubin have been reported in patients receiving ozanimod.

In the post-marketing period, clinically significant hepatic injury has been observed in patients receiving ozanimod. Signs of liver injury, including elevated serum liver enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. Severe hepatic injury may require liver transplantation.

Liver transaminase and bilirubin levels should be within normal limits during the 6 months prior to initiating ozanimod treatment. In the absence of clinical symptoms, liver transaminase and bilirubin levels should be monitored at months 1, 3, 6, 9, and 12 of treatment and periodically thereafter. If transaminase levels exceed the upper limit of normal (ULN) by 5 times, more frequent monitoring, including bilirubin and alkaline phosphatase (ALP), should be performed. If transaminase levels remain above 5 times ULN or exceed 3 times ULN and are accompanied by bilirubin elevation greater than 2 times ULN, ozanimod treatment should be discontinued and may only be resumed after normalization of liver transaminase levels (including if an alternative cause of liver dysfunction is identified).

If a patient develops symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, or dark urine, liver enzyme levels should be checked and ozanimod discontinued if significant hepatic injury is confirmed. Reinitiation of therapy will depend on whether an alternative cause of liver injury is identified and on the benefit-risk assessment for the patient.

Patients with pre-existing liver disease are at increased risk of elevated liver enzyme levels during ozanimod treatment.

The effect of ozanimod has not been studied in patients with pre-existing severe hepatic impairment (Child-Pugh class C); therefore, it should not be used in such patients.

Immunosuppressive effects

Ozanimod has immunosuppressive effects, increasing susceptibility to infections, including opportunistic infections, and increasing the risk of malignancies, including skin malignancies. Physicians should closely monitor patients, particularly those with comorbidities or known risk factors, such as prior immunosuppressive therapy. If complications are suspected, the physician should consider discontinuation of treatment on a case-by-case basis.

Infections

Ozanimod causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline due to reversible sequestration of lymphocytes in lymphoid tissues. Thus, ozanimod may increase susceptibility to infections.

Prior to initiating ozanimod treatment, a complete blood count (CBC), including lymphocyte count, should be performed (no later than 6 months before treatment initiation or after discontinuation of prior MS or UC therapy).

Periodic CBC monitoring is also recommended during treatment. If the absolute lymphocyte count is < 0.2 × 10⁹/L, ozanimod therapy should be discontinued until lymphocyte levels recover to > 0.5 × 10⁹/L. After lymphocyte levels exceed 0.5 × 10⁹/L, reinitiation of ozanimod treatment may be considered.

Patients with any active infection should not initiate ozanimod treatment until the infection is resolved.

Patients should be instructed to promptly report any symptoms of infection to their physician. In patients with signs of infection during ozanimod therapy, appropriate diagnostic and therapeutic measures should be implemented. If a serious infection develops, reinitiation of ozanimod should be reconsidered.

Since elimination of ozanimod after discontinuation may take up to 3 months, monitoring for infections should continue during this period.

Prior and concomitant treatment with anticancer, non-corticosteroid immunosuppressive, or immunomodulatory agents

In clinical trials of MS and UC, patients receiving ozanimod were not permitted to receive concomitant anticancer, non-corticosteroid immunosuppressive (e.g., azathioprine and 6-mercaptopurine in UC), or immunomodulatory therapies used for the treatment of MS and UC. Concomitant use of ozanimod with any of these therapies is expected to increase the risk of immunosuppression; therefore, such concomitant use should be avoided.

In UC clinical trials, concomitant use of corticosteroids was permitted and did not appear to affect the safety or efficacy of ozanimod. However, data on concomitant use of ozanimod and corticosteroids remain limited. When switching from immunosuppressive agents to ozanimod, the half-life and mechanism of action should be considered to avoid additive immune effects while minimizing the risk of disease reactivation.

Ozanimod treatment can typically be initiated immediately after discontinuation of interferon (IFN) or glatiramer.

Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV), typically occurring in immunocompromised patients and potentially leading to death or severe disability. PML has been reported in patients receiving ozanimod. JCV infection leading to PML has been associated with certain risk factors (e.g., polytherapy with immunosuppressants, severe immunodeficiency). Typical PML symptoms are variable, develop over several days or weeks, and include progressive weakness on one side of the body or clumsiness of limbs, visual disturbances, and changes in thinking, memory, and orientation, leading to confusion and personality changes.

Physicians should remain vigilant for clinical symptoms or MRI findings suggestive of PML. MRI findings may indicate PML before clinical symptoms appear. If PML is suspected, ozanimod treatment should be suspended until PML is ruled out. If PML is confirmed, ozanimod treatment must be discontinued.

In patients with multiple sclerosis who received sphingosine-1-phosphate (S1P) receptor modulators and developed PML, cases of immune reconstitution inflammatory syndrome (IRIS) have been reported after discontinuation of ozanimod therapy. IRIS may present with clinical worsening, sometimes rapid, potentially leading to severe neurological complications or death, and is often accompanied by characteristic MRI changes. The onset of IRIS typically occurs from several weeks to several months after discontinuation of S1P receptor modulator therapy. Close monitoring for the development of IRIS is recommended, and appropriate treatment should be provided if it occurs.

Vaccination

There are no clinical data on the efficacy and safety of vaccination in patients taking ozanimod. Live attenuated vaccines should be avoided during and for 3 months after ozanimod treatment.

If immunization with a live attenuated vaccine is required, it should be administered at least 1 month prior to starting ozanimod. Prior to initiating ozanimod treatment, vaccination against varicella-zoster virus is recommended for patients without documented immunity.

Skin malignancies

Half of the malignancies observed during ozanimod use in controlled phase 3 MS studies were non-melanoma skin cancers, with basal cell carcinoma being the most common skin malignancy, observed at a similar frequency with ozanimod (0.2%, 3 patients) and IFN β-1a (0.1%, 1 patient).

Among patients receiving ozanimod in controlled UC clinical trials, one patient (0.2%) developed squamous cell carcinoma during the induction period and one patient (0.4%) developed basal cell carcinoma during the maintenance period. No skin malignancies were observed in patients receiving placebo. Due to the potential risk of skin malignancies, patients receiving ozanimod should be advised to avoid unprotected sun exposure. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA photochemotherapy.

Macular edema

Macular edema, with or without visual symptoms, has been observed with ozanimod use in patients with risk factors or concomitant conditions.

Patients with a history of uveitis or diabetes mellitus, or with primary or concomitant retinal disease, have an increased risk of macular edema. It is recommended that patients with diabetes, uveitis, or retinal disease undergo ophthalmologic examination before starting ozanimod and periodic follow-up examinations during treatment. Patients who develop visual symptoms suggestive of macular edema should be evaluated, and ozanimod treatment should be discontinued if macular edema is confirmed. The decision to reinitiate ozanimod after recovery should be based on the potential benefits and risks for each individual patient.

Posterior reversible encephalopathy syndrome (PRES)

Posterior reversible encephalopathy syndrome (PRES) is characterized by sudden onset of severe headache, confusion, seizures, and visual loss. PRES symptoms are usually reversible but may progress to ischemic stroke or intracranial hemorrhage. In controlled MS clinical trials, one case of PRES was reported in a patient with Guillain-Barré syndrome during ozanimod treatment. If PRES is suspected, ozanimod treatment should be discontinued.

Arterial pressure

In controlled clinical trials of MS and UC, hypertension occurred more frequently in patients receiving ozanimod than in those receiving intramuscular IFN β-1a (MS) or placebo (UC), and in patients receiving concomitant ozanimod and selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. Blood pressure should be monitored regularly during ozanimod treatment.

Respiratory effects

Ozanimod should be used with caution in patients with severe respiratory disorders, pulmonary fibrosis, or chronic obstructive pulmonary disease.

Concomitant medicinal products

Concomitant use of ozanimod with monoamine oxidase inhibitors (MAOIs) or CYP2C8 inducers (e.g., rifampicin) is not recommended.

Women of childbearing potential

Due to the risk of fetal harm, ozanimod is contraindicated in pregnant women and in women of childbearing potential who are not using effective contraception. Prior to initiating treatment, women of childbearing potential should be informed of the fetal risk, have a negative pregnancy test, and use effective contraception during treatment and for 3 months after discontinuation.

Rebound disease activity after discontinuation of ozanimod

Rarely, severe disease exacerbation, including relapse, has been reported after discontinuation of other S1P receptor modulators. In a long-term extension study of ozanimod, clinical relapses were reported in 3.3% of patients after final discontinuation, none of whom experienced severe exacerbation or severe disability impact. Patients should be monitored for disease reactivation after discontinuation of ozanimod, and appropriate treatment initiated if needed.

After discontinuation of ozanimod due to PML, patients should be monitored for the development of IRIS.

Sodium content

1 capsule of Ozanimod-Vista contains less than 1 mmol (23 mg) of sodium, i.e., the medicinal product is essentially sodium-free.

Use during pregnancy or breastfeeding

Women of childbearing potential / contraception in women

Ozanimod is contraindicated in women of childbearing potential who are not using effective contraception (see section "Special precautions for use"). Therefore, prior to initiating treatment, women of reproductive age must have a negative pregnancy test and be counseled on fetal risk. Women of childbearing potential must use effective contraception during ozanimod treatment and for 3 months after discontinuation.

The prescribing information for healthcare professionals also outlines appropriate measures to be taken before and during ozanimod treatment in female patients.

When planning pregnancy after discontinuation of ozanimod, potential disease reactivation should be considered (see section "Special precautions for use").

Pregnancy

Data on the use of ozanimod in pregnant women are absent or limited.

Animal studies have demonstrated reproductive toxicity, including fetal loss and developmental abnormalities, such as vascular malformations, generalized edema (anasarca), and malpositioning of testes and vertebrae. Sphingosine-1-phosphate is known to play a role in vascular formation during embryogenesis. Therefore, ozanimod is contraindicated during pregnancy. Ozanimod should be discontinued 3 months prior to planned pregnancy. If a woman becomes pregnant while taking ozanimod, treatment with Ozanimod-Vista must be discontinued. The patient should receive medical counseling regarding the potential harmful effects on the fetus and undergo ultrasound examination.

Breastfeeding

Ozanimod/metabolites are excreted in the milk of lactating animals. Women should discontinue breastfeeding due to the potential for serious adverse reactions in infants.

Fertility

There are no data on fertility in humans. In animal studies, no adverse effects on fertility were observed.

Ability to influence reaction speed when driving or operating machinery. Ozanimod has no effect or a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Treatment with the medicinal product Ozanimod-Vista should be initiated under the supervision of a physician experienced in the management of multiple sclerosis or ulcerative colitis.

Dosage

The recommended dose is 0.92 mg of ozanimod once daily.

An initial dose-titration regimen of ozanimod is applied from day 1 to day 7, as shown below in Table 1. After the 7-day titration period, the once-daily maintenance dose is 0.92 mg starting from day 8.

Table 1. Dose Titration Schedule

Days 1–4	0.23 mg once daily
Days 5–7	0.46 mg once daily
Day 8 and onwards	0.92 mg once daily

Restarting treatment after interruption of therapy

If treatment is interrupted, a dose escalation regimen as described in Table 1 above is recommended if the interruption duration is:

• 1 day or more during the first 14 days of treatment;
• more than 7 consecutive days between days 15 and 28 of treatment;
• more than 14 consecutive days after day 28 of treatment.

If the treatment interruption is shorter than specified above, treatment should be continued with the next scheduled dose.

Special populations

Patients aged 55 years and older and elderly patients

Limited data are available in patients with MS aged > 55 years and in patients with UC aged ≥ 65 years. Ozanimod should be used with caution in patients with multiple sclerosis aged over 55 years and in patients with UC aged over 65 years, considering that available data are limited and the potential risk of adverse reactions in these populations is increased, especially with long-term treatment.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Hepatic impairment

For patients with mild or moderate chronic hepatic impairment (Child–Pugh class A or B), a 7-day dose escalation regimen is recommended, followed by 0.92 mg of ozanimod once daily.

The effect of ozanimod has not been evaluated in patients with severe hepatic impairment (Child–Pugh class C); therefore, ozanimod is not recommended for use in this patient population.

Method of administration

For oral use. Ozanimod-Vista can be taken with or without food.

Children

The safety and efficacy of ozanimod in children and adolescents (under 18 years of age) have not been established. There is no data available.

Overdose

In case of ozanimod overdose, patients should be monitored for signs and symptoms of bradycardia, including overnight observation if necessary. Heart rate and blood pressure should be measured regularly, and ECG monitoring should be performed. Heart rate reduction caused by ozanimod can be reversed by parenteral administration of atropine or isoprenaline.

Adverse Reactions

The most commonly reported adverse reactions were nasopharyngitis (12.3%), increased alanine aminotransferase (ALT) levels (5%), and increased gamma-glutamyl transferase (GGT) levels (5.4%). Initiation of ozanimod may result in transient bradycardia, which typically resolves by the end of the first week. Other serious adverse reactions include serious opportunistic infections (cases of PML have been reported in patients receiving ozanimod), macular edema, hypertension, and rare cases of clinically significant hepatic injury.

The most common adverse reactions leading to discontinuation of ozanimod in patients with multiple sclerosis (MS) were related to elevated liver enzymes (1.1%). In patients with ulcerative colitis (UC), the incidence of elevated liver enzymes leading to discontinuation of ozanimod during controlled clinical trials was 0.4%.

The overall safety profile was similar in patients with multiple sclerosis and ulcerative colitis.

List of adverse reactions

Adverse reactions identified in MS and UC patients receiving ozanimod in clinical studies and during the post-marketing period, particularly based on spontaneous reports, are listed below by frequency and organ system. Within each organ system group, adverse reactions are listed in order of decreasing severity.

Adverse reaction frequencies are defined using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Table 2. Reported adverse reactions

Organ systems	Frequency	Adverse reactions
Infections and infestations	Very common	Nasopharyngitis
	Common	Pharyngitis, viral respiratory tract infection, urinary tract infection*, herpes zoster, herpes simplex
	Rare	Progressive multifocal leukoencephalopathy
Blood and lymphatic system	Very common	Lymphopenia
Hepatobiliary disorders	Common	Increased alanine aminotransferase, increased gamma-glutamyl transferase, increased blood bilirubin
	Rare	Hepatic injury****
Immune system	Uncommon	Hypersensitivity (including rash and urticaria*)
Nervous system	Common	Headache
Eye disorders	Uncommon	Macular edema**
Cardiac disorders	Common	Bradycardia*
Vascular disorders	Common	Arterial hypertension*†, orthostatic hypotension
General disorders and administration site conditions	Common	Peripheral edema
Investigations	Common	Abnormal lung function test results***

* One of these adverse reactions was recorded as serious.

† Includes hypertension, essential hypertension, and increased blood pressure.

** In patients with risk factors.

*** Including decreased lung function, spirometry abnormalities, reduced forced vital capacity, decreased carbon monoxide diffusion capacity, and reduced forced expiratory volume.

**** Adverse reactions reported based on post-marketing data.

Description of selected adverse reactions

Elevated liver enzymes

In clinical trials involving patients with MS, ALT levels increased to 5 or more times the upper limit of normal (ULN) in 1.6% of patients receiving ozanimod 0.92 mg and in 1.3% of patients receiving IFN β-1a intramuscularly.

Elevations ≥3 times ULN occurred in 5.5% of patients receiving ozanimod and in 3.1% of patients receiving intramuscular IFN β-1a. The median time to ≥3 times ULN elevation was 6 months. The majority (79%) of patients continued ozanimod treatment and returned to <3 times ULN within approximately 2–4 weeks. Ozanimod was discontinued due to confirmed elevations in liver enzymes exceeding 5 times ULN. Overall, the frequency of discontinuation due to elevated liver enzymes was 1.1% in MS patients receiving ozanimod 0.92 mg and 0.8% in those receiving intramuscular IFN β-1a.

In clinical trials involving patients with UC, during the induction period, ALT levels increased to 5 times or more above ULN in 0.9% of patients receiving ozanimod 0.92 mg and in 0.5% of patients receiving placebo; during the maintenance period, such elevations occurred in 0.9% of patients and in none receiving placebo. During the induction period, ALT elevations ≥3 times ULN occurred in 2.6% of UC patients receiving ozanimod 0.92 mg and in 0.5% receiving placebo; during the maintenance period, elevations occurred in 2.3% and were not observed in placebo recipients. In controlled and uncontrolled clinical trials in UC patients, the majority (96%) of patients with ALT levels ≥3 times ULN continued ozanimod treatment and returned to levels <3 times ULN within approximately 2–4 weeks.

Overall, the frequency of treatment discontinuation due to elevated liver enzymes in controlled clinical trials was 0.4% in UC patients receiving ozanimod 0.92 mg. No discontinuations were reported in the placebo group.

In the post-marketing period, severe hepatic injury has been reported (see section "Special warnings and precautions for use").

Bradycardia

Following the initial 0.23 mg dose of ozanimod, the greatest mean decrease in heart rate in the sitting/supine position occurred at hour 5 on day 1 (a decrease of 1.2 bpm in MS patients and 0.7 bpm in UC patients), with return to baseline by hour 6. Subsequent dose escalations were not associated with clinically significant decreases in heart rate.

In clinical trials, bradycardia was reported in 0.5% of MS patients receiving ozanimod compared to 0% of patients receiving intramuscular IFN β-1a on the first day of treatment (Day 1). After Day 1, bradycardia incidence was 0.8% in the ozanimod group versus 0.7% in the intramuscular IFN β-1a group.

Patients with bradycardia were asymptomatic. Heart rates below 40 beats per minute were not observed.

In clinical trials among MS patients, first-degree atrioventricular block was recorded in 0.6% (5/882) of patients receiving ozanimod versus 0.2% (2/885) of patients receiving intramuscular IFN β-1a. First-degree atrioventricular block occurred with ozanimod administration on Day 1 at a frequency of 0.2% and from Day 2 onwards at a frequency of 0.3%.

In clinical trials among UC patients, during the induction period, bradycardia was recorded on the first day of treatment (Day 1) in 0.2% of patients receiving ozanimod. No cases were recorded in the placebo group. After Day 1, bradycardia was reported in 0.2% of patients receiving ozanimod. During the maintenance period, no cases of bradycardia were recorded.

Increased blood pressure

In clinical trials in MS patients receiving ozanimod, mean increases of approximately 1–2 mm Hg in systolic blood pressure and approximately 1 mm Hg in diastolic blood pressure were observed compared to patients receiving intramuscular IFN β-1a. Increases in systolic pressure were first detected approximately 3 months after treatment initiation and remained stable throughout the treatment period.

Adverse events related to hypertension (hypertension, essential hypertension, and increased blood pressure) were reported in 4.5% of patients receiving ozanimod 0.92 mg and in 2.3% of patients receiving intramuscular IFN β-1a.

In clinical trials during the induction period in UC patients receiving ozanimod, mean increases in systolic blood pressure of 1.4 mm Hg were observed compared to placebo group patients (3.7 vs. 2.3 mm Hg) and in diastolic blood pressure of 1.7 mm Hg compared to placebo (2.3 vs. 0.6 mm Hg). During the maintenance period, patients receiving ozanimod had a mean increase in systolic blood pressure of 3.6 mm Hg compared to the placebo group (5.1 vs. 1.5 mm Hg) and in diastolic blood pressure of 1.4 mm Hg compared to placebo (2.2 vs. 0.8 mm Hg).

Hypertension occurred as an adverse reaction in 1.2% of patients receiving ozanimod 0.92 mg. No adverse reactions were observed in placebo recipients during the induction period. During the maintenance period, hypertension was reported in 2.2% of patients in each treatment group. Hypertensive crisis was reported in two patients receiving ozanimod and in one patient receiving placebo.

Patients in the ozanimod group recovered without treatment interruption.

Reduction in lymphocyte count

In clinical trials, lymphocyte counts below 0.2 × 10⁹/L occurred in 3.3% of MS patients and in 3% of UC patients, although overall values during ozanimod treatment generally remained above 0.2 × 10⁹/L.

Infections

In clinical trials in MS patients, the overall infection rate (35%) with ozanimod 0.92 mg was similar to that with intramuscular IFN β-1a. The overall rate of serious infections was similar with ozanimod (1%) and intramuscular IFN β-1a (0.8%).

In clinical trials among UC patients, during the induction period, the overall infection rate and the rate of serious infections were similar in patients receiving ozanimod or placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). During the maintenance period, the overall infection rate was higher in patients receiving ozanimod than in those receiving placebo (23% vs. 12%), while the rate of serious infections was similar (0.9% vs. 1.8%).

Ozanimod increases the risk of herpes infections, upper respiratory tract infections, and urinary tract infections.

Herpes infections

In clinical trials among MS patients, herpes zoster was reported as an adverse reaction in 0.6% of patients receiving ozanimod 0.92 mg and in 0.2% of patients receiving intramuscular IFN β-1a.

In clinical trials involving UC patients, herpes zoster was reported in 0.4% of patients receiving ozanimod 0.92 mg, with no cases in the placebo group during the induction period. During the maintenance period, herpes zoster was reported in 2.2% of patients receiving ozanimod 0.92 mg and in 0.4% of patients receiving placebo. None of the cases were serious or disseminated.

Respiratory system

During ozanimod treatment, a slight dose-dependent reduction in forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC) was observed. At Months 3 and 12 of treatment in clinical trials among MS patients, mean changes in FEV₁ (FVC) in the 0.92 mg ozanimod 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).

Similarly, a small mean reduction in pulmonary function parameters (FEV₁ and FVC) was observed with ozanimod compared to placebo during clinical trials in UC patients in the induction period.

No further decline was observed with long-term ozanimod treatment during the maintenance period, and these small changes in pulmonary function parameters were reversible in patients who were re-randomized to placebo.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging to protect from light. Keep out of the reach of children.

Packaging. Capsules of 0.23 mg, 0.46 mg, 0.92 mg: 7 capsules in a blister, 4 blisters in a cardboard box;

7 capsules in a blister (4×0.23 mg, 3×0.46 mg), 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Sandoz España, S.L.

Manufacturer's address and location of its operations

C/Castello, n°1, Sant Boi de Llobregat, Barcelona, 08830, Spain