Following approval of the new active ingredient in Switzerland, its use in practice is now being investigated. An important practical aspect of the drug is the oral route of administration. If ozanimod is dosed according to guidelines, the risk of adverse cardiac effects such as AV blockade or bradycardia can be kept low. Adequate monitoring of various parameters prevents damage during treatment and contributes to safety and also to further research into this new, promising therapy.
Because of the known effects of S1P receptor modulators on the cardiac conduction system and other potential side effects of ozanimod, both pivotal studies involved up-dosing for 7 days, as well as close monitoring of the heart, liver, lungs, skin, and eyes [1,2]. Under a dosage of 0.25 mg during the first 4 days of treatment, followed by 0.5 mg on days 5 to 7 and the target dose in each case from day 8 onward, cardiac problems were largely avoided. The recommended dosage is 0.92 mg ozanimod once daily, which is equivalent to 1 mg ozanimod hydrochloride. No higher-grade AV block or symptomatic bradycardia occurred in the pivotal studies, although a reduction in heart rate was observed after initial administration. In each case, the lowest average pulse rates were measured 5 hours after initial drug administration, with an average decrease of 1.8 beats per minute in the SUNBEAM study and 0.6 beats per minute in the RADIANCE study [1,2].
Significance for practice
In view of the available data, creeping ozanimod for 7 days does not generally appear to induce adverse cardiac effects [1,2]. Monitoring after initial administration is necessary only in patients with pre-existing cardiac risk factors. Up-dosing as tested in the pivotal studies is still recommended (review 1) [3]. Dose titration should also be repeated for any interruptions in therapy during the first 14 days of treatment, for interruptions of more than 7 days between day 15 and day 28 of therapy, and thereafter for interruptions of more than 14 days in a row [3].
In the phase III RADIANCE [1] and SUNBEAM [2] trials, as well as in previous data from the open-label follow-up DAYBREAK trial [4], the 1 mg dose of ozanimod demonstrated a favorable efficacy and safety profile (Overview 1 and 5). The recommended maintenance dose is therefore one 1 mg tablet per day and is easy for the physician, caregiver, and patient to follow due to its uniformity, oral administration, and independence from meals.
How much monitoring is needed?
With this new substance, monitoring is more complex than the drug administration itself, especially before the start of treatment and in the initial therapy phase after the first administration. Liver values should be determined, a blood count and ECG should be performed, and ophthalmologic examinations should be performed, depending on the situation, prior to the first ozanimod administration (review 2) [3]. In addition, it is recommended that all necessary vaccinations be carried out according to current guidelines, including vaccination against herpes zoster.
Whereas in the phase III trials, all patients underwent 6 hours of cardiac monitoring after the first drug administration, in clinical practice this only needs to be performed in the presence of certain pre-existing cardiac conditions [3]. These include higher-grade AV blocks, a history of myocardial infarction or heart failure, and a resting heart rate below 55 beats/minute (review 3). During this period, hourly pulse and blood pressure measurements are recommended, as well as an ECG before drug administration and after 6 hours [3]. Under certain conditions, cardiac monitoring should be continued beyond the 6-hour period. This is especially true if the heart rate is below 45 beats per minute or at the lowest level since drug administration, signs of higher-grade AV block are seen on the ECG, or the QTc interval is ≥500 ms. Overall, caution should be exercised when administering ozanimod in the presence of cardiac comorbidities, and consultation with cardiology colleagues regarding necessary monitoring is certainly prudent.
Even apart from the heart, there are organs that require regular monitoring during therapy with Ozanimod. Thus, one should not lose sight of the liver even in the longer term. If clinically asymptomatic, checks of transaminases and bilirubin levels are recommended at months 1, 3, 6, 9, 12, and periodically thereafter [3]. In case of a confirmed increase of the parameters to more than 5 times the upper normal value, the treatment must be interrupted.
As with other immunosuppressive therapies, there is an increased risk of infection and potentially an increased risk of developing malignancies. These hazards must be considered during treatment, and the periodic taking of a CBC is recommended [3]. Other investigations that contribute to safety during ozanimod therapy include regular blood pressure measurements and, if risk factors are present, ophthalmologic controls (review 4) [3].
* In patients with diabetes mellitus, uveitis or a history of retinal disease.
Quintessence
If these recommendations for monitoring are followed, there is nothing to prevent the new active ingredient from being used. With the broader application of Ozanimod, monitoring requirements will also be more clearly defined and better tested in the future.
Literature
