*4.3. Ozanimod*

In RADIANCE and SUNBEAM, overall AEs and AEs leading to discontinuation were lower in both groups of patients taking OZM compared to interferon beta-1a. Nasopharyngitis, elevated liver enzymes, hypertension, and urinary tract infections were commonly seen in the OZM groups in both clinic trials. No serious opportunistic infections were reported, and the rate of herpes infections were the same across the three treatment groups.

There was one case of posterior reversible encephalopathy syndrome (PRES) in a patient receiving 1.0 mg OZM, occurring 10 months after starting the medication. Of note, post-approval cases have also been reported in patients treated with FGM [110,111]. Mean absolute lymphocyte count in patients on OZM 1.0 mg were reduced by approximately 45% by 3 months, and maintained at that level thereafter. The rate of macular edema was 0.3% in each OZM and the IFNβ-1a group. Maximum mean reduction in heart rate on day 1 was 0.6 bpm at 5 h in RADIANCE. Four patients treated with OZM had a heart rate less than 45, but had baseline heart rates of 55-64 bpm, and no symptoms were reported. In SUNBEAM, the maximum mean reduction was 1.8 bpm at 5 h, with no rate below 45 bpm reported. No second- or third-degree heart block was observed in either study. Given the minimal reduction in heart rate, FDO is not required for most patients.

As with the other S1PR-1 modulators, mild elevations in liver function enzymes were observed. In RADIANCE, 6.7% of patients on 1.0 mg of OZM had an ALT of 3 X ULN normal, as did 3.9% of patients on IFNβ-1a. In SUNBEAM, the rate was 4.3% for OZM and 2.2% for IFNβ-1a treated patients.

### *4.4. Contraindications and Cautions*

The use of FGM, SPM, and OZM is contraindicated in patients with recent (within the past 6 months) myocardial infarction or stroke, unstable angina, class III/IV heart failure4.4, recent transient ischemic attack and in patients receiving class I and Class III anti-arrhythmics, patients with Mobitz type 2 s or third degree heart block, sino-atrial block, or sick sinus syndrome without a functioning pacemaker. In addition, specifically for OZM there is a contraindication for the concomitant use of monoamine oxidase inhibitors and in patients with untreated severe sleep apnea. The concomitant use of SSRIs, SNRIs and narcotics is not recommended for any of the S1PR modulators [85,91,109].
