*4.2. Siponimod*

The SPM safety profile is similar to that of FGM. In EXPAND [97], 89% of patients receiving SPM and 82% of patients receiving placebo had an AE. Non-serious adverse events leading to discontinuation in the study was 4% versus 3% respectively. Serious adverse events occurred in 18% of the SPM group compared to 15% in the placebo group.

Rate of infections were also similar in both groups, but upper and lower respiratory infections, as well as herpes zoster reactivation, were more common in the SPM treated group. The risk of herpes infection was 2.5% in SPM versus 0.7% in placebo treated patients. No cases of PML or cryptococcal infections were reported, although these opportunistic infections may emerge as larger populations are treated for longer durations, given the similar mechanism of action compared to FNM. The reduction in the peripheral lymphocyte count was between 20 to 30% which is less than that observed in patients treated with FGM [93,94], but whether this impacts the comparative rate of infection is ye<sup>t</sup> to be determined.

Liver function abnormalities were observed in 10.7% of SPM treated patients and 3.7% in the placebo group.

Rate of macular edema was 1.8% in patients on SPM and 0.2% of patients treated with placebo. This is higher than 0.4% reported in the phase III clinical trials with FGM [93,94].

Seizures occurred in 1.7% of SPM treated patients and was 0.4% in the placebo group.

The reduction in heart rate was a mean of six beats per minute in the SPM treated group, with the maximum reduction occurring on average 4 h after the first dose. Bradycardia was reported as an AE in 6% of patients receiving SPM compared to 3% receiving placebo. Cases of Mobitz type II or higher degree atrio-ventricular (AV) block were not observed. As a result, first dose observation is not required except for patients with recent history of myocardial infarction, unstable angina, recent stroke, TIA or baseline heart rate of less than 55 beats per minute [109]. Clinicians may also recommend first dose observation for patients on medication which may lower heart rate, particularly those medication that slow AV conduction.

Elevation in liver enzymes was 10.1% in patients on SPM, versus 3.7% of patients on placebo. Overall, rate of malignancies was the same in each group.

Medications which inhibit the hepatic enzymes CYP2C9 and CYP3A4 can result in elevated concentration of SPM, and the opposite is true for hepatic enzyme inducers. Furthermore, in patients with the CYP2C9 genotype variants CYP2C9 1\*/3\* or 2\*/3\* should receive only 1.0 mg a day maintenance dosing and those with the 3\*/3\* genotype should not receive SPM at all due to their inhibition of SPM degradation in the liver [109].
