*4.1. Fingolimod*

In FREEDOMS, 94% of patients receiving FGM compared to 93% of patients receiving placebo had an AE. The majority of these events were mild to moderate with 7.5% of patients on FGM stopping due to side effects compared to 7.7% on placebo. In TRANSFORMS, 86% of FGM 0.5 mg patients compared to 92% of patients on IFNβ-1a had an AE. However, 6% of patients on FGM versus 4% or patients on IFNβ-1a discontinued due to an AE [93,94].

In FREEDOMS, overall, incidence of infections was the same in all treatment groups; however, lower respiratory infections were more common in patients receiving FGM. There were two deaths in the 1.25 mg FGM group, one each of disseminated primary varicella zoster and herpes simplex encephalitis. The overall rate of herpes infections receiving FGM was 0.01 (10/854) and 0.01 (4/418) in placebo treated patients. As of this writing, there have been 36 confirmed cases of PML in greater than 746,700 patient years since FGM approval. In an analysis of 21 PML cases, age at treatment initiation was not a risk factor for the development of PML; however, longer duration of exposure to FGM increased the risk of developing PML [102]. As of February 2019, 46 cases of cryptococcal infections have been reported. (Novartis data on file), the majority of whom were treated for 2 or more years

Macular edema was slightly more common in patients on 0.5 mg of FGM compared to placebo, 0.5 verses 0.4%, and typically occurred within the first 3 to 4 months of therapy. Because patients with diabetes and uveitis are at higher risk of developing macular edema, they were excluded from the clinical trials. Given the risk of macular edema, a baseline eye exam is recommended within 6 months of starting and then 3 to 4 months after beginning FGM [91].

Fingolimod, on average, lowered the heart rate by eight beats per minute. Following the first dose, 0.6% of patients receiving FGM developed symptomatic bradycardia compared to 0.1% in the placebo group, with rare cases of second degree AV block reported. Nonetheless, patients are required to undergo an ECG prior to the first dose observation (FDO), and then at leasta6h FDO, during which time hourly pulse and blood pressure are obtained, followed by an additional ECG at the end of monitoring. Medications which can cause bradycardia or prolong the QT interval, such as beta blockers. Selective serotonin and norepinephrine reuptake inhibitors are to be used with caution and may prompt, overnight or more prolonged ambulatory cardiac rhythm monitoring. Fingolimod is contraindicated in patients with recent myocardial infarction, unstable angina, stroke, transient ischemic attack, or heart failure within the last 6 months [91]. There was also an average 3 mm Hg increase in systolic blood pressure and 2 mm Hg increase in diastolic pressure in patients on FGM. Elevation in liver enzymes was more commonly seen in the patients receiving FGM, with elevations of three times the upper limit of normal (ULN) or greater were seen in 14% of patients treated with FGM and in 3% of patients on placebo, typically occurring within 6 to 9 months of starting FGM. Peripheral lymphocyte counts dropped by 73% on average in patients receiving FGM, and typically return to baseline values 1–2 after stopping FGM (Novartis data on file). To date, there has been no evidence that lower lymphocyte counts are predictive of increased infection risk [103].

Skin cancer, particularly basal cell carcinoma, may be more common in patients on FGM [91]. Post-marketing studies have also reported rare cases of cutaneous melanoma and squamous cell carcinoma [104,105].

In the pediatric population (PARADIGM), the incidence of AEs was 88.8% in FGM and 95.3% in IFNβ-1a treated patients. The most common side effects in the FGM treated patients were headache (31.8%), viral upper respiratory infections (21.5%), Upper respiratory infections (15.9%), leukopenia (14%), influenza (1.2%), cough (9%), and pyrexia (7.5%). Serious AEs occurred in the FGM treated cohort and 4.7 % of FGM treated patients discontinued the trial because of SAEs. These AEs included convulsions (5.6%), and 3.7% of patients had serious infections, including one case each of appendicitis, cellulitis, oral abscess, and viral pharyngitis. Single SAE cases also included agranulocytosis, arthralgia, auto-immune uveitis, gastrointestinal necrosis, vasculitis, second degree AV conduction block, and small bowel obstruction.

Fingolimod is not recommended during pregnancy and lactation, based upon its teratogenicity, increased fetal loss and its presence in the milk of lactating animals. Prescribing information currently recommends stopping FGM 3-months prior to planning conception; however this recommendation may require revision in light of recent reports of increased MS breakthrough activity, occurring in 10–25% of patients within 12 weeks of discontinuing FGM [106,107]. Patients with a higher annualized risk of relapse or higher EDSS prior to starting FGM may be at greater risk of rebound disease once stopping FGM [108].
