The safety profile of fingolimod has been extensively studied, and the available data indicate that the drug has a relatively good safety profile. It is clear that the incidence of AEs for fingolimod is dose-dependent.40
In the Phase III trials, the incidence of AEs was approximately the same across all study groups. AEs related to fingolimod included infections, particularly respiratory, urinary tract, and herpes virus infections, increased levels of alanine aminotransferase, bradycardia and atrioventricular block at the time of treatment initiation, hypertension, and macular edema. The incidence of serious AEs was comparable among the study groups, with the exception of the TRANSFORMS trial,42
in which serious AEs were more frequent in patients assigned to the higher dose of fingolimod (1.25 mg; 11%) than in those receiving 0.5 mg (7%).
However, the pathophysiology of macular edema in patients treated with fingolimod is still unclear; macular edema was confirmed in 13 patients receiving fingolimod in Phase III trials, of which 11 were treated with 1.25 mg. Most cases occurred within the first 3–4 months and resolved after treatment discontinuation.43
As expected, the drug decreased peripheral blood lymphocyte counts to 20%–30% of baseline values. Lymphocyte counts remained stable throughout the treatment period, and returned to baseline values within weeks after treatment discontinuation. As a consequence of the effects of fingolimod on circulating lymphocyte, the drug apparently increased the risk of infections. In Phase III trials, the overall incidence of infections was similar across the study groups, between 51%–72%. Mild and moderate upper and lower respiratory tract infections occurred more frequently among patients receiving fingolimod. In the FREEDOMS study, herpes virus infections were reported in similar proportions across study groups (1.25 mg: 5.8%; 0.5 mg: 8.7%; placebo: 7.9%). On the contrary, in the TRANSFORMS study, these were more common in the 1.25-mg group (5.5% of patients) than in the 0.5-mg and IFN-b-1a groups (2.1% and 2.8%, respectively). Most herpes virus infections were mild, but a total of six serious AEs were reported, including one case of fatal disseminated varicella zoster virus infection and one case of fatal herpes simplex virus type 1 encephalitis both in patients assigned to fingolimod 1.25 mg. Both patients were undergoing concomitant corticosteroid treatment when the infection occurred.43
Thus, a possible increase in the risk of reactivation of latent herpes should be investigated when considering fingolimod treatment. Besides lymphopenia, asymptomatic elevation of liver enzyme levels was the most frequent laboratory abnormality and occurred in a dose-dependent manner within the whole range of doses investigated. In clinical studies, alanine aminotransferase levels returned to normal values after treatment discontinuation. In all these cases, other signs or symptoms of significant hepatocellular injury were not observed.43
Moreover, fingolimod induced a small, dose-dependent increase in the airway resistance upon treatment initiation, with no evidence of further progression with continuous dosing.40
As was expected according to previous findings, rarely symptomatic, dose-dependent reduction in heart rate was observed within 6 hours after administration of the first dose. This drop in heart rate was already evident after 1 hour post dosing, reached a maximum mean reduction of approximately 10 bpm at 4–5 hours, and began to attenuate at 6 hours, returning to baseline values.43
In Phase III trials, symptomatic bradycardia after the first dose of fingolimod, mainly dizziness, chest discomfort, or palpitations, was observed in <1% of patients. No cases of syncope have been observed. Most events were mild-to-moderate in severity and resolved within 24 hours without requiring pharmacological interventions. There were no episodes of symptomatic bradycardia occurring beyond 24 hours and no clinically significant effects on heart rate were observed with sustained administration of the drug.43
Although during these clinical trials, pharmacological treatment was not required to treat bradycardia, it has been suggested that intravenous atropine can ameliorate the negative effect of fingolimod on cardiac rhythm.45
In addition to transient changes in cardiac rhythm, fingolimod induced cardiac conduction abnormalities. In the Phase III trials, first- and second-degree atrioventricular blocks were infrequently reported (0.4%–1.4% of patients) and these were not symptomatic. However, in the FREEDOMS study, electrocardiography performed on day 1 post-dosing revealed first- and second-degree atrioventricular block in 7% and 0.6% of patients, respectively. No effect on atrioventricular conduction was observed with continued treatment beyond 24 hours.43
Initial administration of fingolimod was also associated with a mild reduction in mean arterial blood pressure within 4–5 hours post-dosing. This transient reduction in mean arterial pressure was followed by a small and sustained increase (2–3 mmHg over the baseline values) during the first 6 months of treatment, with no further changes in the subsequent months. In the Phase III trials, hypertension was reported in 4%–6% of participants.43
Malignant neoplasms were reported in patients undergoing therapy with fingolimod in the Phase III trials, including localized skin cancer (Bowen’s disease: 1 case; basal cell carcinoma: 10 cases; malignant melanoma: 4 cases), all of which were successfully excised, and breast cancer (5 cases). One woman died from metastatic breast cancer 10 months after discontinuing fingolimod. 43
Both skin and breast cancer were also reported in the control groups (6 and 3 cases in total, respectively). The number of events was not enough to establish a statistical association between fingolimod and the risk of cancer in clinical trials. However, further long-term observation is needed before definitive conclusions can be detected.
Besides more frequent serious AEs, there were two cases of particular interest during these clinical trials. One case of posterior reversible encephalopathy syndrome occurred in a woman with no evident predisposing factors after 10 weeks of treatment with 5 mg of fingolimod. The symptoms and MRI abnormalities improved 72 hours after discontinuation of medication, leaving residual neurological deficits.44
A case of temporo-occipital hemorrhagic and centrally necrotic focal encephalitis of unknown etiology was reported in a woman after 7 months of treatment with 1.25 mg of fingolimod. Although bacterial and viral causes were excluded, antimicrobial treatment was administered. The patient recovered with sequelae.46