Overall, serious adverse events ranged from 10.4 to 51.7% depending on the dose and use of other concomitant immunosuppressant medications such as cyclosporine. In contrast, 13.1% of patients on placebo experienced a serious adverse event as shown in Table 3.
The most common adverse events reported were nasopharyngitis and upper respiratory tract infections. Inflammatory nasopharyngitis was reported as a separate category in several trials in the range of 23.4–25.3% in MS, with lower rates of 9.2–11.4% in the renal transplant trial. A significant proportion of those on placebo (25.9%) also reported similar symptoms. Lower rates of upper respiratory tract infections were reported by fingolimod (13.8–27.1%) compared with those on placebo (38.4%) as shown in Table 2. Urinary tract infections were also reported in up to 28.1% of patients in renal transplant cohorts – it must be noted that these patients received a full dose of cyclosporine in addition to fingolimod.
Bradycardia occurred in 1.1–26.4% and hypertension in 7.9–24.7% of the patients. Higher percentages were observed in patients on cyclosporine and these rates are significantly higher than those on placebo alone. Case reports of cardiac toxicity included asystole and sudden cardiac death 31–33. Negative chronotropic effects were also observed in an adolescent population 34. A case report of endocarditis was found in a patient with multiple other medical problems 35.
This was evaluated in an open-label single-arm study of 906 patients where more than 95% of the patients did not experience an adverse event after their first dose 36. Bradycardia was observed in 1.3% and heart blocks in up to 0.2% of the patients. The other cardiovascular events included palpitations, sinus arrhythmia and premature beats. In the Kappos 2006 study, it was observed that all episodes occurred within the first 24 h, with the maximal reductions in heart rate all occurring within 6 h 37.
A total of 15 case reports were reviewed. None of these events reported in these case studies were significant adverse events in any of the larger studies or RCTs. A case report of a patient with Wolf–Parkinson–White syndrome (a cardiac conduction abnormality) and safe use of fingolimod for a period of 1 year has also been reported 38. A registry-based study reported fewer than 10% cardiac events after the first dose, none of which were fatal 39. In another registry-based study, the most common adverse events noted were headaches and lymphopaenia 40. Macular oedema was noted in 0.9% of the larger studies (Table 2), but in 4.7% as a part of a case series whereas haemorrhagic focal encephalitis was observed in a single case report 41–43.
PP2A is a serine/threonine phosphatase that negatively regulates a multitude of signal transduction pathways and plays a key role in proliferation and cell survival 44. It is now considered a tumour suppressor 45. In-vitro studies in AML have shown that the pharmacological activation of PP2A with fingolimod subsequently inhibits proliferation, survival and in-vivo leukaemogenesis, suggesting that this approach is a potential therapeutic strategy 9.
The mean age of patients in the MS trials ranged from 37.8 to 44.5 years in the pooled analysis of trials. Over 70% of the patients were women, in keeping with the epidemiology of the disease. The renal transplant group was slightly older (the mean age of the cohorts was 44 and 43 years, respectively), with equal proportions of patients of both sexes. The mean age for myelodysplasia or acute myeloid leukaemia is significantly higher.
Any serious adverse event was reported in 10.4–52.9% compared with 13.1% of patients in the placebo group. Nasopharyngitis and upper respiratory tract infections (UTRIs) were reported as common clinical adverse events in many studies and were the most common adverse events in our pooled analysis. In some studies, UTRIs are combined with nasopharyngitis; whether the aetiology was proven to be infective is unclear from the literature. It appears from our analysis that both inflammatory nasopharyngitis as well as UTRIs occurred at similar or lower rates in patients on fingolimod compared with those on placebo. An extension of the Kappos study reported a serious infection rate of 0–3% and serious nasopharyngitis or upper respiratory tract infection in the range of 1–2% 47. These rates are markedly lower than that in our pooled analysis, where the severity or the nature of infections was not taken into consideration. In an open-label study, Hoitsma et al.48 reported serious infection rates of 14.3% in the fingolimod group compared with 33.3% with mycophenolate when both drugs were combined with tacrolimus in postrenal transplant patients. The fingolimod group had 4.1% serious bacterial and 6.1% serious viral infections compared with 22.2 and 11.1%, respectively, in the mycophenolate group 48. Although fatigue and headaches were reported in a higher proportion, these symptoms were reported in equally higher proportions, even in patients on placebo 47.
Any cytotoxic or immunosuppressive drug used in AML increases the risk of haematological, infective and cardiac side effects. The myelosuppressive therapy that is currently used for elderly AML (using a combination of anthracycline and cytosine) has a 10–15% serious adverse infective risk rate 49. A less intensive regimen such as subcutaneous cytosine reduces the toxicity related to myelosuppression and is a preferable regimen in the elderly, where more toxic regimens may not be tolerable 50. The key concern in the treatment of patients with haematological malignancy is the risk of infections. With traditional chemotherapy, the main risk is myelosuppression, which is the basis for neutropenic infections 49. Myelosuppression is not a side effect with fingolimod 27. In our pooled analysis, the overall risk of upper respiratory tract infections ranged from 11 to 13%, where inflammatory nasopharyngitis was excluded, depending on the dose of fingolimod and combination with other immunosuppression.
Bradycardia was encountered in 1.1–25.8% and hypertension in 6.1–22.5% of patients in our analysis of fingolimod. The proportion of patients with bradycardia or hypertension was higher among patients in whom cyclosporine was coadministered. First dose effect (bradycardia) is a well-recognized side effect and is considered to be because of the interaction of fingolimod with sphingosine-1-phosphate receptors, particularly in the cardiac tissue 54. A transient increase in heart rate is directly linked to the expression of sphingosine-1-phosphate receptors in atrial myocytes. The evidence for the subsequent transient decrease in heart rate after the first dose of fingolimod has also been reported in a pharmacodynamics study of a single dose in renal transplant patients 55. The Kappos 2006 study reported that maximal reductions in heart rate occurred within the first 6 h and all episodes within 24 h, followed by spontaneous resolution 37. Holter monitoring, at months after starting the 1.25 mg fingolimod dose, was normal in all patients 37.
One common issue in elderly patients, as with the disease group of AML, is that concomitant medications can significantly alter heart rate and blood pressure. The study by Kovarik et al. 54 specifically evaluated this issue and studied the impact of β-blockers (atenolol) or other antihypertensive drugs (diltiazem) on heart rate and blood pressure when used in combination with fingolimod. They observed that the combination of fingolimod with atenolol, a β-blocker, with fingolimod resulted in a 15% mean lower day time heart rate, whereas if combined with diltiazem, a calcium channel blocker, the mean heart rate was not lower than that when fingolimod was administered alone. The blood pressure was stable irrespective of whether fingolimod was combined with atenolol or dialtiazem 54. The first dose–effect study had a third of patients with other significant medical problems and 15% (136/906) on medications that influenced heart rate and conduction 36. Very significantly, they did not find any association with the use of many medications including β-blockers or antipsychotic drugs (which can prolong QT interval) to significant first dose cardiac adverse events from fingolimod 36. They observed the need for prolonged monitoring with two drugs, topiramate and trazodone; however, the authors could not draw firm conclusions because of small numbers. Another study that looked at predictors of cardiac side effects in MS patients and observed that pre-existing autonomic instability, in patients with MS, is an important indicator of heart rate and blood pressure changes 57. This is unlikely to be a significant issue in most patients with leukaemia.
The FDA (USA) and European Medicines Agency (Europe) independently reviewed safety data from clinical trials as well as postmarketing surveillance in 2012 59,61. They both recommend screening for cardiac conditions, assessing concomitant medications and monitoring heart rate for at least 6 h. The FDA also ruled that the contribution of fingolimod towards the cardiovascular deaths, as reported in the literature, was unclear 59.
Laboratory abnormalities were reported in some studies; however, there is heterogeneity in how they were reported as the abnormalities are an expected pharmacodynamic effect of the drug. Lymphopenia was not reported as an adverse event in some studies, unless the value decreased to less than 0.2×109/l. Lymphopenia is a common side effect of fingolimod and this may increase the risk of particular infections such as pneumocystis or respiratory viruses as discussed earlier. Fingolimod inhibits the re-entry of lymphocytes from lymph nodes into circulation by inhibiting SIP receptors on lymphocytes and hence their ability to bind to the respective ligand 62. Data on the recovery period for lymphopenia after the drug is stopped in healthy volunteers suggest that peripheral blood reconstitution occurred within 2–4 weeks of discontinuing the drug 63. Follow-up of patients in clinical trials indicates that there was a 24–30% decrease in the lymphocyte count from baseline 64. This occurred within about 2 weeks from starting therapy and was stable on long-term follow-up of up to 5 years. The kinetics of lymphocytes in the long-term use of fingolimod suggest that following cessation of the drug, reconstitution of counts occurred within about 3 months 64. Infection rate per patient-year was 1.4 with placebo compared with 1.0 in patients treated with fingolimod in the group with the lowest lymphocyte counts (FREEDOMS study phase 3 core group), suggesting that lymphopenia per se may not be a major risk factor for infection 64. The liver function abnormalities were mainly noted to be increases in alanine transaminase. This appeared to return to normal when the drug was stopped and even in some patients who continued study treatment 56. Bilirubin was noted to be stable, with no clinically significant change in any of the studies 56. This is important as an increase in bilirubin may preclude the use of certain types of chemotherapy such as anthracyclines or vinca alkaloids.
Rarer side effects such as macular oedema and haemorrhagic focal encephalitis have been reported as case reports 42,43. However, in a recent publication, macular oedema was more carefully evaluated and observed only in about 0.5% of the patients 65. Fingolimod-associated macular oedema is now considered to be dose dependent with a tenfold increased incidence with dose increases from 0.5 to 5 mg 65. However, in a case series of patients with MS, who were not on fingolimod, 4.7% of the patients were noted to have a microcystic pattern of macular oedema. This related more to disease severity and occurred more commonly in those with previous optic neuritis 42. The coexistence of diabetes-related macular changes as well as difficulty distinguishing from primary optic neuritis, were likely confounders in these studies 65. Patients with a history of eye problems, diabetes or uveitis would need to undergo an ophthalmic assessment before starting fingolimod; the drug would need to be avoided in those with active macular oedema 65.
In summary, an oral antileukaemia drug with potential to reduce the dosage or the intensity of standard chemotherapy is an attractive therapeutic option in AML. Fingolimod or other more specific PP2A activators, in combination with hydroxyurea or subcutaneous cytarabine, may be a potential strategy in the elderly, with low tumour burden AML, or high-risk myelodysplasia. As a potential drug, fingolimod may need to be used with caution in those with active infections or pre-existing cardiac toxicity. A close surveillance monitoring with ECGs as well as having a low threshold for investigation and treatment or prophylaxis for viral infections would be a suggested approach for any phase I trials with fingolimod in patients with acute myeloid leukaemia or high-risk myelodysplasia. Development of more specific PP2A activators, such as the nonphosphorylatable analogues AAL(S) or OSU-2S, may avoid several of the cardiac and infective complications that are likely to occur with the broader effects of fingolimod 2. Given that fingolimod has also shown preclinical efficacy in chronic lymphocytic leukaemia and chronic myeloid leukaemia models, the safety/toxicity profiles outlined here may also be relevant for treating other leukaemias as an investigational agent.
This work was supported by a grant from the Hunter Cancer Research Alliance (HCRA) and Cancer Council, NSW. A.E. was supported by Calvary Mater Newcastle research and HCRA research grants; he is also a recipient of an HCRA fellowship grant. N.M.V. is supported by a Cancer Institute NSW fellowship. The authors acknowledge the input of Anita Ariyarajah for critical review of the tables and manuscript.
Author contributions: A.E. and A.D.C.: project overview, analysis and manuscript; K.M. and A.E.: references review, tables and manuscript; N.V. and P.R: manuscript.
There are no conflicts of interest.
1. Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE. Medical Research Council Adult Leukemia Working Party. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98:1302–1311.
2. Perrotti D, Neviani P. Protein phosphatase 2A: a target for anticancer therapy. Lancet Oncol 2013; 14:e229–e238.
3. Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 2007; 445:53–57.
4. Kranias G, Watt LF, Carpenter H, Holst J, Ludowyke R, Strack S, et al.. Protein phosphatase 2A carboxymethylation and regulatory B subunits differentially regulate mast cell degranulation. Cell Signal 2010; 22:1882–1890.
5. Sim AT, Ludowyke RI, Verrills NM. Mast cell function: regulation of degranulation by serine/threonine phosphatases. Pharmacol Ther 2006; 112:425–439.
7. Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, et al.. CIP2A inhibits PP2A in human malignancies. Cell 2007; 130:51–62.
8. Li M, Damuni Z. I1PP2A and I2PP2A. Two potent protein phosphatase 2A-specific inhibitor proteins. Methods Mol Biol 1998; 93:59–66.
9. Roberts KG, Smith AM, McDougall F, Carpenter H, Horan M, Neviani P, et al.. Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers. Cancer Res 2010; 70:5438–5447.
10. Cristóbal I, Garcia-Orti L, Cirauqui C, Alonso MM, Calasanz MJ, Odero MD. PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. Leukemia 2011; 25:606–614.
11. Yang Y, Huang Q, Lu Y, Li X, Huang S. Reactivating PP2A by FTY720 as a novel therapy for AML with C-KIT tyrosine kinase domain mutation. J Cell Biochem 2012; 113:1314–1322.
12. Oaks JJ, Santhanam R, Walker CJ, Roof S, Harb JG, Ferenchak G, et al.. Antagonistic activities of the immunomodulator and PP2A-activating drug FTY720 (Fingolimod
, Gilenya) in Jak2-driven hematologic malignancies. Blood 2013; 122:1923–1934.
13. Liu Q, Zhao X, Frissora F, Ma Y, Santhanam R, Jarjoura D, et al.. FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood 2008; 111:275–284.
14. Perrotti D, Neviani P. Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. Cancer Metastasis Rev 2008; 27:159–168.
15. Switzer CH, Glynn SA, Ridnour LA, Cheng RY, Vitek MP, Ambs S, Wink DA. Nitric oxide and protein phosphatase 2A provide novel therapeutic opportunities in ER-negative breast cancer. Trends Pharmacol Sci 2011; 32:644–651.
16. Rosen H, Gonzalez-Cabrera P, Marsolais D, Cahalan S, Don AS, Sanna MG. Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev 2008; 223:221–235.
17. Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, et al.. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2006; 2:434–441.
18. Neviani P, Santhanam R, Oaks JJ, Eiring AM, Notari M, Blaser BW, et al.. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest 2007; 117:2408–2421.
19. Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, et al.. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell 2005; 8:355–368.
20. Collison A, Hatchwell L, Verrills N, Wark PA, de Siqueira AP, Tooze M, et al.. The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity. Nat Med 2013; 19:232–237.
21. Mani R, Mao Y, Frissora FW, Chiang CL, Wang J, Zhao Y, et al.. Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia. Leukemia 2015; 29:346–355.
22. Omar HA, Chou CC, Berman-Booty LD, Ma Y, Hung JH, Wang D, et al.. Antitumor effects of OSU-2S, a nonimmunosuppressive analogue of FTY720, in hepatocellular carcinoma. Hepatology 2011; 53:1943–1958.
23. Saddoughi SA, Gencer S, Peterson YK, Ward KE, Mukhopadhyay A, Oaks J, et al.. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol Med 2013; 5:105–121.
24. Moher D, Liberati A, Tetzlaff J, Altman DG. Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.
25. O’Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, et al.. Oral fingolimod
(FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009; 72:73–79.
26. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al.. A placebo-controlled trial of oral fingolimod
in relapsing multiple sclerosis. N Engl J Med 2010; 362:387–401.
27. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al.. Oral fingolimod
or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402–415.
28. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, et al.. Safety and efficacy of fingolimod
in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2014; 13:545–556.
29. Tedesco-Silva H, Szakaly P, Shoker A, Sommerer C, Yoshimura N, Schena FP, et al.. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation 2007; 84:885–892.
30. Uccelli A, Ginocchio F, Mancardi GL, Bassetti M. Primary varicella zoster infection associated with fingolimod
treatment. Neurology 2011; 76:1023–1024.
31. Lindsey JW, Haden-Pinneri K, Memon NB, Buja LM. Sudden unexpected death on fingolimod
. Mult Scler 2012; 18:1507–1508.
32. Espinosa PS, Berger JR. Delayed fingolimod
-associated asystole. Mult Scler 2011; 17:1387–1389.
33. Hengstman GJ, Kusters B. Sudden cardiac death in multiple sclerosis caused by active demyelination of the medulla oblongata. Mult Scler 2011; 17:1146–1148.
34. Ettenger R, Schmouder R, Kovarik JM, Bastien MC, Hoyer PF. Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose fingolimod
(FTY720) in adolescents with stable renal transplants. Pediatr Transplant 2011; 15:406–413.
35. Cocco G. A patient with Leiden V mutation, multiple sclerosis, psoriasis, and sicca syndrome: could celecoxib and fingolimod
adversely affect the heart? Cardiovasc Toxicol 2012; 12:266–272.
36. Laroni A, Brogi D, Morra VB, Guidi L, Pozzilli C, Comi G, et al.. Safety of the first dose of fingolimod
for multiple sclerosis: results of an open-label clinical trial. BMC Neurol 2014; 14:65.
37. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, et al.. Oral fingolimod
(FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355:1124–1140.
38. Huys AC, Lalive PH, Sekoranja L. Fingolimod
in a patient with Wolff–Parkinson–White syndrome. Mult Scler 2014; 20:636–637.
39. Fragoso YD, Arruda CC, Arruda WO, Brooks JB, Damasceno A, Damasceno CA, et al.. The real-life experience with cardiovascular complications in the first dose of fingolimod
for multiple sclerosis. Arq Neuropsiquiatr 2014; 72:712–714.
40. Al-Hashel J, Ahmed SF, Behbehani R, Alroughani R. Real-world use of fingolimod
in patients with relapsing remitting multiple sclerosis: a retrospective study using the national multiple sclerosis registry in Kuwait. CNS Drugs 2014; 28:817–824.
41. Leypoldt F, Münchau A, Moeller F, Bester M, Gerloff C, Heesen C. Hemorrhaging focal encephalitis under fingolimod
(FTY720) treatment: a case report. Neurology 2009; 72:1022–1024.
42. Gelfand JM, Nolan R, Schwartz DM, Graves J, Green AJ. Microcystic macular oedema in multiple sclerosis is associated with disease severity. Brain 2012; 135 (Pt 6):1786–1793.
43. Saab G, Almony A, Blinder KJ, Schuessler R, Brennan DC. Reversible cystoid macular edema secondary to fingolimod
in a renal transplant recipient. Arch Ophthalmol 2008; 126:140–141.
44. Arnold HK, Sears RC. Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation. Mol Cell Biol 2006; 26:2832–2844.
45. Janssens V, Goris J, Van Hoof C. PP2A: the expected tumor suppressor. Curr Opin Genet Dev 2005; 15:34–41.
46. Yiu EM, Banwell B. Update on emerging therapies for multiple sclerosis. Expert Rev Neurother 2010; 10:1259–1262.
47. Comi G, O’Connor P, Montalban X, Antel J, Radue EW, Karlsson G, et al.. Phase II study of oral fingolimod
(FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010; 16:197–207.
48. Hoitsma AJ, Woodle ES, Abramowicz D, Proot P, Vanrenterghem Y. FTY720 combined with tacrolimus in de novo renal transplantation: 1-year, multicenter, open-label randomized study. Nephrol Dial Transplant 2011; 26:3802–3805.
49. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, et al.. Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG), Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 2009; 361:1235–1248.
50. Sekeres MA, Lancet JE, Wood BL, Grove LE, Sandalic L, Sievers EL, Jurcic JG. Randomized phase IIb study of low-dose cytarabine and lintuzumab versus low-dose cytarabine and placebo in older adults with untreated acute myeloid leukemia. Haematologica 2013; 98:119–128.
51. Lech-Maranda E, Seweryn M, Giebel S, Holowiecki J, Piatkowska-Jakubas B, Wegrzyn J, et al.. Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG). Int J Infect Dis 2010; 14:e132–e140.
52. Arvin AM, Wolinsky JS, Kappos L, Morris MI, Reder AT, Tornatore C, et al.. Varicella-zoster virus infections
in patients treated with fingolimod
: risk assessment and consensus recommendations for management. JAMA Neurol 2015; 72:31–39.
53. Tedesco-Silva H, Lorber MI, Foster CE, Sollinger HW, Mendez R, Carvalho DB, et al.. FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study. Clin Transplant 2009; 23:589–599.
54. Kovarik JM, Lu M, Riviere GJ, Barbet I, Maton S, Goldwater DR, Schmouder RL. The effect on heart rate of combining single-dose fingolimod
with steady-state atenolol or diltiazem in healthy subjects. Eur J Clin Pharmacol 2008; 64:457–463.
55. Budde K, L Schmouder R, Nashan B, Brunkhorst R, W Lücker P, Mayer T, et al.. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 2003; 3:846–854.
56. Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, et al.. Comparison of fingolimod
with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011; 10:520–529.
57. Rossi S, Rocchi C, Studer V, Motta C, Lauretti B, Germani G, et al.. The autonomic balance predicts cardiac responses after the first dose of fingolimod
. Mult Scler 2014. [Epub ahead of print].
58. Marti V. Sudden cardiac death due to risperidone therapy in a patient with possible hypertrophic cardiomyopathy. Ann Pharmacother 2005; 39:973.
59. FDA.GOV. FDA Drug Safety Communication: revised recommendations for cardiovascular monitoring and use of multiple sclerosis drug Gilenya (fingolimod
): Food and Drug Administration, USA; 2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm303192.htm
. [Accessed 10 June 2015].
60. Kovarik JM, Slade A, Riviere GJ, Neddermann D, Maton S, Hunt TL, Schmouder RL. The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod
in healthy subjects. Br J Clin Pharmacol 2008; 66:199–206.
62. Chiba K, Matsuyuki H, Maeda Y, Sugahara K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol 2006; 3:11–19.
63. Kovarik JM, Schmouder R, Barilla D, Wang Y, Kraus G. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 2004; 57:586–591.
64. Francis G, Kappos L, O'Connor P, Collins W, Tang D, Mercier F, Cohen JA. Temporal profile of lymphocyte counts and relationship with infections
therapy. Mult Scler 2014; 20:471–480.
65. Jain N, Bhatti MT. Fingolimod
-associated macular edema: incidence, detection, and management. Neurology 2012; 78:672–680.