Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings

Multiple Sclerosis and Related Disorders

Volumn 3, Issue 4, 2014, Pages 494-504

  Kappos, Ludwig ^a   Cohen, Jeffrey ^b   Collins, William ^c   De Vera, Ana ^c   Zhang Auberson, Lixin ^c   Ritter, Shannon ^c   Von Rosenstiel, Philipp ^c   Francis, Gordon ^c  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

^b LERNER RESEARCH INSTITUTE   (United States)

^c NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Adverse events; Cardiovascular events; Fingolimod; Multiple sclerosis; Pooled analysis; Safety

Indexed keywords

ALANINE AMINOTRANSFERASE; BETA1A INTERFERON; BILIRUBIN; FINGOLIMOD; PLACEBO;

APPENDICITIS; ARTICLE; ATRIOVENTRICULAR CONDUCTION; BACKACHE; BASAL CELL CARCINOMA; BRADYCARDIA; BRAIN HEMORRHAGE; BRAIN ISCHEMIA; BREAST CANCER; BRONCHITIS; CARDIOVASCULAR DISEASE; CHOLELITHIASIS; CONTROLLED STUDY; COUGHING; DEPRESSION; DIARRHEA; DOSE RESPONSE; DRUG EFFICACY; DRUG FATALITY; DRUG SAFETY; DRUG WITHDRAWAL; ENDOMETRIUM CARCINOMA; EPILEPSY; EPSTEIN BARR VIRUS INFECTION; FATIGUE; FIRST DEGREE ATRIOVENTRICULAR BLOCK; HEADACHE; HEART INFARCTION; HEART PALPITATION; HEART RATE; HERPES SIMPLEX; HERPES SIMPLEX ENCEPHALITIS; HERPES ZOSTER; HUMAN; HYPERTENSION; HYPERTRANSAMINASEMIA; INFLUENZA; LARGE CELL LYMPHOMA; LOWER RESPIRATORY TRACT INFECTION; LYMPHOCYTE COUNT; LYMPHOCYTOPENIA; MAJOR CLINICAL STUDY; MELANOMA; META ANALYSIS (TOPIC); MIGRAINE; MORTALITY; MULTIPLE SCLEROSIS; OUTCOME ASSESSMENT; OVARY CANCER; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PROSTATE CANCER; RANDOMIZED CONTROLLED TRIAL (TOPIC); RETINA MACULA EDEMA; RHINOPHARYNGITIS; SECOND DEGREE ATRIOVENTRICULAR BLOCK; SIDE EFFECT; SKIN CARCINOMA; T CELL LYMPHOMA; THORAX PAIN; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; UTERINE CERVIX CARCINOMA; UTERUS MYOMA; VERTIGO;

EID: 84902546920     PISSN: 22110348     EISSN: 22110356     Source Type: Journal    
DOI: 10.1016/j.msard.2014.03.002     Document Type: Article

References (39)

1. D.D. Alexander, P.J. Mink, H.O. Adami, E.T. Chang, P. Cole, and J.S. Mandel et al. The non-Hodgkin lymphomas: a review of the epidemiologic literature Int J Cancer 120 Suppl. 12 2007 S1 S39
2. E. Arias United States life tables, 2007 Natl Vital Stat Rep 59 2011 1 60
3. V. Brinkmann Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology Pharmacol Ther 115 2007 84 105
4. V. Brinkmann FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system Br J Pharmacol 158 2009 1173 1182
5. V. Brinkmann, A. Billich, T. Baumruker, P. Heining, R. Schmouder, and G. Francis et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis Nat Rev Drug Discov 9 2010 883 897
6. P.A. Calabresi, E.-W. Radue, D. Goodin, D. Jeffery, K. Rammohan, and A.T. Reder et al. Efficacy and safety of fingolimod in patients with relapsing-remitting multiple sclerosis: results from the 24-month phase 3 double-blind, randomised, placebo-controlled study (FREEDOMS II) Lancet Neurol 2014 10.1016/S1474-4422(14)70049-3, in press
7. J. Chun, and H.P. Hartung Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis Clin Neuropharmacol 33 2010 91 101
8. J.A. Cohen, F. Barkhof, G. Comi, H.P. Hartung, B.O. Khatri, and X. Montalban et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis N Engl J Med 362 2010 402 415
9. G. Comi, P. O'Connor, X. Montalban, J. Antel, E.W. Radue, and G. Karlsson et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results Mult Scler 16 2010 197 207
10. C. de Kerguenec, S. Hillaire, V. Molinie, C. Gardin, C. Degott, and S. Erlinger et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30 cases Am J Gastroenterol 96 2001 852 857
11. J.P. DiMarco, P. O'Connor, J.A. Cohen, A.T. Reder, L. Zhang-Auberson, and D. Tang et al. Fingolimod treatment initiation experience: cardiac and Holter electrocardiogram findings from three phase 3 studies Mult Scler 18 Suppl. 4 2012 S55 S277
12. J.P. DiMarco, P. O'Connor, J.A. Cohen, A.T. Reder, L. Zhang-Auberson, and D. Tang et al. First-dose effects of fingolimod: pooled safety data from three phase 3 studies 2014 (in preparation)
13. European Medicines Agency. Annex I. Summary of Product Characteristics. Gilenya (fingolimod). http://www.ema.europa.eu/docs/en-GB/document-library/EPAR- Product-Information/human/002202/WC500104528.pdf; 2011 [accessed 30.01.13].
14. European Medicines Agency. Revised Summary of Product Characteristics. Gilenya (fingolimod). http://www.ema.europa.eu/docs/en-GB/document-library/ Other/2012/04/WC500125687.pdf; 2012 [accessed 30.01.13].
15. E. Eypasch, R. Lefering, C.K. Kum, and H. Troidl Probability of adverse events that have not yet occurred: a statistical reminder Br Med J 311 1995 619 620
16. G. Francis, L. Kappos, P. O'Connor, W. Collins, D. Tang, and F. Mercier et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy Mult Scler 20 2014 471 480
17. C.M. Gross, A. Baumgartner, S. Rauer, and O. Stich Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod Neurology 79 2012 2006 2007
18. J.A. Hanley, and A. Lippman-Hand If nothing goes wrong, is everything all right? Interpreting zero numerators J Am Med Assoc 249 1983 1743 1745
19. E. Ishii, S. Ohga, S. Imashuku, M. Yasukawa, H. Tsuda, and I. Miura et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan Int J Hematol 86 2007 58 65
20. G.E. Janka Hemophagocytic syndromes Blood Rev 21 2007 245 253
21. G.E. Janka Familial and acquired hemophagocytic lymphohistiocytosis Annu Rev Med 63 2012 233 246
22. G. Karlsson, G. Francis, G. Koren, P. Heining, X. Zhang, and J.A. Cohen et al. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis Neurology 82 8 2014 674 680
23. L. Kappos, J. Antel, G. Comi, X. Montalban, P. O'Connor, and C.H. Polman et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis N Engl J Med 355 2006 1124 1140
24. L. Kappos, E.W. Radue, P. O'Connor, C. Polman, R. Hohlfeld, and P. Calabresi et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis N Engl J Med 362 2010 387 401
25. B. Khatri, F. Barkhof, G. Comi, H.P. Hartung, L. Kappos, and X. Montalban et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study Lancet Neurol 10 2011 520 529
26. L. Koyrakh, M.I. Roman, V. Brinkmann, and K. Wickman The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I Am J Transplant 5 2005 529 536
27. A. Lanzavecchia, and F. Sallusto Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells Science 290 2000 92 97
28. N.R. Maakaroun, A. Moanna, J.T. Jacob, and H. Albrecht Viral infections associated with haemophagocytic syndrome Rev Med Virol 20 2010 93 105
29. D. Marsolais, and H. Rosen Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules Nat Rev Drug Discov 8 2009 297 307
30. M. Mehling, V. Brinkmann, J. Antel, A. Bar-Or, N. Goebels, and C. Vedrine et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis Neurology 71 2008 1261 1267
31. Novartis AG. Novartis Statement: Gilenya (fingolimod) Safety Information Update. http://www.novartis.com/downloads/newsroom/product-related-info-center/ statement-PML.pdf [last updated 13.04.12; accessed 30.01.13].
32. T.H. Pham, T. Okada, M. Matloubian, C.G. Lo, and J.G. Cyster S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress Immunity 28 2008 122 133
33. J.N. Ratchford, K. Costello, D.S. Reich, and P.A. Calabresi Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod Neurology 79 2012 2002 2004
34. US Food and Drug Administration. Gilenya Prescribing Information. http://www.accessdata.fda.gov/drugsatfda-docs/label/2011/022527s002lbl.pdf; 2010 [accessed 30.01.13].
35. US Food and Drug Administration. Gilenya (fingolimod): Drug Safety Communication - Safety Review of a Reported Death After the First Dose. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ SafetyAlertsforHumanMedicalProducts/ucm284355.htm; 2011 [posted 20.12.11; accessed 30.01.13].
36. US Food and Drug Administration. Gilenya (fingolimod): Revised US Prescribing Information. http://www.accessdata.fda.gov/drugsatfda-docs/label/ 2012/022527s008lbl.pdf; 2012a [accessed 30.01.13].
37. US Food and Drug Administration. Gilenya (fingolimod): Drug Safety Communication - Revised Recommendations for Cardiovascular Monitoring and Use of Multiple Sclerosis Drug Gilenya (fingolimod). http://www.fda.gov/Drugs/ DrugSafety/ucm303192.htm; 2012b [accessed 30.01.13].
38. M. Zarbin, A. Reder, W. Collins, G. Francis, X. Zhang, and Y. Zhao et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis Neurology 76 2011 A238
39. M.A. Zarbin, L.M. Jampol, R.D. Jager, A.T. Reder, G. Francis, and W. Collins et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis Ophthalmology 120 2013 1432 1439