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SAFETY

As demonstrated in adult clinical trials

The first-dose effect on heart rate with GILENYA is expected and transient1,6,7

  • S1P1 receptors, which are found on certain lymphocytes, are also found in the heart14
  • GILENYA binds to S1P1 receptors, and can result in temporarily slowed heart rate (bradycardia) and atrioventricular (AV) conduction delays1,17
  • The mechanism by which GILENYA exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the CNS. The mechanism of action (MOA) for GILENYA was observed in animal models
  • The mechanism by which GILENYA exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the CNS. The mechanism of action (MOA) for GILENYA was observed in animal models
  • This effect on heart rate is temporary and only happens when initiating treatment. S1P1 receptors in the heart adapt, or desensitize, making this effect self-limited14,17
  • A maximal decrease in heart rate was reached 4 to 5 hours after first dose and began to recover at 6 hours.6,7* Because of natural nightly fluctuations, some patients may experience a second reduction in heart rate within 24 hours1,18
  • The mechanism by which GILENYA exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the CNS. The mechanism of action (MOA) for GILENYA was observed in animal models
Heart rates below 40 beats per minute were not observed in adult clinical trials 1
*Mean sitting pulse.
  • By month 1, heart rates in adult patients returned to baseline values and remained stable throughout the studies (up to 24 months).1 No chronic effects on heart rate or AV conduction were observed1,6,7
No chronic effects on heart rate with GILENYA 1,6,7,17
The first-dose effect on heart rate with GILENYA
  • Adapted from DiMarco et al, 2014, with permission.
    • In adult clinical trials, 0.6% of people experienced symptoms of slowed heart rate following first dose. Conduction abnormalities were usually transient and asymptomatic. Patients should be monitored during GILENYA initiation1

    Incidence of symptomatic bradycardia and AV block after first dose1

    • All patients should be monitored for at least 6 hours following the first dose of GILENYA due to risk of developing bradycardia or AV block
    Incidence of bradycardia and AV block following first dose of GILENYA vs placebo
    • *

      Following first dose, some patients experienced hypotension, dizziness, fatigue, palpitations, and/or chest pain that usually resolved within the first 24 hours on treatment.

    • Conduction abnormalities were usually transient and asymptomatic and resolved within the first 24 hours on treatment, but occasionally required treatment with atropine or isoproterenol.

    • Based on 24-hour Holter monitoring data, second-degree AV blocks (Mobitz type I [Wenckebach] or 2:1 AV blocks) occurred in 4% of patients on GILENYA and 2% of patients on placebo.

    The mechanism by which GILENYA exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the CNS. The mechanism of action (MOA) for GILENYA was observed in animal models.
     
    References: 1. Gilenya [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; May 2018. 2. Kappos L, Radue E-W, O’Connor P, et al; for FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. 3. Cohen JA, Barkhof F, Comi G, et al; for TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415. 4. Data on file. Summary of Clinical Efficacy in Multiple Sclerosis. Novartis Pharmaceuticals Corp; East Hanover, NJ. November 2009. 5. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability scale (EDSS). Neurology. 1983;33(11):1444-1452. 6. Data on file. CSR 2302. Novartis Pharmaceuticals Corp; East Hanover, NJ. July 2009. 7. Data on file. CSR 2301. Novartis Pharmaceuticals Corp; East Hanover, NJ. July 2009. 8. Ge Y. Multiple sclerosis: the role of MR imaging. AJNR Am J Neuroradiol. 2006;27(6):1165-1176. 9. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: The McGraw-Hill Companies, Inc; 2008:2611-2621. 10. Data on file. Briefing document. Novartis Pharmaceuticals Corp; East Hanover, NJ. May 2010. 11. Data on file. GILENYA exposure: May 2018 cutoff. Novartis Pharmaceuticals Corp; July 2018. 12. Data on file. Hub SRF and Sales Table. Novartis Pharmaceuticals Corp. Q4 2017. 13. Data on file. CSR 2309. Novartis Pharmaceuticals Corp; East Hanover, NJ. July 2009. 14. Chun J, Hartung H-P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010;33(2):91-101. 15. Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60(2):181-195. 16. Data on file. GILENYA exposure: February 2018 cutoff. Novartis Pharmaceuticals Corp; May 2018. 17. DiMarco JP, O’Connor P, Cohen JA, et al. First-dose effects of fingolimod: pooled safety data from three phase 3 studies. Mult Relat Disord. 2014;3(5):629-638. 18. Degaute JP, van de Borne P, Linkowski P, et al. Quantitative analysis of the 24-hour blood pressure and heart rate patterns in young men. Hypertension. 1991;18(2):199-210. 19. Zdanowicz MM, Lynch LM. Teaching the pharmacology of antiarrhythmic drugs. Am J Pharm Educ. 2011;75(7):139. 20. Ganusov VV, De Boer RJ. Do most lymphocytes in humans reside in the gut? Trends Immunol. 2007;28(12):514-518. 21. Zhang ZQ, Notemans DQ, Sedgewick G, et al. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc Natl Acad Sci U S A. 1998;95(3):1154-1159. 22. Haynes BF, Soderberg KA, Fauci AS. Introduction to the immune system. In: Fauci AS, ed. Harrison’s Rheumatology. 2nd ed. New York, NY: The McGraw-Hill Companies; 2010:2-43. 23. Aubagio [prescribing information]. Cambridge, MA: Genzyme Corp; October 2014a.