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Fingolimod

Classification: C

Drug products: Gilenya, GILENYA®

ATC code: L04AA27

Substances: fingolimod, fingolimod hydrochloride

Summary

The effect of fingolimod in patients with relapsing remitting Multiple Sclerosis has been shown in both men and women. Regarding adverse events, female sex has been associated with increased risk of lymphopenia and more infections during treatment with fingolimod. An increased frequency of alterations in transaminases have been reported among men.

Fingolimod should not be used in pregnancy. Swedish users, please consult Janusmed Drugs and Birth Defects.

In our opinion, the present evidence does not motivate differentiation in dosing or treatment between men and women. Monitoring women for signs and symptoms of infection and
lymphopenia
and men for AST/ALT alterations is recommended.

Additional information

Multiple Sclerosis (MS) is more common in women than in men [1, 2]. The gender gap in prevalence has been increasing and is today estimated to be two to three times more common in women than in men [1-3].

Several risk factors of MS have been suggested to have a larger impact on women. Sunlight deprivation, vitamin D deficiency, overweight, low urate levels, and smoking are such risk factors that increase the risk more in women than in men. Suggested mechanisms are that smoking yields increased levels of mature peripheral functioning T cells (OKT3+) in women [1]. Men have a worse prognosis and the role of sex hormones have been discussed [1, 2].

In a biomarker study of MS patients (30 men, 70 women) and healthy controls (24 men, 51 women), insulin growth factor binding protein1 (IGFBP1) was higher in women with MS compared to men [4]. The authors suggest this could reflect different MS progression pathways in men and women.

Pharmacokinetics and dosing

According to the manufacturer, there are no sex differences in the pharmacokinetics of fingolimod or the active metabolite fingolimod phosphate and different dosing of fingolimod in men and women has not been suggested [7].

The influence of sex on the pharmacokinetics of fingolimod and fingolimod phosphate has been evaluated in population pharmacokinetic analyses including data from 1252 patients with MS (881 women, 371 men) involved in phase III studies [8]. No significant differences in apparent clearance according to sex were observed for fingolimod or fingolimod phosphate.

Effects

In the FREEDOMS I-II studies, RCTs comparing the effect of fingolimod and placebo in patients with relapsing MS (622 men, 1733 women) found fingolimod to be more effective than placebo [9, 10]. However, no sex divided results were presented in the original publications. However, a subgroup analysis of the FREEDOMS 1 study (249 men, 594 women) indicated a higher relative reduction in annualized relapse rates (ARRs) in men with fingolimod 0.5 mg compared to women. Men in the placebo group seemed to have higher ARRs than women [11].

In the TRANSFORMS trial, a RCT (422 men, 870 women) comparing the effect of fingolimod and interferon beta-1a, found fingolimod to be more effective than interferon beta-1a [12]. No sex divided results were presented.

Adverse effects

In a cohort of fingolimod treated patients (154 women, 71 men) with relapsing MS (observation period 2 years ± 7 months) infectious episodes after the first year of treatment (8.8%) were more common among women than men [13]. Aspartate aminotransferase (AST) and alanine-amino transferase (ALT) alterations were observed after 12 months mostly in men (28.8% vs 3.5%, and 38.4% vs 10%). The authors suggest monitoring women for signs and symptoms of infection for a longer period and men for AST/ALT alterations.

In a prospective study of MS patients treated with fingolimod (79 men, 221 women) female sex and prior exposure to natalizumab increased the probability of lymphopenia [14]. The risk of developing lymphopenia grade 4 (< 200) (OR 0.30 (95% CI 0.112, 0.718)) and grade 3b+4 (< 350) (OR: 0.37 (95% CI 0.211, 0.668) was higher in female patients. The results are consistent with data from German and Swedish registries (including 856 RRMS patients treated with fingolimod) in which female sex and previous treatment with natalizumab were among two predictors of profound lymphopenia (<200/mm3) [15]. 

A small study (16 women, 11 men) of autonomic heart rhythm regulation found continuous fingolimod dosing to shift cardiac autonomic regulation towards sympathetic predominance, particularly in men. This increases the risk higher heart rate and heart disease [16].

Drug interactions

Swedish users, please consult Janusmed Interactions(Janusmed interaktioner).

Birth defects

Fingolimod should not be used during pregnancy. Swedish users, please consult JanusmedDrugs and Birth Defects(Janusmed fosterpåverkan).

Other information

In a US study based on questionnaires with a response rate of 44%, women with MS reported better awareness of disease symptoms and were found to express more positive perceptions of their ability to manage therapy with disease modifying drugs than men with MS [5].

In a survey study of patient risk tolerance in MS treatment 10 259 patients (response rate 53 %, resulting in 1196 men, 4250 women), women, elderly and those caring for dependents had a lower risk tolerance, while individuals with a more pronounced disability had a higher risk tolerance [6].A reduction of the bone resorption marker type 1 collagen cross-linked N-telopeptide (uNTx) in urine was seen in women treated with fingolimod (n=20) but not in men (n=9) [17]. The patients had been treated with fingolimod 0.5 mg for at least 3 months. The authors of the study suggest fingolimod may have a beneficial effect on bone mass loss in female MS patients.

Updated: 2018-11-01

Date of litterature search: 2018-02-10

References

  1. Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler. 2014;20:520-6. PubMed
  2. Voskuhl RR, Gold SM. Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol. 2012;8:255-63. PubMed
  3. Johnson KM, Zhou H, Lin F, Ko JJ, Herrera V. Real-World Adherence and Persistence to Oral Disease-Modifying Therapies in Multiple Sclerosis Patients Over 1 Year. J Manag Care Spec Pharm. 2017;23:844-852. PubMed
  4. Al-Temaimi R, AbuBaker J, Al-Khairi I, Alroughani R. Remyelination modulators in multiple sclerosis patients. Exp Mol Pathol. 2017;103(3):237-241. PubMed
  5. Vlahiotis A, Sedjo R, Cox ER, Burroughs TE, Rauchway A, Lich R. Gender differences in self-reported symptom awareness and perceived ability to manage therapy with disease-modifying medication among commercially insured multiple sclerosis patients. J Manag Care Pharm. 2010;16:206-16. PubMed
  6. Fox RJ, Salter A, Alster JM, Dawson NV, Kattan MW, Miller D et al. Risk tolerance to MS therapies: Survey results from the NARCOMS registry. Mult Scler Relat Disord. 2015;4(3):241-9. PubMed
  7. GILENYA (fingolimod). Summary of Product Characteristics. European Medicines Agency (EMA); 2018.
  8. David OJ, Kovarik JM, Schmouder RL. Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet 2012 Jan 1;51(1):15-28 PubMed
  9. 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(5):387-401. PubMed
  10. 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(6):545-56. PubMed
  11. Devonshire V, Havrdova E, Radue EW, O'Connor P, Zhang-Auberson L, Agoropoulou C et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012;11(5):420-8. PubMed
  12. 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(5):402-15. PubMed
  13. Manni A, Direnzo V, Iaffaldano A, Di Lecce V, Tortorella C, Zoccolella S et al. Gender differences in safety issues during Fingolimod therapy: Evidence from a real-life Relapsing Multiple Sclerosis cohort. Brain Behav. 2017;7(10):e00804. PubMed
  14. Baharnoori M, Gonzalez CT, Chua A, Diaz-Cruz C, Healy BC, Stankiewicz J et al. Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count. Mult Scler Relat Disord. 2018;20:51-57. PubMed
  15. Warnke C, Dehmel T, Ramanujam R, Holmen C, Nordin N, Wolfram K et al. Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology. 2014;83(23):2153-7. PubMed
  16. Simula S, Laitinen T, Laitinen TM, Tarkiainen T, Hartikainen P, Hartikainen JE. Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis. Mult Scler. 2016;22(8):1080-5. PubMed
  17. Miyazaki Y, Niino M, Kanazawa I, Suzuki M, Mizuno M, Hisahara S et al. Fingolimod suppresses bone resorption in female patients with multiple sclerosis. J Neuroimmunol. 2016;298(1):24-31. PubMed
  18. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2016 [cited 2018-02-02.] länk

Authors: Sebastian Ek, Linnéa Karlsson Lind

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson