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Natalizumab

Classification: A

Drug products: Tysabri

ATC code: L04AA23

Substances: natalizumab

Summary

The effect of natalizumab in patients with relapsing remitting Multiple Sclerosis has been shown in both men and women. Regarding adverse events, no data with a relevant sex analysis were found.
 
In our opinion, the present evidence does not motivate differentiation in dosing or treatment between men and women.

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

No published analysis of pharmacokinetic characteristics in men and women have been found. No difference in dosing in men and women have been suggested by the producer [7].

Effects

In the AFFIRM study, a RCT comparing the effect of natalizumab and placebo in patients with relapsing MS (282 men, 660 women) found natalizumab to be more effective in preventing progression of disability than placebo [8]. However, no sex divided results were presented. Women developed anti-drug antibody (ADA) more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0) according to retrospective data from 3440 patients (987 men, 2453 women) on natalizumab treatment [9].

Adverse effects

No studies with a clinically relevant sex analysis regarding adverse effects of natalizumab have been found.

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, 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]. Natalizumab discontinuation is associated with a disease reactivation in MS patients. In a cohort of relapsing remitting multiple sclerosis patients discontinuing natalizumab due to progressive multifocal leukoencephalopathy (23 women, 7 men) concern significant reduction of cognitive impairment index (CII) was found after 1 year. Predictors of cognitive worsening was male sex, disease duration, and the treatment discontinuation [10].

In a prospective study of MS patients (n=300 on fingolimod, 221 women, 79 men) female sex and prior exposure to natalizumab (n=34) increased the probability of lymphopenia on fingolimod [11].

MS treatment with natalizumab is associated with Progressive Multifocal Leukoencephalopathy (PML) in patients seropositive for anti-JCV antibodies (JCV+) [11, 12]. In the STRATIFY-1 study, a longitudinal observational study of relapsing MS patients treated or considered for treatment with natalizumab (830 women, 266 men) in the United States, overall anti-JC virus antibody prevalence was 56.0% (95% CI, 53.0-59.0) [12]. Prevalence was significantly lower in women (53.4%; 95% CI, 49.9-56.8) than men (64.3%; 95% CI, 58.2-70.0). Similarly, in a Portuguese study among MS patients (253 women, 118 men), 253 (68%) patients were JCV+ [13]. More men (76%) than women (64%) were JCV+. There were few patients who converted in JCV status and no sex analysis was presented.

Updated: 2019-02-26

Date of litterature search: 2017-12-15

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. Tysabri (natalizumab). Summary of Product Characteristics. European Medicines Agency (EMA); 2017.
  8. Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. PubMed
  9. Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam R et al. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis. PLoS One. 2016;11(11):e0162752. PubMed
  10. Iaffaldano P, Viterbo RG, Trojano M. Natalizumab discontinuation is associated with a rebound of cognitive impairment in multiple sclerosis patients. J Neurol. 2016;263(8):1620-5. PubMed
  11. 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
  12. Bozic C, Richman S, Plavina T, Natarajan A, Scanlon JV, Subramanyam M et al. Anti-John Cunnigham virus antibody prevalence in multiple sclerosis patients: baseline results of STRATIFY-1. Ann Neurol. 2011;70(5):742-50. PubMed
  13. Correia I, Jesus-Ribeiro J, Batista S, Martins AI, Nunes C, Macário MC et al. Anti-JCV antibody serostatus and longitudinal evaluation in a Portuguese Multiple Sclerosis population. J Clin Neurosci. 2017;45:257-260. PubMed

Authors: Sebastian Ek

Reviewed by: Mia von Euler

Approved by: Karin Schenck-Gustafsson