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Darifenacin

Klassificering: B

Preparat: Emselex®

ATC kod: G04BD10

Substanser: darifenacin, darifenacinhydrobromid

Sammanfattning

Data från kliniska studier ger varierande resultat gällande könsskillnader. Eftersom genes och symptombild för urininkontinens och överaktiv blåsa delvis skiljer sig åt mellan kvinnor och män är könskillnader i effekt av darifenacin svårtolkade. De flesta studier har inkluderat få män vilket ytterligare försvårar bedömning av potentiella könsskillnader.
Studier har visat att långtidspersistens vid antikolinergikabehandling är låg hos både kvinnor och män.
Det finns med nuvarande kunskapsunderlag inget skäl att generellt differentiera i behandling mellan kvinnor och män med trängningsinkontinens.

Additional information

Anticholinergic drugs reduce the bladder detrusor muscle contractions and are used to treat urgency incontinence and symptoms of overactive bladder. Due to sex differences in etiology of these symptoms, drug therapy differs as urinary retention must be ruled out before starting treatment with anticholinergic drugs. In women,anticholinergic drugs are commonly used when non-pharmacological treatments such as bladder training are insufficient. In men, benign prostate hyperplasia is a common cause of urgency symptoms. Non-anticholinergic drugs, primarily alpha-1 blockers, are therefore often used as first-line treatment in men even though anticholinergic drugs are used in addition or as monotherapy [1-3].

The baseline symptoms described in studies differ between men and women regarding prevalence of incontinence episodes and frequency of urgency episodes [4, 5]. Treatment effects on these parameters are common outcomes in clinical studies and differences in treatment effect between men and women need to be interpreted in relation to differences at baseline. The placebo effect seen in clinical studies of overactive bladder treatment is relatively high. According to a meta-analysis, 41% of the patients in placebo groups report cure or symptom improvement [6]. Two other meta-analysis report that changes from baseline with placebo treatment are significant for mean micturitions, mean incontinence episodes and mean voided volume [7, 8].

It should be noted that most studies include more women than men, and the low number of men included can affect the ability to make statistically significant analysis.

Pharmacokinetics and dosing

According to studies conducted by the manufacturer, clearance was 39% higher and AUC 28% lower in men [11]. In a population pharmacology study with pooled data from 18 studies (44 men, 293 women), clearance was 31% lower in women [12]. Despite the pharmacokinetic differences of darifenacin, the clinical studies have shown effect with similar doses in men and women, and no sex differentiation in dosing has been suggested [11].

Effects

A post hoc analysis of an open label study of 3766 patients (77% women) treated with darifenacin for overactive bladder symptoms reported a correlation between men and women and efficacy of darifenacin treatment, measured as improvement in urgency, micturition and nocturia episodes. However the differences were small and probably not clinically relevant according to the authors [13].

Both men and women were reported to have long-term effect of darifenacin regarding health related quality of life in a long term open-label study, designed as a two year extension to two placebo-controlled double blind studies (41 men and 262 women on darifenacin) [14].

According to the manufacturer’s documentation to FDA [11] the magnitude of treatment effect of darifenacin was higher in women. The effect is shown as reduction in incontinence episodes.

Adverse effects

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

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Patient satisfaction with anticholinergic treatment was evaluated in a survey study in Japanese patients with overactive bladder syndrome (in total 514 men, 455 women). In the entire study one third of all patients were satisfied and one third dissatisfied with their treatment, men were overall less satisfied than women. Dissatisfaction was commonly influenced by poor efficacy or adverse effects, mainly constipation [9].In a Swedish register study of the prescription of potentially inappropriate drugs in elderly patients, women were more likely to be prescribed anticholinergic drugs then men [10].A German database study (26,834 patients, 1995 treated with darifenacin) evaluated discontinuation rate of anticholinergic drugs in patients with urinary incontinence. Discontinuation rate for all drugs was 75% in women and 78% in men in the first year and 86% in women and 88% in men within three years. After adjusting for demographic and clinical variables, the risk of discontinuation was higher in men [15].

Försäljning på recept

Fler kvinnor än män hämtade ut tabletter innehållande darifenacin (ATC-kod G04BD10) på recept i Sverige år 2015, totalt 681 kvinnor och 424 män [16].

Uppdaterat: 2019-02-26

Litteratursökningsdatum: 2015-03-12

Referenser

  1. Kaplan SA, Roehrborn CG, Abrams P, Chapple CR, Bavendam T, Guan Z. Antimuscarinics for treatment of storage lower urinary tract symptoms in men: a systematic review. Int J Clin Pract. 2011;65:487-507. PubMed
  2. Giannitsas K, Athanasopoulos A. Male overactive bladder: pharmacotherapy for the male. Curr Opin Urol. 2013;23:515-9. PubMed
  3. Andersson KE. The use of pharmacotherapy for male patients with urgency and stress incontinence. Curr Opin Urol. 2014;24:571-7. PubMed
  4. Coyne KS, Sexton CC, Thompson CL, Milsom I, Irwin D, Kopp ZS et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int. 2009;104:352-60. PubMed
  5. Irwin DE, Milsom I, Hunskaar S, Reilly K, Kopp Z, Herschorn S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol. 2006;50:1306-14; discussion 1314-5. PubMed
  6. Nabi G, Cody JD, Ellis G, Herbison P, Hay-Smith J. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev. 2006;18:CD003781. PubMed
  7. Lee S, Malhotra B, Creanga D, Carlsson M, Glue P. A meta-analysis of the placebo response in antimuscarinic drug trials for overactive bladder. BMC Med Res Methodol. 2009;9:55. PubMed
  8. Mangera A, Chapple CR, Kopp ZS, Plested M. The placebo effect in overactive bladder syndrome. Nat Rev Urol. 2011;8:495-503. PubMed
  9. Johnell K, Weitoft GR, Fastbom J. Sex differences in inappropriate drug use: a register-based study of over 600,000 older people. Ann Pharmacother. 2009;43:1233-8. PubMed
  10. Akino H, Namiki M, Suzuki K, Fuse H, Kitagawa Y, Miyazawa K et al. Factors influencing patient satisfaction with antimuscarinic treatment of overactive bladder syndrome: results of a real-life clinical study. Int J Urol. 2014;21:389-94. PubMed
  11. Food and Drug Administration (FDA). Clinical Pharmacology and Biopharmaceutics Review - ENABLEX (darifenacin) [updated 2004-12-22, cited 2015-03-16]. länk
  12. Kerbusch T, Wählby U, Milligan PA, Karlsson MO. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Br J Clin Pharmacol. 2003;56:639-52. PubMed
  13. Schneider T, Marschall-Kehrel D, Hanisch JU, Michel MC. Do gender, age or lifestyle factors affect responses to antimuscarinic treatment in overactive bladder patients?. Int J Clin Pract. 2010;64:1287-93. PubMed
  14. Dwyer P, Kelleher C, Young J, Haab F, Lheritier K, Ariely R et al. Long-term benefits of darifenacin treatment for patient quality of life: results from a 2-year extension study. Neurourol Urodyn. 2008;27:540-7. PubMed
  15. Kalder M, Pantazis K, Dinas K, Albert US, Heilmaier C, Kostev K. Discontinuation of treatment using anticholinergic medications in patients with urinary incontinence. Obstet Gynecol. 2014;124:794-800. PubMed
  16. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk

Författare: Ludvig Petersson, Desirée Loikas

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson