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VERDICT & SUMMARY Testosterone patch (Intrinsa®▼) For the treatment of female hypoactive sexual desire disorder Committee’s Verdict: Category D BNF: 6.4.2 The testosterone patch is not considered suitable for prescribing. Current clinical evidence for efficacy is weak, based on short-term (24-week) trials using subjective outcomes. The size of benefit found was small, with questionable clinical relevance and a large placebo effect. There is concern about potential harmful effects of long-term use on breast tissue and the cardiovascular system (and endometrium if used outside the product license). Category D: cannot be recommended for prescribing because of inadequate evidence for efficacy and/or safety MTRAC reviewed this drug because it is a new formulation with potential for prescribing in primary care. Licensed indication For the treatment of hypoactive sexual desire disorder (HSDD) in bilaterally oophorectomised and hysterectomised (surgically-induced menopause) 1 women receiving concomitant oestrogen therapy. Background information In the Diagnostic and Statistical Manual of Mental Disorders, hypoactive sexual desire disorder (HSDD) is defined as a persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity.2 The American Urological Association characterises clinical lack of desire as occurring when a woman fails to feel desire at any stage during the sexual episode, and defines HSDD as one characterised by 'absent or diminished feelings of sexual interest or desire, absent sexual thoughts or fantasies, and a lack of responsive desire. Motivations for attempting to become sexually aroused are scarce or absent. Lack of interest goes beyond a normal lessening with increasing age and relationship duration'.3 There is debate whether lack of sexual desire is a disorder or a normal state in some women. What is generally agreed is that a lack of desire that causes distress to the woman or problems in the relationship with her partner is clinically important.4 In women, testosterone production is divided evenly between the ovaries and the adrenal gland. Removal of the ovaries during oophorectomy may lead to testosterone deficiency and, in some women, 4 concomitant loss of libido. A detailed history should be obtained from both partners in the relationship to eliminate other factors that may be affecting the woman’s desire for sex such as painful intercourse or previous sexual trauma. Psychological approaches such as cognitive behavioural therapy or sex therapy may enable the couple to focus their relationship in a more positive direction. October 2007 For the treatment of decreased libido in perimenopausal women, testosterone has been used as an adjunct to hormone replacement therapy.5,6 It is available as an intramuscular injection or implant (50 to 100 mg every 4 to 8 months).6 The testosterone transdermal patch has recently been licensed for the treatment of HSDD. The aim of treatment is to replace testosterone in patients who may have androgen deficiency as a result of removal of the ovaries. Clinical efficacy Four double-blind, randomised, controlled trials7-10 compared the testosterone 300 µg/day patch with a placebo patch in women who had undergone surgically-induced menopause, were receiving a stable dose of oestrogen, and expressed concern about their loss of libido. One study also evaluated patches delivering 150 µg and 450 µg of testosterone per day.9 The studies were of 24 weeks’ duration and involved 1,619 women with a mean age of about 49 years. The primary outcome measure in the studies was the change in the number of satisfying sexual episodes during the last four weeks of treatment compared with baseline as reported in the Sexual Activity Log, a weekly diary of sexual activity kept by participants. In two studies,9,10 the sexual desire domain of the Profile of Female Sexual Function (PFSF) was also used as a primary endpoint. Both outcome measures were developed and validated by the manufacturer of the testosterone patch. The PFSF7 is a 37-item questionnaire measuring seven different domains of sexual function: sexual desire, sexual pleasure, sexual arousal, orgasm, sexual responsiveness, lessening of sexual concerns and sexual self-image. Scores from the domains are summed and converted to a scale (0 to 100). Results from three studies7-9 showed that the increase in the total number of satisfying sexual episodes in a four-week period was significantly greater for Page 1 of 2 testosterone-treated patients than placebo-treated patients (an average increase of about two episodes per four-week period with testosterone treatment compared with about one episode with placebo, from a baseline of two to four episodes in four weeks). There was no significant difference compared with placebo in the fourth study (which may have been underpowered for the primary endpoint).10 Doses of 150 µg and 450 µg of testosterone per day showed no significant difference compared with placebo for this outcome.9 There was a large placebo response in the trials; 46% of patients on testosterone vs. 35% on placebo were responders (i.e. had an increase from baseline of at least one satisfying sexual episode per four-week period). Fifty-four percent of patients on testosterone were non-responders.5 In all four studies, there was a significantly greater improvement with testosterone treatment for the sexual-desire domain of the PFSF compared with placebo after 24 weeks’ treatment (increases of 6 or 7 points more than placebo on a 100-point scale). The differences for women using 150 µg and 450 µg patches were not statistically significant compared with placebo.9 Significantly greater improvements after 24 weeks’ treatment were reported for testosterone-treated women compared with placebo in the remaining six domains of the PFSF in two studies7,8 in five domains in one study10 and in one 9 domain (sexual arousal) in the final study. Adverse effects The most commonly reported adverse events were application-site reactions, headaches, upper respiratory tract infections and acne. None of the trials reported any significant differences in the incidence of androgenic side effects between testosterone- or placebo-treated women; the incidences were 18% in testosterone-treated women and 14% in placebo-treated women. The EMEA’s Committee for Medicinal Products for Human use (CHMP) expressed concern about the lack of long-term safety data, especially with regard to potential harmful effects on the breast, the cardiovascular system and, in the case of unlicensed use in women with a uterus, the endometrium.11 The manufacturer was requested to provide a Risk Management Plan to address the need for longer-term safety data. As part of the Plan, prescribing will be monitored. Off-license use in women with natural menopause and in those not taking additional hormone replacement therapy will be discouraged.11 Additional information • The recommended daily dose of testosterone is 300 µg via a patch applied to the abdomen twice weekly. • The response to treatment should be evaluated within 3 to 6 months of initiation, and treatment discontinued if no meaningful benefit is reported. • At current prices, a year’s treatment with the testosterone 300 µg/day transdermal patch costs £364. References 1. Procter and Gamble Pharmaceuticals UK Ltd. Intrinsa transdermal patch. Summary of Product Characteristics. 2007. http://www.emc.medicines.org.uk/ 2. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-R. 4th ed. Washington DC: American Psychiatric Association; 2003. 3. Basson R. Sexual desire and arousal disorders in women. N Engl J Med 2006;354:1497-1506. 4. Butcher J. ABC of Sexual Health. Female sexual problems I: Loss of desire - what about the fun? BMJ 1999;3318:41-43. 5. UK Medicines Information Service. Testosterone ® Transdermal Patch (Intrinsa ) for female hypoactive sexual desire disorder. 07/03a. UKMi. 2007. http://www.nelm.nhs.uk/Documents/TestosteroneNM PRevisedJun07.pdf?id=578766 6. Anon. Male sex hormones and antagonists. British National Formulary. 53 ed. 2007. pp. 389-391. 7. Simon J, Braunstein G, Nachtigall L et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005;90:5226-5233. 8. Buster JE, Kingsberg SA, Aguirre O et al. Testosterone patch for low sexual desire in surgically menopausal women: A randomised trial. Obstet Gynecol 2005;105:944-952. 9. Braunstein G, Sundwall DA, Katz M et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women. Arch Intern Med 2005;165:1582-1589. 10. Davis SR, van der Mooren MJ, van Lunsen RHW et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomised, placebo-controlled trial. Menopause 2006;13:387396. 11. European Medicines Agency. European Public Assessment Report: Intrinsa. EMEA. 2007. http://www.emea.europa.eu/humandocs/PDFs/EPAR/ intrinsa/063406en6.pdf <accessed 4/10/2007> Launch date: April 2007 Manufacturer: Procter & Gamble Pharmaceuticals UK Ltd EU/1/06/352/002 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk Relevant NICE guidance was not available at time of issue of this verdict Date: October 2007 ©Midlands Therapeutics Review & Advisory Committee VS07/20