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DTB | Dapoxetine for premature ejaculation
DTB CME/CPD* BNF 7.4.6
Dapoxetine for premature ejaculation Premature ejaculation, also referred to as rapid or early ejaculation, is a poorly understood disorder with no single, widely-recognised, evidence-based definition. Studies based on patient self-reporting indicate that premature ejaculation is a common complaint with estimated prevalence ranging from 4%–39% of men in the general community.1 However, a lack of an accurate validated definition has made comparison of the results of such studies difficult.2 In addition, perception of normal ejaculatory latency varies by country and differs when assessed by the patient or their partner.3 Dapoxetine (Priligy—A. Menarini Farmaceutica Internazionale SRL), a short-acting selective serotonin reuptake inhibitor (SSRI) is the first drug to be licensed in the UK for on-demand management of diagnosed premature ejaculation.4 In this article we review the evidence for dapoxetine and discuss some of the challenges associated with its introduction.
Background There are a number of definitions of premature ejaculation, all of which refer to a measure of time-to-ejaculation, an inability to control or delay ejaculation and negative personal consequences from premature ejaculation. Recently published definitions including those of the International Society for Sexual Medicine (ISSM)5 and the Diagnostic and Statistical Manual of Mental Disorders (DSM)-56 stipulate an intravaginal ejaculation latency time (IELT) of less than 1 minute as a criterion, based on data supporting the idea that an IELT of less than 1 minute is abnormal.1 Estimates of the prevalence of men with an IELT of less than 1 minute range from 1%–3%.7,8 However, many of the studies of drug therapy of premature ejaculation used earlier DSM definitions that did not include a specified limit for IELT. As a result, an IELT of less than 2 minutes was generally used as an inclusion criterion in studies. ISSM and DSM-5 definitions specifically refer to vaginal penetration and are only applicable to heterosexual relationships.
Treatment options Management of premature ejaculation is determined by whether it is lifelong (primary) or acquired (secondary). Acquired premature ejaculation can be gradual or sudden in onset but follows normal ejaculation experiences before onset. Time-to-ejaculation is usually shorter in men with lifelong premature ejaculation.2 European Association of Urology guidelines suggest that after removal of potential reversible causes (e.g. relationship problems), first-line treatment of acquired premature ejaculation is behavioural therapy, with drug therapy recommended second-line.2 For lifelong premature ejaculation (estimated prevalence of 2%–5%) drug therapy is used as first-line treatment.2 Drugs used to treat premature ejaculation include topical anaesthetic agents (e.g. lidocaine-prilocaine cream), tricyclic antidepressants, phosphodiesterase type-5 inhibitors and alpha-1 selective alpha blockers. However, as serotonin has been shown to have an inhibitory role in ejaculation9 research has focussed mainly on the use of SSRIs and the efficacy and safety of daily use compared with on-demand use. Most drug therapy studies included patients with acquired and lifelong premature ejaculation but there appears to be no difference in treatment outcomes between the classifications.10 * DTB CME/CPD A CME/CPD module based on this article is available for completion online via BMJ Learning (learning.bmj.com) by subscribers to the online version of DTB. If prompted, subscribers must sign into DTB with their username and password. All users must also complete a one-time registration on BMJ Learning and subsequently log in (with a BMJ Learning username and password) on every visit. The answers to the multiple choice questions will be freely available on dtb.bmj.com on publication of the next issue of DTB.
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What is dapoxetine? Dapoxetine is indicated for the treatment of premature ejaculation in men aged 18–64 years who meet all of the following criteria: • an IELT of less than 2 minutes; • persistent or recurrent ejaculation with minimal sexual stimulation and before the patient wishes; • marked personal distress or difficulty due to premature ejaculation; • poor control over ejaculation; • a history of premature ejaculation in the majority of intercourse attempts over the previous 6 months.4 The dose of dapoxetine is 30mg taken 1–3 hours before anticipated sexual activity. The maximum dose of 60mg may be used by patients with insufficient benefit and no moderate or severe adverse effects, or prodromal symptoms suggestive of syncope with the 30mg dose.4 However, there is an increased incidence and severity of adverse effects with the 60mg dose. The maximum frequency of dosing is once every 24 hours. Dapoxetine is rapidly absorbed, achieves peak plasma concentrations in about 1 hour, is rapidly eliminated and does not appear to accumulate.11
Dapoxetine versus placebo A number of large randomised double-blind placebo-controlled studies have assessed efficacy of dapoxetine in heterosexual men. Four phase III studies included in the licence application used the DSM-IV definition of premature ejaculation and a baseline IELT of less than or equal to 2 minutes on at least 75% of at least four sexual intercourse events as inclusion criteria.12–14 Two-thirds of subjects in two of these studies13,14 were categorised as having lifelong premature ejaculation.10 All four studies included at least 1,000 subjects. The primary outcome was mean IELT at study endpoint at 12–24 weeks, measured by partner stopwatch.12–14 Other evidence used in the licence application included a subanalysis of a tolerability study that examined patient reported outcomes15 and an unpublished 9-month extension study enrolling patients from two previous studies.16 There is some debate about how changes in IELT from baseline should be presented; as an arithmetic mean (the mean value of the sum of values) or as a geometric mean (using an average of the log-transformation of each IELT value). The geometric mean tends to give more conservative results that are less affected by data outliers.11 Although the geometric mean is considered to be more representative of treatment outcome1 it was not used in all studies. All four pivotal studies reported that dapoxetine 30mg or 60mg on-demand significantly increased IELT from baseline compared with placebo (p