London Medicines Evaluation Network Review. Dapoxetine (Priligy ) for premature ejaculation Updated January 2014

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1 London Medicines Evaluation Network Review Dapoxetine (Priligy ) for premature ejaculation Updated January 2014 Summary Dapoxetine is the first oral treatment for premature ejaculation (PE) to be licensed in the UK. It is a short-acting SSRI which can be taken when required up to 1-3 hours prior to anticipated sexual intercourse, no more than once a day. It is not intended for continuous daily dosing and should only be used by men who meet specific criteria. Use of dapoxetine is contra-indicated in a number of medical conditions (such as cardiovascular) and with certain medications (such as those affecting serotonin release or CYP3A4 enzyme inhibitors). Efficacy and safety have been demonstrated in five phase 3 placebo-controlled studies. The primary endpoint, intravaginal ejaculation latency time (IELT), was increased from a baseline mean of 0.9 minutes to minutes with dapoxetine. A change of at least 1 minute in IELT was perceived by the men to be clinically meaningful to them. Significant improvements in PE with dapoxetine were also evidenced by the more subjective secondary endpoints of patient-reported outcomes. These included control of PE, satisfaction with sexual intercourse, personal distress relating to ejaculation and interpersonal difficulties relating to ejaculation, as well as how the patient perceived improvements in PE. The main adverse events seen in the trials were nausea, dizziness and headache. The cost of dapoxetine, used 3-6 times a month, is significantly higher than that of other SSRIs used off-label. 1. Background and introduction The prevalence of premature ejaculation (PE) varies according to definition and is difficult to assess in view of many men not wanting to seek help or even discuss the problem. 1 The aetiology of, and risk factors for, PE are unknown but it is important to distinguish PE from erectile dysfunction (ED); if ED exists, it should be treated before or at the same time as PE. 2 The prevalence of PE is not related to age and ranges from 3-30%. 1 The neurophysiology of ejaculation is complex, involving the sympathetic, parasympathetic and somatic spinal centres. Serotonin has an inhibitory effect on ejaculation and selective serotonin reuptake inhibitor antidepressants (SSRIs), by increasing serotonin activity, cause a delay in ejaculation. 3 Because of this side effect, SSRIs, such as paroxetine, sertraline and fluoxetine, have been used off-label to treat PE. 1;4 These SSRIs have a relatively long onset of action, taking 2-3 weeks to achieve efficacy, and continual dosing is required to have an on-going effect on delaying ejaculation. Continual use can also be associated with other side effects, and there is a risk of withdrawal symptoms if they are stopped suddenly. 3;4 Dapoxetine is a more potent SSRI and is the first licensed treatment for premature ejaculation in men aged years of age. 5 Dapoxetine has a different pharmacokinetic profile to those SSRIs licensed for the treatment of depression. 4 The time to maximum serum concentration of dapoxetine is about 1-2 hours and it is rapidly eliminated, with a half-life of 1.5 hours. 5 This allows for on-demand treatment, i.e. taken as needed 1-3 hours prior to sexual activity. The European Association of Urology guidelines (2010) state that daily treatment with SSRIs has become the first choice treatment in PE. 2 The use of local anaesthetics to delay ejaculation is the oldest form of pharmacological therapy for PE and is a viable alternative to SSRIs. Within these guidelines it is recommended that dapoxetine should be considered for on-demand use: the EAU acknowledge that this is the only licensed treatment for PE. 2. Proposed place in therapy Dapoxetine is the first licensed oral treatment for PE in men aged years who meet all of the following criteria: 5 An intravaginal ejaculatory latency time (IELT) of less than two minutes; and Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the patient wishes; and Marked personal distress or interpersonal difficulty as a consequence of PE; and Poor control over ejaculation; and A history of premature ejaculation in the majority of intercourse attempts over the prior 6 months. Dapoxetine should be taken 1-3 hours prior to sexual activity, starting with the 30mg dose and only increasing to 60mg if 30mg is insufficient and the patient has not experienced any moderate or severe adverse events or prodromal symptoms suggestive of syncope. Dapoxetine is not intended for continuous daily use and must not be taken more than once daily. 5 Dapoxetine has been available in the UK prior to November 2013 on a private prescription only. From November 2013, it will prescribable on the NHS. 6 However it may still need to go through local approval processes before it becomes routinely available. 3. Evidence selected for inclusion There are five randomised, double-blind, placebo-controlled phase 3 studies evaluating dapoxetine 30mg and 60mg over 9-24 weeks. 4;7-9 In all studies, men had to meet the diagnostic criteria for PE as specified in the Diagnostic and Statistical Manual of 1

2 Mental Disorders 4 th edition (DSM-IV-TR): onset of orgasm and ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wished, in most intercourse episodes in the 6 months before enrolment, and marked distress or interpersonal difficultly due to PE. Men were enrolled if they had been in a stable monogamous, heterosexual relationship for 6 months and had an intravaginal ejaculatory latency time (IELT) of 2 minutes in at least 75% of intercourse episodes at baseline in four of the studies. 4;7;8 Exclusion criteria included erectile dysfunction, concomitant use of SSRIs or tricyclic antidepressants, major psychiatric disorders, history of medical illness, uncontrolled hypertensions or other forms of sexual dysfunction. Dapoxetine was taken 1-3 hours prior to anticipated sexual intercourse, and not more than once every 24 hours. The primary endpoint of four of the phase 3 studies was average IELT, measured using a stopwatch by participants/partners. 4;7;8 In the fifth study, the primary endpoint was evaluation of potential withdrawal effects. 9 Mean baseline IELT times were minute. 4;7;8 All of the studies reported patient orientated outcomes based on the Premature Ejaculation Profile (PEP) (see Appendix table 1). The IELT should be used alongside recognised questionnaires such as the PEP to characterise PE and determine treatment effects. 2 Geometric means and mean fold-increases were reported in two studies; these are based on logarithmic transformed values of the average IELT and are less affected by outliers. 7;8 Geometric means were not reported in the integrated analysis because this was carried out prior to the recommendation that geometric means should be used. The following four studies evaluated the efficacy and safety of dapoxetine. Study NCT Men (mean age 40 years) were randomised to 24-weeks of treatment with placebo (n=385), dapoxetine 30mg (n=388) or 60mg (n=389). Most (92%) men enrolled had poor or very poor perceived control over ejaculation, with PE causing quite a bit - extreme personal distress in 68%, although PE was perceived to cause little or no interpersonal difficulties in just under half (49%). A sample size of 258 patients per group was deemed sufficient to detect a 1 minute difference in IELT between placebo and dapoxetine 60mg with 90% power. Stratification was according to IELT: 1 minute or 0.5 minutes. Of the 1,162 men enrolled, on 53% completed the study. Analysis was in the intention-to-treat population. a. The primary endpoint, mean IELT at week 24, increased significantly with dapoxetine to 3.1 minutes (30mg) and 3.5 minutes (60mg) vs. 1.9 minutes (placebo), (p<0.001 both doses vs. placebo). Mean IELT improvements were also significantly greater with both doses of dapoxetine in men with baseline IELT 1 min and 0.5min (see Appendix table 2). NCT (Asia-Pacific study). 8 Men were randomised to 12 weeks of treatment with placebo (n=357) or dapoxetine 30mg (n=354) or 60mg (n=356). Most (89%) men enrolled had poor or very poor perceived control over ejaculation, with PE causing moderate-extreme personal distress in 68%, and moderate extreme interpersonal difficulties in 80%. Stratification was according to IELT: 1 minute or >1 minute. Of the 1,067 men enrolled, 80% completed the study. The most common reasons for discontinuation in 11.6% were personal reasons, insufficient response or other reasons. Few patients discontinued due to lack of efficacy (1.1%). No power or sample size calculation was stated. The primary endpoint, mean IELT at 12 weeks, increased significantly with dapoxetine 30mg (3.9 minutes) and 60mg (4.2 minutes) compared with placebo (2.4 minutes), (p<0.001 both doses vs. placebo, see table 2). Significant mean IELT increases were seen in men with baseline IELT 1 minute with both doses of dapoxetine, but only with the 30mg dose in men with baseline IELT 0.5 minutes (see Appendix table 3). Studies NCT and NCT (integrated analysis). 4 Men aged 18 to 65 years with PE (mean duration 10 years) were randomised to 12 weeks of treatment with dapoxetine 30mg (n=874) or 60mg (n=870) or placebo (n=870) and instructed to have sexual intercourse six or more times per month. Stratification was according to IELT: 1 minute or >1 minute. A sample size of 300 patients per group was deemed sufficient to detect a 1 minute difference in IELT between the best performing and worst performing treatments with 98% power. Of the 2,614 men enrolled, 75% completed the study. Few patients (1%) discontinued due to lack of efficacy. b. The primary endpoint, mean IELT at week 12, was increased 3-4-fold with dapoxetine and to a greater extent than placebo with endpoint values of: 2.78 minutes (30mg) and 3.32 minutes (60mg), vs minutes (placebo) (p<0.0001, both doses vs. placebo and p=0.0007, 60mg vs. 30mg) (see Appendix table 5 for further details). Dapoxetine was better than placebo from the first dose. Even though patients were instructed to take dapoxetine 1-3 hours before anticipated sexual intercourse, not all reported events were inside this time window, but even when taken 30 mins -1 hour before, or more than 3 hours before, IELT was still significantly increased with both doses of dapoxetine vs. placebo. The primary endpoint of study NCT was the evaluation of potential withdrawal effects after abrupt discontinuation. 9 These results have been published as a conference abstract and are discussed in section Men (n=1238) were randomised to treatment with placebo, dapoxetine 60mg as needed + placebo once daily or dapoxetine once daily + placebo as needed for 9 weeks. 9 Patients were expected to attempt sexual intercourse at least six times a month. At the end of the double-blind phase, men taking dapoxetine were re-randomised in a double-blind fashion to take the same treatment or switch to placebo for an additional 7 days in order to assess withdrawal symptoms. Other endpoints were the treatment benefits of dapoxetine vs. placebo, based on patient reported outcomes. 9 All efficacy analyses were based on the modified ITT population; patients who took 1 doses of study drug and answered either or both of the perceived control and satisfaction patient-reported outcome (PRO) questions at baseline and at 1 sample times after baseline. No power or sample size calculation was stated. Results are shown in the Appendix table 4, and summarised in the Patient reported outcomes section below. 2

3 Patient reported outcomes There were a number of patient reported outcomes in all of the studies (see Appendix for further details). Improvements were seen with dapoxetine treatment from the first study visit (4 weeks in all studies). Perceived control over ejaculation: In the integrated analysis, control over ejaculation improved in all three groups with no significant differences between placebo and dapoxetine. 4 In the other studies, significant improvements with control over ejaculation were seen with dapoxetine compared with placebo (p<0.001). 7-9 Satisfaction with sexual intercourse: In the integrated analysis, satisfaction improved in all three groups with no significant differences between placebo and dapoxetine and approximately three-quarters of partners of those using dapoxetine reported fair, good, very good satisfaction with sexual intercourse at end of study, compared with just over half of those using placebo. 4 In the other studies, significant improvements with sexual intercourse were seen with dapoxetine compared with placebo (p<0.001). 7-9 Personal distress related to ejaculation: Improvements in distress were significantly better with dapoxetine at most time points, including week 24 (p<0.001). 7-9 Interpersonal difficulties related to ejaculation: Improvements in interpersonal difficulty were significantly better with dapoxetine at most time points, including week 24 (p<0.05). 7-9 Change in patients perception of PE: Severity rating of PE improved with dapoxetine treatment in the integrated analysis, with PE rated as none/mild by 12% taking placebo and 27% and 34% taking dapoxetine 30mg and 60mg respectively (p< vs. placebo). 4 In the other studies, significantly higher proportions of men using dapoxetine (30.6%-41.5%) reported that their PE was better or much better than with placebo (15.6%-22%). 7;8 In study NCT , more men met the composite PRO definition of clinical benefit with dapoxetine than placebo at weeks 12 and 24 (p<0.001): this corresponds with improvements in IELT, satisfaction and the man s perception of his condition. 7 In the Asia-Pacific study, significantly more men treated with dapoxetine met the composite PRO-defined level of clinical benefit (p<0.001) and the mean IELT achieved by these men, regardless of treatment group, was 5.4 minutes Critical evaluation a. Clinical application Many factors influence intravaginal ejaculatory latency time (IELT) and the clinical relevant of PE treatments may best be evaluated using patient reported outcomes that assess feelings, such as perceived control over ejaculation and personal distress related to ejaculation. 7;9 Clinically meaningful improvements in IELT time (determined to be at least 1 minute by study participants 4 ) were seen with dapoxetine, with mean IELT increased from minutes to minutes with 60mg. 4;7;8 Greater increases were seen in men with longer IELTs at baseline: in those with baseline IELT >1-2 minutes, mean IELT increased from 1.4 to 5.0 minutes with 60mg dapoxetine. 8 It is worth noting that the average improvement in IELT in men treated with placebo in the Asia-Pacific study (for the population overall and in each sub-group) and in study NCT (overall) would also have been considered clinically meaningful. 7;8 Improvements in PE were also evidenced by the more subjective patient-reported outcomes, which significantly improved with dapoxetine, including control of PE and reduction in distress caused by PE. These definitions of treatment benefit capture changes in both patient functioning (control of PE) and feeling (distress caused by PE), rather than just reporting the measure of biological response (IELT). There are a number of limitations to the studies. 4;7;8 o Even though the majority of results with dapoxetine were significantly better than those with placebo (and proportionately greater), there were still some placebo effects in terms of the subjective secondary endpoints. A quarter of men taking placebo in the integrated analysis still perceived that they had slight better/better/much better improvements in PE. 4 In the Asia-Pacific study, over half of those treated with placebo achieved 1 category increase in satisfaction with sexual intercourse, or decrease in personal distress related to ejaculation at endpoint. 8 o The study populations were restricted to those with IELT consistently 2 minutes and with PE described as moderate to severe. These results cannot be generalised to milder forms of PE, but do reflect the criteria for dapoxetine use stated in the Summary of Product Characteristics (SPC). o The effects of dapoxetine on PE associated with erectile dysfunction or PE due to other causes has not been assessed. o Only three of the studies stated how often men were to try to attempt sexual intercourse 4;9 ; the other two did not and some men may have been more active than others, potentially influencing the results. 7;8 o In three studies the majority of men were Caucasian (84-87%) and in one the majority were Asian (92%), and most were 49 years of age; robust conclusions of the efficacy of dapoxetine in other ethnic groups and older men could not be made. o Only men in stable, monogamous, heterosexual relationships were included in the studies. o No active comparators were used, which may reflect the fact that no other oral therapies are licensed to treat PE. o Just over half of those enrolled completed study NCT , with 21% in each of the dapoxetine groups and 31% of the placebo group discontinuing by choice. 7 Factors contributing to discontinuation included the long trial duration and the burden of evaluation (stopwatch-measured IELT and more than five monthly questionnaires). Analysis using subjects with both baseline and post-baseline IELT measurements showed that the discontinuation rate did not affect the treatment outcomes. Protocol deviations occurred in a large number of patients with treatment deviations in approximately 60% (including subjects taking >1 dose in a 24 hour period or receiving the wrong dose/medication): the investigators did not explain if these affected the treatment results or not. 3

4 b. Safety Of the 4224 men who participated in the clinical trial programme, 1616 took dapoxetine 30mg as required, and 2608 used 60mg either as needed or once daily. 5 The most common side effects, occurring in 1/10 patients, were headache, dizziness and nausea. Syncope has been reported in clinical trials and is considered medicine-related. Most cases occurred within the first 3 hours after doses, after the first dose or associated with study-related procedures in the clinical setting (such as blood tests or blood pressure measurements). 5 In the integrated analysis, in study NCT and in study NCT , syncope occurred in two men taking placebo and nine taking dapoxetine (<1%). 4;7;9 Discontinuation rates in the studies ranged from 2-4% with 30mg, 5-10% with 60mg and 1% taking placebo. Nausea and dizziness were the main adverse events leading to discontinuation in around 2.5% and 1% respectively. Withdrawal effects Two studies (n>2,000) have evaluated the withdrawal effects seen after discontinuing dapoxetine 7;9 ; results have been published in a conference abstract. 10 Patients who took dapoxetine every day and were switched to placebo were more likely to experience withdrawal effects compared with those who continued with treatment, although the incidence was low. These included mild or moderate insomnia (6.1% vs. 2.4%) and dizziness (4.8% vs. 1.2) but nausea was reduced on stopping dapoxetine (0.6% vs. 2.4%). Note that daily use is not recommended in the UK product licence. In patients who took dapoxetine as required (PRN), the incidence of withdrawal syndrome was similar among those who continued with PRN dosing and those who switched to placebo. Contraindications, precautions and drug interactions 5 Dapoxetine should not be used by men with cardiac conditions (such as heart failure (NYHA II-IV), conduction abnormalities, significant ischaemic heart or valvular disease or a history of syncope), a history of mania or severe depression, severe renal impairment, unstable epilepsy, moderate and severe hepatic impairment, or raised intraocular pressure. There are a number of drug interactions involving medicinal products with serotonergic effects, such as MAOI, thioridazine, SSRIs, SNRIs, tricyclic antidepressants and St Johns Wort; dapoxetine should not be used concomitantly with these. Further details are on the SPC. Potent CYP3A4 inhibitors should not be used with dapoxetine and the dose should be no more than 30mg in men taking moderate CYP3A4 inhibitors. Caution is advised if increasing the dose to 60mg in patients taking potent CYP2D6 inhibitors or if the patient is known to be a poor CYP2D6 metaboliser. Dapoxetine should not be used with PDE5 inhibitors due to possible orthostatic hypotension. Further details for all contraindications, precautions and drug interactions can be found on the SPC. 5 c. Potential advantages and disadvantages over existing technologies i. Convenience Dapoxetine can be started in primary care and only needs to be taken when required. ii. Drug cost Commonly used SSRIs to treat PE are paroxetine, sertraline and fluoxetine, which must be taken on a daily basis. 2 Drug and dose Cost per pack 6;11 Cost per year Fluoxetine, 20-60mg/day 2 [off-label indication] 30 x 20mg capsules = (20-60mg capsules/day) Paroxetine, 20-40mg/day 2 [off-label indication] 30 x 20mg tablets = Sertraline, mg/day 28 x 50mg tablets = 6.35 [off-label indication] 2 28 x 100mg tablets = 7.71 Dapoxetine, 30-60mg prn 5 3 x 30mg = x 30mg = x 60mg = x 60mg = Based on six attempts a month (as per study requirements): (30mg prn) to ~ 400 (60mg, but initiating with 30mg). iii. Healthcare resource utilisation Currently oral SSRIs are used off-label; dapoxetine offers a licenced therapeutic option that could be initiated in primary care. PE must be distinguished from ED and if ED exists, it should be treated before or at the same time as PE. iv. Suitability for shared care None required. v. Likely budgetary impact The budget impact model below is based on a general population of 100,000 and 25% of those with severe PE seeking treatment. 12 Note that the model is based on a mean number of 3 tablets per month; this is less than used in the trials (at least 6 per month). 4

5 Budget impact: based on a population of 100, General population 100,000 Total male population, years 31,120 Men affected by premature ejaculation 5,851 Men severely affected by premature ejaculation % likely to seek treatment % seeking treatment likely to be given dapoxetine 1,151 25% of 1,151 [user assumption] 70% = 202 men Mean number of tablets per month 3 Dose split 75% = 30mg 25% = 60mg [user assumption] Pack size split 60%: 3 tablets 40%: 6 tablets [user assumption] % prescribed in general practice 100% Proportion of patients discontinuing treatment 40% (28-38% in trials discontinued due to no improvement) Drug acquisition costs (with 40% discontinuation rate) Number of patients GP costs Year 1 (20% uptake) 24 4,647 Year 2 (40% uptake) 48 9,050 Year 3 (60% uptake) 73 13,452 Year 4 (80% uptake) 97 17,854 Year 5 (100% uptake) ,257 Budget impact: Outpatient referrals 12 Current situation Potential future situation With diagnosis and treatment for suitable patients in primary care Men affected by PE 5,851 5,851 5,851 Proportion of these presenting each year 3.2% 19.2% 19.2% Proportion of these referred to secondary care 30% 8% 50% Number of referrals to secondary care Cost per attendance at hospital outpatient clinic Overall cost of referrals 7,245 11,592 72,453 Without diagnosis and treatment for suitable patients in primary care 5. Health economic data We have been unable to identify any health economic data which supported an estimate of cost utility of dapoxetine. A retrospective analysis of US medical claim data relating to men with premature ejaculation found that men diagnosed with PE (n=1,245) visited their physician more frequently in the year before their diagnosis compared with age-matched controls (n=3,915), with 5.23 visits vs visits (p<0.01). 13 All comparisons are for the year prior to and the year following PE diagnosis. Following diagnosis, the number of visits relating to other conditions fell but the number of visits relating to PE increased. Total prescription costs rose by 37% ($85) but this was offset by a 24% decrease (~$300) in the mean total cost of diagnosis and medications (including those unrelated to PE). Men diagnosed with PE were also more likely to be diagnosed with disorders of the penis, hyperplasia of the prostate and urinary system symptoms. ` 6. Likely commissioning and funding pathway This is likely to fall under prescribing budgets in a similar way to that of treatments for erectile dysfunction. 7. Suggested place in therapy Dapoxetine is the first oral treatment for PE to be licensed in the UK and unlike other SSRIs, which are used off-label and must be taken daily, dapoxetine is short-acting and taken as required (maximum once a day). Dapoxetine should only be used in men aged years who meet all of these criteria: 5 An intravaginal ejaculatory latency time (IELT) of less than two minutes. [Note that the efficacy of dapoxetine has not been studied outside of heterosexual relationships but in theory the effects should be the same in all men, regardless of sexual orientation.] Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the patient wishes. Marked personal distress or interpersonal difficulty as a consequence of PE. Poor control over ejaculation. A history of premature ejaculation in the majority of intercourse attempts over the prior 6 months. The cost of dapoxetine is significantly greater than that of other SSRIs used off-label. A licensed treatment should be prescribed in preference to a medicine used outside of its product licence: unlicensed/off-label medicines should only be prescribed if there is no licensed medicine available or if a suitable licensed medicines that would meet the patients need is not available. 14 5

6 Reference List (1) Premature Ejaculation. Last Checked: 12/04/2013. Document ID: 2652 Version: 22. Tidy, C (2) Wespes E, Amar E, Eardley I et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010; doi /j.eururo ysfunction.pdf (3) Hutchinson K, Cruickshank K, Wylie K. A benefit-risk assessment of dapoxetine in the treatment of premature ejaculation. Drug Saf 2012; 35(5): (4) Pryor JL, Althof SE, Steidle C et al. Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised, controlled trials. Lancet 2006; 368(9539): (5) Summary of Product Characteristics. Priligy 30mg and 60mg film-coated tablets. Date of revision of the text: 28 February A.Menarini Farmaceutica Internazionale SRL. (6) Personal communication. Priligy (Dapoxetine) costs. October A.Menarini Farmaceutica Internazionale SRL. (7) Buvat J, Tesfaye F, Rothman M et al. Dapoxetine for the treatment of premature ejaculation: results from a randomized, double-blind, placebo-controlled phase 3 trial in 22 countries. Eur Urol 2009; doi: /j.eururo (8) McMahon C, Kim SW, Park NC et al. Treatment of premature ejaculation in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine. J Sex Med 2010; 7: (9) Kaufman JM, Rosen RC, Mudumbi RV et al. Treatment benefit of dapoxetine for premature ejaculation: results from a placebo-controlled phase III trial. BJU Int 2008; 103: (10) Giuliano F, Levine SB, Buvat J et al. Lack of withdrawal syndrome or effects on anxiety with dapoxetine (DPX) for the treatment of premature ejaculation (PE): results from 2 phase III trials. Eur Urol 2008; 7(3 (Suppl)):187. (11) National Health Service Drug Tariff for England and Wales, October (12) Priligy (dapoxetine) in premature ejaculation. Budget Impact Model. A.Menarini Farmaceutica Internazionale SRL (13) Nuyts GD, Hill K, Jones MP. Current practice and resource utilisation in men diagnosed with premature ejaculation. Int J Clin Pract 2008; 62(10): (14) Prescribing guidance: Prescribing unlicensed medicines. General Medical Council. Medline: dapoxetine.af AND PREMATURE EJACULATION/ [Limit to: English Language and Humans] Medline: ERECTILE DYSFUNCTION/ OR *PREMATURE EJACULATION AND ECONOMICS, MEDICAL/ Medline: PHOSPHODIESTERASE INHIBITORS/ OR PHOSPHODIESTERASE 5 INHIBITORS/ AND ECONOMICS, MEDICAL/ Embase: *DAPOXETINE/ and *PREMATURE EJACULATION/ Embase: [*CITALOPRAM/ OR *ESCITALOPRAM/ OR *FLUOXETINE/ OR *PAROXETINE/ OR *SERTRALINE] AND DAPOXETINE NHS Evidence: premature ejaculation Embase: exp SEROTONIN UPTAKE INHIBITOR/ AND *DAPOXETINE AND *PREMATURE EJACULATION/ [Limit to: Human and English Language] Embase: DAPOXETINE/ AND HEALTH ECONOMICS/ Embase: PHOSPHODIESTERASE INHIBITOR/ AND ERECTILE DYSFUNCTION/ AND HEALTH ECONOMICS/ Embase: PHOSPHODIESTERASE INHIBITOR/ AND HEALTH ECONOMICS/ Written by Alexandra Denby, Regional MI Manager, London Medicines Information Service, Northwick Park Hospital, Harrow, HA1 3UJ. alexandra.denby@nhs.net. A.Menarini Farmaceutica Internazionale SRL have commented on this review. 6

7 Appendix: Additional study results Table 1: Outcome measures 7;9 Outcome measure Premature ejaculation profile Clinical Global Impression of change in premature ejaculation Perceived control over ejaculation. Satisfaction with sexual intercourse Personal distress related to ejaculation Interpersonal difficulty related to ejaculation Question Over the past month, was your control over ejaculation during sexual intercourse: Over the past month was your satisfaction with sexual intercourse: Over the past month, how distressed were you by how fast you ejaculated during sexual intercourse Over the past month, to what extent did how fast you ejaculated during sexual intercourse cause difficultly in your relationship with your partner? Compared to the start of the study, would you describe your premature ejaculation problem as: -3 = Much worse -2 = Worse -1 = Slight worse 0 = No change Score and response options 0 = Very poor 1= Poor 2 = Fair 3 = Good 4 = Very good 0 = Not at all 1 = A little bit 2 = Moderately 3 = Quite a bit 4 = Extremely 1 = Slightly better 2 = Better 3 = Much better Table 2: Results from study NCT Characteristic at week 24: Primary endpoint Placebo (n=382) Dapoxetine 30mg (n=385) Dapoxetine 60mg (n=387) All patients (ITT analysis) IELT baseline (mins) IELT endpoint (mins) , p< , p<0.001 Patients with baseline IELT 1mins N=236 N=240 N=235 IELT baseline (mins) IELT endpoint (mins) , p= , p<0.001 Patients with baseline IELT 0.5min N=100 N=98 N=105 IELT baseline (mins) IELT endpoint (mins) , p= , p<0.001 Geometric mean IELT N=332 N=355 N=350 IELT baseline (mins) IELT endpoint (mins) , p< , p<0.001 Geometric mean fold increase , p< , p<0.001 Characteristic at week 24: Secondary endpoints Placebo (n=382) Dapoxetine 30mg (n=385) Dapoxetine 60mg (n=387) Achieved composite Patient Reported Outcome for clinical benefit Achieved 1 category increase in satisfaction with sexual intercourse Achieved 1 category decrease in personal distress related to ejaculation 45/346 (13%) 91/359 (25.3%), p< /353 (37.1%), p< /347 (35.7%) 174/359 (48.5%), p< /353 (55.8%), p< /347 (47.8%) 216/360 (60%), p< /353 (68.6%), p<0.001 Achieved CGI rating of better or much better 54/347 (15.6%) 110/359 (30.6%), p< /352 (39.2%), p<0.001 Adverse events in 5% N=385 N=388 N=389 Nausea 11 (2.9%) 64 (16.5%) 119 (30.6%) Headache 32 (8.3%) 25 (6.4%) 53 (13.6%) Dizziness 10 (2.6%) 30 (7.7%) 52 (13.4%) Diarrhoea 6 (1.6%) 15 (3.9%) 44 (11.3%) Somnolence 4 (1%) 15 (3.9%) 28 (7.2%) Insomnia 12 (3.1%) 10 (2.6%) 27 (6.9%) Fatigue 8 (2.1%) 22 (5.7%) 26 (6.7%) Nasopharyngitis 13 (3.4%) 21 (5.4%) 24 (6.2%) Geometric mean: only subjects with both baseline and post-baseline observations Patient Reported Outcomes clinical benefit: control over ejaculation and personal distress over ejaculation. CGI: clinical global impression of change 7

8 Table 3: Results from the Asia-Pacific study, NCT Characteristic at week 24: Primary endpoint Placebo (n=357) Dapoxetine 30mg (n=354) Dapoxetine 60mg (n=356) All patients (ITT analysis) IELT baseline (mins) IELT endpoint (mins) , p< , p<0.001 Patients with baseline IELT 1mins N=161 N=160 N=161 IELT baseline (mins) IELT endpoint (mins) , p= , p< Patients with baseline IELT 0.5min N=54 N=42 N=50 IELT baseline (mins) IELT endpoint (mins) , p= , p= Patients with baseline IELT >1-2mins N=196 N=194 N=195 IELT baseline (mins) IELT endpoint (mins) , p< , p<0.001 Geometric mean IELT N=340 N=331 N=328 IELT baseline (mins) IELT endpoint (mins) , p< , p< Geometric mean fold increase , p< , p< Patient reported outcome measures Perceived control over ejaculation: good or very good Personal distress related to ejaculation: quite a bit or extremely Interpersonal difficulty related to ejaculation: quite a bit or extremely Satisfaction with sexual intercourse: good or very good Baseline 0.6% 1.6% 0.9% Endpoint 18.7% 33.5%, p< %, p<0.001 Baseline 76.4% 73.5% 74.3% Endpoint 36.4% 25.2%, p< %, p<0.001 Baseline 48.8% 51.9% 50.3% Endpoint 27.3% 17.9%, p %, p Baseline 3.9% 4.3% 4.3% Endpoint 29% 41.3%, p< %, p<0.001 Characteristic at week 24: Secondary endpoints Placebo (n=341) Dapoxetine 30mg (n=329) Dapoxetine 60mg (n=336) Achieved composite Patient Reported Outcome for clinical benefit Achieved 1 category increase in satisfaction with sexual intercourse Achieved 1 category decrease in personal distress related to ejaculation 74 (21.7%) 114 (34.7%), p< (37.2%), p< (57.8%) 228 (69.3%), p= (75.9%), p< (56%) 219 (66.6%), p= (72.7%), p<0.001 Achieved CGI rating of at least slightly better 180 (52.8%) 235 (71.4%), p< (79.2%), p<0.001 Achieved CGI rating of at least better 75 (22%) 123 (37.4%), p< (41.5%), p<0.001 Adverse events in 5% N=357 N=354 N=356 Nausea 7 (2%) 37 (10.5%) 94 (26.4%) Dizziness 14 (3.9%) 37 (10.5%) 67 (18.8%) Somnolence 2 (0.6%) 12 (3.4%) 22 (6.2%) Geometric mean: only subjects with both baseline and post-baseline observations Patient Reported Outcomes clinical benefit: control over ejaculation and personal distress over ejaculation. CGI: clinical global impression of change 8

9 Table 4: Results from the study NCT Characteristic at week 9: Primary endpoint Placebo (n=221) Dapoxetine 60mg (n=431) Patient reported outcome measures at week 9 (mean score) Perceived control over ejaculation Personal distress related to ejaculation Interpersonal difficulty related to ejaculation Satisfaction with sexual intercourse Extent of therapeutic response at week 9 Perceived control over ejaculation Baseline Endpoint , p<0.001 Baseline Endpoint , p<0.001 Baseline Endpoint , p<0.001 Baseline Endpoint , p< category increase 143 (64.7%) 344 (79.8%) 2 category increase 57 (25.8%) 220 (51%) Personal distress related to ejaculation 1 category decrease 124 (56.1%) 323 (74.8%) Adverse events in 5% Nausea 4 (1.6%) 75 (15.3%) Dizziness 7 (2.9%) 50 (10.2%) Headache 15 (6.1%) 40 (8.1%) Diarrhoea 5 (2%) 30 (6.1%) 9

10 Table 5: Results from the integrated analysis of studies NCT and NCT Characteristic Placebo (n=870) Dapoxetine 30mg (n=874) Dapoxetine 60mg (n=870) All patients IELT baseline (mins) IELT endpoint (mins) Difference vs. placebo (95% CI) ( ) 1.66 ( ) Patients with baseline IELT >1 to 2mins N=328 N=332 N=328 IELT baseline (mins) IELT endpoint (mins) , p=0.018 vs. 30mg Difference vs. placebo (95% CI) ( ), p< ( ), p< Patients with baseline IELT 1min N=541 N=542 N=540 IELT baseline (mins) IELT endpoint (mins) , p= vs. 30mg Difference vs. placebo (95% CI) ( ), p< ( ), p< Patients with baseline IELT 30 seconds N=200 N=184 N=187 IELT baseline (mins) IELT endpoint (mins) Difference vs. placebo (95% CI) ( ), p= ( ), p< Distribution of IELT at study endpoint N=787 N=801 N=763 0 to 1 min 342 (44%) 203 (25%) 157 (21%) 1 to 2 min 251 (32%) 250 (31%) 216 (28%) 2 to 3 min 85 (11%) 116 (15%) 129 (17%) 3 to 4 min 42 (5%) 90 (11%) 59 (8%) 4 min 67 (9%) 142 (18%) 202 (27%) Missing Time dapoxetine taken before sexual activity 30-60mins N=182 N=182 N=185 IELT (mins) hrs N=287 N=269 N=259 IELT (mins) >4 hrs N=157 N=169 N=160 IELT (mins) Patient perception of control over ejaculation * Patient satisfaction with sexual intercourse * Patient global impression of change Slightly better, better or much better Partner satisfaction with sexual intercourse * Patient rating of severity of premature ejaculation * Baseline Endpoint Baseline Endpoint (26%) 467 (58%), p<0.001 vs. placebo 515 (67%), p<0.001 vs. placebo Baseline: Fair, good, very good 445 (58%) 457 (53%) 489 (58%) Endpoint: Fair, good, very good 429 (56%) 561 (72%), p<0.001 vs. placebo 576 (78%), p<0.001 vs. placebo Baseline Endpoint None/mild at endpoint 90 (12%) 217 (27%) 258 (34%) Baseline Endpoint , p<0.001 vs. placebo 1.84, p<0.001 vs. placebo * Score: 0=very poor, 4= very good 10