BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC)

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1 BEDFORDSHIRE AND LUTON JOINT PRESCRIBING COMMITTEE (JPC) April 2014 Review April 2017 Bulletin 197: Dapoxetine for Premature Ejaculation JPC Recommendations: To support the East of England Priorities Advisory Committee (PAC) policy statement and recommendations as outlined below:- The commissioning of dapoxetine is low priority and is not recommended. N:\Medicines Management\JPC\Approved Bulletins and Papers\Approved bulletins & papers (from Aug 13 )\April 14\Dapoxetine for Premature Ejaculation - Bulletin 197.docx

2 GUIDANCE STATEMENT The East of England Priorities Advisory Committee A function of the Programme Dapoxetine (Priligy) for premature ejaculation (PE) PAC recommendations The commissioning of dapoxetine is low priority and is not recommended. Background information Selective Serotonin Reuptake Inhibitors [SSRIs (e.g. paroxetine, fluoxetine, fluvoxamine, sertraline, clomipramine)] have beneficial effects on premature ejeculation (PE). They are used off-label as first-line treatment for this condition and their effectiveness is often maintained for several years. 2 Dapoxetine is a more potent SSRI and is the first licensed treatment for PE in men aged years of age. 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. 1 This allows for on-demand treatment, i.e. taken as needed 1-3 hours prior to sexual activity. Dapoxetine is the only drug with this dosing schedule. 1,2 The British Association of Urological Surgeons state that: PE is usually lifelong (i.e. it usually dates back to the first sexual experience). Rarely, PE may develop in later life when it is often progressive. We do not know accurately how common it is but between 1 in 3 and 1 in 5 men (20-30%) are thought to have PE. Less than a quarter of men with PE actually seek medical advice for their condition. Evidence PE is often associated with erectile dysfunction (impotence) and with rapid loss of erection after ejaculation. 2 In 5 studies, men had to meet the diagnostic criteria for PE as specified in the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV-TR): the 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. 3-5 Exclusion criteria included erectile dysfunction, concomitant use of SSRIs or tricyclic antidepre ssants, major psychiatric disorders, history of medical illness, uncontrolled hypertensions or other forms of sexual dysfunction. This is an NHS document not to be used for commercial or marketing purposes 1 of 5

3 PAC: Dapoxetine (Priligy) for premature ejaculation (PE) v1 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. 3-5 In the fifth study, the primary endpoint was evaluation of potential withdrawal effects. 6 Mean baseline IELT times were minute. 3-5 The following four studies evaluated the efficacy and safety of dapoxetine. Studies NCT and NCT (integrated analysis). 3 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.» 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). 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. 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 extreme personal distress in 68%, and 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, 53% completed the study. Analysis was in the intention-to-treat population.» 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. NCT (Asia-Pacific study). 5 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). 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. This is an NHS document not to be used for commercial or marketing purposes 2 of 5

4 PAC: Dapoxetine (Priligy) for premature ejaculation (PE) v1 The primary endpoint of study NCT was the evaluation of potential withdrawal effects after abrupt discontinuation. 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. 6 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 rerandomised 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. 6 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 summarised in the Patient reported outcomes section below. Patient reported outcomes There were a number of patient reported outcomes in all of the studies. 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. 3 In the other studies, significant improvements with control over ejaculation were seen with dapoxetine compared with placebo (p<0.001). 4-6 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. 3 In the other studies, significant improvements with sexual intercourse were seen with dapoxetine compared with placebo (p<0.001). 4-6 Personal distress related to ejaculation: Improvements in distress were significantly better with dapoxetine at most time points, including week 24 (p<0.001). 4-6 Interpersonal difficulties related to ejaculation: Improvements in interpersonal difficulty were significantly better with dapoxetine at most time points, including week 24 (p<0.05). 4-6 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). 3 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%). 4,5 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. 4 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. 5 Safety The safety of dapoxetine was evaluated in 4224 subjects with premature ejaculation who participated in five double blind, placebo controlled clinical trials. Of the 4224 subjects, 1616 received dapoxetine 30 mg as needed and 2608 received 60 mg, either as needed or once daily. 1 Adverse effects: 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- This is an NHS document not to be used for commercial or marketing purposes 3 of 5

5 PAC: Dapoxetine (Priligy) for premature ejaculation (PE) v1 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). 1 Withdrawal: Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disorders has been reported to result in the following symptoms: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. A double blind clinical trial in subjects with PE designed to assess the withdrawal effects of 62 days of daily or as needed dosing with 60mg dapoxetine showed mild withdrawal symptoms with a slightly higher incidence of insomnia and dizziness in subjects switched to placebo after daily dosing. 1 Cost 7 Commonly used SSRIs to treat PE are paroxetine, sertraline and fluoxetine, which must be taken on a daily basis. Drug and dose Cost per pack Cost per year Fluoxetine, 20-60mg/day [off-label indication] 30 x 20mg capsules = (20-60mg capsules/ day) Paroxetine, 20-40mg/day [off-label indication] 30 x 20mg tablets = Sertraline, mg/day [off-label indication] 28 x 50mg tablets = x 100mg tablets = Dapoxetine, 30-60mg prn 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). Document history PAC approval date 3 March 2014 Version 1 Consultation process QA process PAC members Katie Smith Director of East Anglia Medicines Information Service. This is an NHS document not to be used for commercial or marketing purposes 4 of 5

6 References PAC: Dapoxetine (Priligy) for premature ejaculation (PE) v1 1. Summary of Product Characteristics Priligy 30mg and 60mg film-coated tablets. A.Menarini Farmaceutica Internazionale SRL. Date of revision of the text: 26 February The British Association of Urological Surgeons. Information for patients. Accessed 16th February 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): 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 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: 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: Dapoxetine (Priligy ) for premature ejaculation, London New Drugs Group/London Medicines Evaluation Network Review. November finalnov2013.pdf Acknowledgement The evidence and patient reported outcomes are based on dapoxetine review by London New Drugs Group/London Medicines Evaluation Network. 7 This is an NHS document not to be used for commercial or marketing purposes 5 of 5