Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study

The summary of product characteristics states that dapoxetine should only be prescribed to men who meet all the following criteria: An intravaginal ejaculatory latency time of less than 2 minutes and An intravaginal ejaculatory latency time of less than 2 minutes and Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the man wishes and Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the man wishes and Marked personal distress or interpersonal difficulty as a consequence of premature ejaculation and Marked personal distress or interpersonal difficulty as a consequence of premature ejaculation and A history of premature ejaculation in the majority of intercourse attempts over the prior 6 months. Therefore, men will need to be appropriately assessed and given a diagnosis of premature ejaculation in line with the above criteria before dapoxetine can be considered. In addition, the summary of product characteristics states that a careful appraisal of the individual benefit/risk ratio should be carried out after the first 4 weeks of treatment (or at least after 6 doses of treatment) to determine whether continuing treatment is appropriate. If dapoxetine is continued, the benefit/risk balance should be re-evaluated at least every 6 months.

PE and Erectile Dysfunction: A Common Overlap

The efficacy outcomes were reported to be based on the intention-to-treat (ITT) population, classed as all randomised participants. However, in the pooled analysis, numbers of participants for whom data were available was also presented. It is unclear if the analysis was based on the ITT population or the population for whom data were available. Discontinuation rates were high in the studies but were similar for dapoxetine and placebo (31.1% of all participants in the dapoxetine groups and 28.9% of all participants in the placebo groups). For missing data post-baseline, the last post-baseline observation carried forward (LPOCF) method was used.

Current and emerging treatment options for premature ejaculation

In this approach, regardless of when a patient left the trial (for example, after week 1, week 6 or week 12), the last available result for that patient was carried forward and analysed as though it were the result at the study end. As stated in the summary of product characteristics, the efficacy and safety of dapoxetine in men with both premature ejaculation and erectile dysfunction treated with both dapoxetine and phosphodiesterase type 5 inhibitors (for example, sildenafil) has not been established. The summary of product characteristics states that dapoxetine should not be used in men taking phosphodiesterase type 5 inhibitors. There are limited data available on the safety and efficacy of dapoxetine 'on demand' for longer than 24 weeks. The European Association of Urology 2014 guidelines on male sexual dysfunction recommend that pharmacological treatment options include 'on demand' dapoxetine, daily use of a longer-acting selective serotonin reuptake inhibitor (SSRI) [off-label use], daily use of clomipramine (off-label use), 'on demand' topical local anaesthetic agents (off-label use) and 'on demand' tramadol (off-label use). Consideration will need to be given to how treatment efficacy can be assessed given the subjective nature of efficacy outcomes.

• Dapoxetine can improve confidence and sexual satisfaction.
• It is contraindicated in men with severe heart or liver conditions.
• The optimal dose varies; typically, 30 mg or 60 mg based on tolerance.
• Do not take dapoxetine with other SSRIs or serotonin drugs without medical advice.
• The onset of action is usually within 1-3 hours after intake.
• Dapoxetine is rapidly absorbed and eliminated from the body.

Premature ejaculation can occur in conjunction with erectile dysfunction and the European Association of Urology 2014 guidelines on male sexual dysfunction states that if premature ejaculation is secondary to erectile dysfunction then the erectile dysfunction should be treated before or at the same time as the premature ejaculation. It should be noted however, that the summary of product characteristics states that dapoxetine should not be used in men taking phosphodiesterase type 5 inhibitors (for example, sildenafil) as this increases the risk of syncope.

Attribute	Description	Notes
Purpose	Delays ejaculation time during intercourse	Often prescribed for PE
Typical Dosage	30 mg to 60 mg	Taken 1-3 hours before sex
Onset of Action	Within 1-3 hours	Peak effect approximately 1 hour after intake
Duration of Effect	2 to 4 hours	Varies per individual
Common Side Effects	Nausea, dizziness, headache	Usually mild
Contraindications	Use with MAO inhibitors, severe cardiac issues	Consult doctor before use

For a number of men pharmacological treatment of premature ejaculation will not be acceptable. A prospective observational study from a single clinical centre in Italy (Mondaini et al.

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2013) assessed the acceptance and discontinuation rates of 'on demand' dapoxetine 30 mg (titrated to 60 mg after 3 months if low efficacy) in 120 men with lifelong premature ejaculation.

Country	Approval Status	Notes
USA	Approved by FDA for PE	Prescription required
European Union	Approved in several countries	Prescription essential
Australia	Approved for PE	Sold under brand names
India	Available OTC in some pharmacies	Consult healthcare provider before use
Canada	Approved with prescription	Used for PE treatment

Twenty-four (20%) of the men decided not to start dapoxetine.

• Dapoxetine is sometimes used off-label to treat other sexual dysfunctions.
• It is not a cure but a symptom management medication.
• Men should discuss potential side effects thoroughly before starting treatment.
• The medication has been studied and approved in several countries for PE.
• In case of overdose, seek emergency medical help immediately.
• Dapoxetine use requires careful monitoring for long-term safety.

Fear of using a 'drug' was the most frequently reported reason for treatment non-acceptance (50%). In addition, the majority of men who took dapoxetine discontinued treatment.

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Because longer-acting SSRIs such as citalopram, fluoxetine or paroxetine have a longer onset of action than the shorter-acting dapoxetine they need to be taken on a daily basis and cannot be used as an 'on demand' treatment. The European Association of Urology 2014 guidelines on male sexual dysfunction states that in men for whom premature ejaculation causes few if any problems treatment should be limited to psychosexual counselling and education. The guidelines recommend that before beginning dapoxetine 5mg treatment, it is essential to discuss the expectations of treatment thoroughly. Various behavioural techniques have demonstrated benefit in treating premature ejaculation and are indicated for men who are uncomfortable with pharmacological therapy. In lifelong premature ejaculation, the European guidelines state that behavioural techniques are not recommended for first-line treatment because they are time-intensive, require the support of a partner and can be difficult to do.

Evidence review

The guidelines recommend that pharmacological treatment options include 'on demand' dapoxetine and daily use of a longer-acting SSRI such as citalopram, fluoxetine or paroxetine (off-label use) or daily use of clomipramine (off-label use). Dapoxetine is taken 'on demand' approximately 1 to 3 hours before anticipated sexual activity. This may reduce the incidence of SSRI-related adverse effects compared with the off-label use of once-daily longer acting SSRIs, although there are no direct RCTs to provide evidence for this. However, some men may prefer to take a daily dose which may allow more spontaneity than a planned 'on demand' treatment. Dapoxetine is licensed for treating premature ejaculation in adult men aged 18 to 64 years. The main reasons for treatment discontinuation were efficacy below expectations, side effects and costs. Out of the 96 men who decided to start dapoxetine, only 10 men were continuing the treatment after 1 year. Dapoxetine is the only medicine licensed in the UK for the treatment of premature ejaculation, although other treatments are used off-label for this indication. The General Medical Council advice to use a licensed medicine whenever possible should be taken into consideration.

Types of Premature Ejaculation

The summary of product characteristics states that contraindications to the use of dapoxetine include significant pathological cardiac conditions such as heart failure, significant ischaemic heart disease or history of syncope; a history of mania or severe depression; and concomitant treatment with thioridazine, monoamine oxidase inhibitors, SSRIs, tricyclic antidepressants or other herbal/medicinal products with serotonergic effects and potent CYP3A4 inhibitors. It also states that dapoxetine should not be used in men taking phosphodiesterase type 5 inhibitors (for example, sildenafil). Dapoxetine should be used with caution in men with mild or moderate renal impairment, and is not recommended for use in men with severe renal impairment. It is contraindicated in men with moderate and severe hepatic impairment. The efficacy and safety of dapoxetine have not been established in men aged 65 years and over (summary of product characteristics).

Study selection

Very common (greater than 1 in 10 men) adverse reactions reported in the summary of product characteristics are dizziness, headache and nausea. Common (between 1 in 100 and 1 in 10 men) adverse reactions reported include anxiety, agitation, insomnia, somnolence, abnormal dreams, tremor, paraesthesia, blurred vision, tinnitus, erectile dysfunction, decreased libido, increased blood pressure, hyperhidrosis and gastrointestinal disorders. The summary of product characteristics states that patients should be advised not to use dapoxetine in combination with recreational drugs or alcohol. Dapoxetine has a number of potential drug interactions; these are similar to those which occur with other SSRIs. For further information on contraindications, cautions and warnings please refer to the summary of product characteristics. The manufacturer has estimated that based on a GP-registered population of 100,000 people, 5851 men aged 18 to 64 will be affected by premature ejaculation with 1151 men severely affected (A. Menarini Farmaceutica Internazionale: personal communication January 2014).

HERTFORDSHIRE AND WEST ESSEX AREA PRESCRIBING COMMITTEE (HWE APC) Dapoxetine for the treatment of premature ejaculation Double Red

The pooled analysis included data from 6081 men and reported results for both IELT and patient-reported outcomes such as perceived control over ejaculation. However, there are no RCTs that compare 'on demand' dapoxetine with an active comparator, such as daily use of a longer-acting SSRI (off-label use). The studies only included men aged 18 years and over who had been in a monogamous heterosexual relationship for at least 6 months and who met Diagnostic and Statistical Manual of Mental Health Disorders, 4th edition, text revision (DSM-IV-TR) criteria for premature ejaculation. In 4 of the RCTs included in the pooled analysis, participants also had to have an intravaginal ejaculatory latency time of 2 minutes or less, and this is reflected in the licensed indication. Only 3 of the studies included in the pooled analysis stated how frequently men were to try to attempt sexual intercourse; the other 2 included studies did not state this.

Drug-related adverse effects (AEs)

The average age of men in the pooled analysis was 41 years. The efficacy and safety of dapoxetine have not been established in men aged 65 years and over. 2006) included in the pooled analysis, the method of allocation described suggests that this was concealed. However, in the other 2 RCTs (McMahon et al. 2009) it is unclear if allocation was concealed.

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