East & South East England Specialist Pharmacy Services East of England, London, South Central & South East Coast East Anglia Medicines Information Service Medicine Review Medicine / Trade name Dapoxetine / Priligy Manufacturer Menarini Document status Reviewed at Suffolk CCGs D&TC 22 January 2014 and CPG 14 April 2014 Date of last revision 15 January 2014 Traffic light decision Double red – Prescribing not supported in either general practice or secondary/tertiary care Prescribers rating Nothing new Mechanism of action Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI). Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculatory pathway originates from a spinal reflex centre, mediated by the brain stem, which is influenced initially by a number of nuclei in the brain (medial preoptic and paraventricular nuclei). The mechanism of action of dapoxetine in premature ejaculation is presumed to be linked to the inhibition of neuronal reuptake of serotonin and the subsequent potentiation of the neurotransmitter's action at pre− and postsynaptic receptors [1]. Licensed indication Dapoxetine is indicated for the treatment of premature ejaculation (PE) in adult men aged 18 to 64 years [1]. Dosage The recommended starting dose for all patients is 30 mg, taken as needed approximately 1 to 3 hours prior to sexual activity. Treatment with dapoxetine should not be initiated with the 60 mg dose [1]. Dapoxetine is not intended for continuous daily use. Dapoxetine should be taken only when sexual activity is anticipated dapoxetine must not be taken more frequently than once every 24 hours. If the individual response to 30 mg is insufficient and the patient has not experienced moderate or severe adverse reactions or prodromal symptoms suggestive of syncope, the dose may be increased to a maximum recommended dose of 60 mg taken as needed approximately 1 to 3 hours prior to sexual activity. The incidence and severity of adverse events is higher with the 60 mg dose. If the patient experienced orthostatic reactions on the starting dose, no dose escalation to 60 mg should be performed (see section 4.4). A careful appraisal of individual benefit risk of dapoxetine should be performed by the physician after the first four weeks of treatment (or at least after 6 doses of treatment) to determine whether continuing treatment with dapoxetine is appropriate. Treatment alternatives The European Association of Urology 2010 guidelines on male sexual dysfunction state daily treatment with SSRIs has become the first choice treatment in PE. The use of local anaesthetics to delay ejaculation have also been used and are a viable alternative to SSRIs. These treatments are unlicensed [2]. Place in therapy Dapoxetine should only be prescribed to patients who meet all the following criteria: • 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 not be prescribed to delay ejaculation in men who have not been diagnosed with PE [1]. Future alternatives Lidocaine and prilocaine spray and tramadol [3] Evidence for use The London New Drugs Group / Medicines Evaluation Network reviewed the clinical evidence for dapoxetine in November 2013 [4]. I have embedded the review here and it is also available to download at http://www.medicinesresources.nhs.uk/upload/Dapoxetine_finalNov2013 .pdf Dapoxetine review There are five randomised, double-blind, placebo-controlled phase 3 studies evaluating dapoxetine 30mg and 60mg over 9-24 weeks. Four evaluated efficacy and safety (NCT00229073, NCT00210704 (Asia- Pacific study), and NCT00211107 and NCT00211094 (integrated analysis)) and one evaluated the potential withdrawal effects after abrupt discontinuation (NCT00210613). Clinically meaningful improvements in IELT time (determined to be at least 1 minute by study participants) were seen with dapoxetine, with mean IELT increased from 0.9-1 minutes to 3.3-4.2 minutes with 60mg. 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. Full results are available in the above paper. 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. 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. 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. 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). The effects of dapoxetine on PE associated with erectile dysfunction or PE due to other causes has not been assessed. Only three of the studies stated how often men were to try to attempt sexual intercourse; the other two did not and some men may have been more active than others, potentially influencing the results. 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. Only men in stable, monogamous, heterosexual relationships were included in the studies. No active comparators were used, which may reflect the fact that no other oral therapies are licensed to treat PE. Just over half of those enrolled completed study NCT00229073, with 21% in each of the dapoxetine groups and 31% of the placebo group discontinuing by choice. 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. Contra-indications Significant cardiac disease; history of syncope; history of mania, bipolar disorder, or severe depression; discontinue if psychiatric disorder develops. Moderate and severe hepatic impairment. Concomitant use of MOAIs, thioridazine, SSRIs, SNRIs, TCADs, other medicinal or herbal products with serotonergic effects (tiptans, tramadol, lithium, St Johns wort). See SPC for further details [1]. Cautions Bleeding disorders; concomitant use of drugs that increase risk of bleeding; epilepsy (avoid if uncontrolled, discontinue if convulsions develop); susceptibility to angle-closure glaucoma. Test for postural hypotension before starting treatment—avoid dapoxetine if postural hypotension occurs. Do not use with alcohol or recreational drugs. Use with caution if eGFR 30–80 mL/minute/1.73 m2; avoid if eGFR less than 30 mL/minute/1.73 m2. See SPC for further details [1]. Drug Interactions In addition to the interactions listed above, potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir) 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. Caution is advised if concomitant treatment with antiepileptics, antipsychotics, anxiolytics, sedative hypnotics is required as use has not been evaluated. Dapoxetine should not be used with PDE5 inhibitors due to possible orthostatic hypotension. See SPC for further details [1]. Side effects 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. The most common side effects, occurring in ≥1/10 patients, were headache, dizziness and nausea [4]. 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). In the integrated