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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 analysis, in study NCT00229073 and in study NCT00210613, syncope occurred in two men taking placebo and nine taking dapoxetine (<1%) [4].

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 [4].

Two studies (n>2,000) have evaluated the withdrawal effects seen after discontinuing dapoxetine; results have been published in a conference abstract. 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 [4].

See SPC for further details [1].

NNT/NNH Not calculated.

Cost 3 x 30mg = £14.71 6 x 30mg = £26.48 3 x 60mg = £19.12 6 x 60mg = £34.42

Annual cost based on 6 attempts a month (as per study protocols) = £317.76 using 30mg PRN and ~£400 using 60mg after initiating with 30mg. Costs of alternatives Drug / dose Cost per year Fluoxetine 20-60mg/day £12.14 - £36.72 (off label indication) Paroxetine 20-40mg/day £19.56 - £39.12 (off label indication) Sertraline 30-60mg/day £82.55 - £200.46 (off label indication) Potential number of A budget impact model in the London New Drugs Group / Medicines patients per 100,000 Evaluation Network review from the manufacturers calculates that 5851 population men aged 18-64 years per 100,000 population are affected by premature ejaculation of which 1151 are severely affected. 25% are likely to seek treatment (288) and 70% (202) of these are likely to be given dapoxetine. Up to 40% of patients may discontinue treatment [4].

As well as the drug costs, there may also be costs of patient referrals to secondary care [4].

Points for  Dapoxetine is the first oral treatment for premature ejaculation (PE) consideration 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 3.5-4.2 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.

Decisions sought from  NICE - Not reviewed other bodies  Cambridgeshire Joint Prescribing Group - Not reviewed  Norfolk & Gt Yarmouth & Waveney Therapeutic Advisory Group (TAG) Nov 2013 – the TAG considered the evidence available for this treatment for diagnosed premature ejaculation. The TAG noted that there is some risk of harm with the treatment and that relative cost over benefit does not currently justify the drug being routinely provided by the NHS. A classification of Double Red was recommended. Prescriber's rating 7 - not acceptable.  Scottish Medicines Consortium - Not reviewed  All Wales Medicines Strategy Group - Use not endorsed as no submission from the manufacturer Decision review date TBC References 1. Summary of Product Characteristics. Priligy 30mg and 60mg film-coated tablets. Date of revision of the text: 28 February 2013. A.Menarini Farmaceutica Internazionale SRL. http://www.medicines.org.uk/emc/medicine/28284/SPC/Priligy+30+mg+and+60+mg+film- coated+tablets/ 2. Hatzimouratidis K, Amar E, Eardley I et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010; doi.10.1016/j.eururo.2010.02.020. http://www.uroweb.org/fileadmin/tx_eauguidelines/2010/Trans/2010_Guidelines_on_Male_Sexua l_Dysfunction.pdf 3. New Drugs Online. Accessed 18/12/13 http://www.ukmi.nhs.uk/applications/NDO/ 4. Denby A. Dapoxetine (Priligy) for premature ejaculation. London New Drugs Group / London Medicines Evaluation Network Review. November 2013. http://www.medicinesresources.nhs.uk/upload/Dapoxetine_finalNov2013.pdf

Comments The numbers here will be small in secondary care. It would nice to have around but I suspect will not be a frequent usage item. I spoke to David Ralph recently (he is the highest authority on andrology in UK). He mentioned this He didn’t seem to feel it was not a major advance forwards but it was the first to be licensed (I think).For those men who need to try an alternative to Stud Spray or Paroxetine he felt it to be a reasonable option although possibly not as good as the reps say. John McLoughin, West Suffolk Hospital

Thank you for producing a helpful, informative and well written paper. I suggest we confer and provide a joint view, as far as we can. I do not think we get many referrals for this problem, and I do not know if other disciplines are seeing them either. Peter Donaldson, Ipswich Hospital

Small numbers but nice to have on the shelf for the occasional patient. James Allan, West Suffolk Hospital

This drug will be the first approved for PE treatment however other SSRIs, such as paroxetine, sertraline and fluoxetine, have been used off-label. All the 5 studies compared Dapoxetine with placebo and the question will be does this drug have superiority over other SSRIS to justify the extra cost? Raouf Moussa, Consultant Sexual Health and HIV, Ipswich Hospital

Is dapoxetine consider like other ED management and on SLS basis?? If yes, please seek approval with red recommendation at least. I usually see about 3-4 patients annually in the ED clinic and usually very young. Using paroxitine usually produce unacceptable side effects. They usually agree to use PDE5 inhibitor on private prescription basis, it helps despite not liesenced for this indication. Mohsen Habib, Ipswich Hospital

I can confirm that dapoxetine for premature ejaculation does not need to have SLS written on the prescription. Katie Smith, East Anglia MI

I wonder if it should therefore be green i.e. hospital recommended – GP continuation or does it need hospital prescription all the time? Kevin Purser, Chief Pharmacist, Ipswich Hospital

Thank you, I think it will be better as you suggested (green) if possible. Mohsen Habib, Ipswich Hospital

Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications

For many years scientists have recognised two types of research:  Primary: original studies, based on observation or experimentation on subjects.  Secondary: reviews of published research, drawing together the findings of two or more primary studies.

In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this-

Rank: Methodology Description

1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews."

Randomised controlled trials Individuals are randomly allocated to a control group and a group who receive a 2 (finer distinctions may be drawn within this specific intervention. Otherwise the two groups are identical for any significant group based on statistical parameters like the variables. They are followed up for specific end points. confidence intervals)

3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.

4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups.

5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time

6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series

7 Expert opinion A consensus of experience from the good and the great.

8 Anecdotal Something a bloke told you after a meeting or in the bar.

Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 Review prepared by xx, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes

To Decide if a Medication Is To Be Used In Suffolk

Criterion to be measured Tends to poor Medium Tends to good 5 4 3 2 1 Quality of evidence in the papers reviewed Low Medium High Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical usefulness of trial end-points Low Medium High Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Severe Medium Trivial Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration – maximum and minimum uptake) Is the drug to be used in Suffolk?

Prescriber’s Rating Definitions 1. Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. 2. A real advance - The product is an important therapeutic innovation but has certain limitations. 3. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. 4. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. 5. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. 6. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are “me-too” products. 7. Not acceptable - Product without evident benefit over others but with potential or real disadvantages.

(With acknowledgement to Prescrire)

Review prepared by xx, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes

To Decide Where A Medication Is To Be Used In Suffolk

Criterion Red Amber Green Blue 4 3 2 1 Skills of the Experience Of The Condition Specific Specific Specific General prescriber Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General

Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Dealing with side effects/complications Complex Specific Specific Easy Discontinuation Of Treatment Complex Complex Easy Easy

References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2

Review prepared by xx, East Anglia Medicines Information Service May be freely copied by NHS agencies Not to be used for promotional purposes