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J&J's dapoxetine effective for premature ejaculation
 
 
  11/09/2006
www.pharmatimes.com
www.medpagetoday.com
 
Data published in The Lancet over the weekend lent further support to Johnson & Johnson's hope of developing the first treatment option for premature ejaculation, a condition thought to be more common that erectile dysfunction.
 
The publication of the data, which prompted wide coverage in the press, comes just months after the US Food and Drug Administration turned down J&J's application to market dapoxetine for premature application.
 
At the time, the Alza Corporation, a division of Johnson & Johnson, said it "continues to believe that dapoxetine provides important benefits for men who suffer from premature ejaculation." As of yesterday, Alza said it was still exploring its options.
 
The data on dapoxetine, first reported in May 2005, show that the drug was able to triple the duration of intercourse in men who had been with the same partner for at least six months and persistently suffered from premature ejaculation. It was also effective in extending intercourse in men with the worst symptoms, those who ejaculated within seconds of penetration.
 
The study, by researchers from the University of Minnesota in the USA, enrolled 2,614 men and who received either placebo or a low or high dose of dapoxetine, taken one to three hours before sex.
 
At the start of the 12-week trial, the men ejaculated on average less than a minute after penetration. By the end, those taking the lower 30mg dose were lasting 2.78 minutes, while those on the higher 60mg dose managed 3.32 minutes. Those in the placebo group lasted an average of 1.75 minutes by the end of the study.
 
For comparison, a recent study published in the Journal of Sexual Medicine found that the average duration of intercourse for a normal man is around seven minutes.
 
"On-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation," said Dr Jon Pryor of the University of Minnesota, who led the study
 
If it reaches the market, dapoxetine would be the first treatment option for patients developed specifically for premature ejaculation, which at present is managed using behavioural therapy or older, 'off-label' drugs, mainly antidepressants.
 
Dapoxetine is a selective serotonin reuptake inhibitor, in the same class as many of the antidepressants used to treat premature ejaculation at the moment, but is the only one to have been studied this extensively in clinical trials. Side effects from the treatment included nausea, headache and upset stomach.
 
Critics claim that other SSRIs have been shown to be more effective in treating the condition, and that while premature ejaculation is claimed to affect around a quarter of men at some point, less than 5% suffer from it chronically. It is only the latter group that should be treated with drugs, they suggest, as premature ejaculation in most men is part of the normal spectrum of sexual performance.
 
The drug has not been submitted in Europe, as J&J is mindful of the difficulties faced by Pfizer when it first tried to persuade health systems to reimburse its erectile dysfunction treatment Viagra (sildenafil).
 
If approved, the short-acting SSRI could replace chronic continuous-dose off-label treatment with an SSRI, or non-drug therapy approaches. Dapoxetine is the first on-demand agent for premature ejaculation, Jon Pryor, M.D., of the University of Minnesota here, and colleagues, reported in the Sept. 9 issue of The Lancet.
 
In addition to inconvenience, these continuous-dose compounds, Dr. Pryor said, are associated with drawbacks, such as psychiatric and neurologic issues, anticholinergic side-effects, and sexual side effects such as erectile dysfunction.
 
To determine the safety and efficacy of on-demand dapoxetine, the researchers did a prospectively predefned integrated analysis of two 12-week randomized, double-blind, placebo-controlled, phase III trials.
 
The trials were identical in design and were done in parallel at 121 sites in the U.S. The analysis included 2,614 men in stable heterosexual relationships with moderate to severe premature ejaculation and their partners.
 
Of 2,614 men (mean age 40.5, range 18 to 77) with moderate-to-severe premature ejaculation, 870 were given a placebo, 874 took 30 mg of dapoxetine, and 870 took 60 mg of dapoxetine as needed, one to three hours before anticipated sexual activity.
 
At baseline, 1,623 (62%) of the men ejaculated under a minute after penetration, with mean values much the same across the groups. according to the intravaginal ejaculatory latency time as measured by stopwatch. Mean intravaginal ejaculatory latency time at baseline for the three groups was 0.90 minute (SD 0-47), 0.92 minute (0.50), and 0.91 minute (0.48).
 
At week 12, both dapoxetine doses were more effective than placebo. (P<0.0001, for all doses versus placebo). Intravaginal ejaculatory latency time was 1.75 (SD 2.21) minutes for placebo, 2.78 (3.48) minutes for 30 mg dapoxetine, and 3.32 (3.68) minutes for 60 mg dapoxetine.
 
Only 14% of the placebo patients had an intravaginal ejaculatory latency time of three minutes or more, compared with 29% for the 30 mg dose and 34% for the 60 mg dose. Both dapoxetine doses were effective on the first dose, the researchers reported.
 
Dapoxetine improved patients' perception of control over ejaculation and overall satisfaction with sexual intercourse, a benefit shred by their partners, Dr. Pryor said. Although a placebo effect was apparent in terms of intravaginal ejaculatory latency time, a corresponding improvement in satisfaction with sexual intercourse with placebo treatment was not, he said.
 
The drug was generally well tolerated, the researchers said. Common adverse events, usually mild and transient, for 30 mg and 60 mg dapoxetine, respectively, were nausea (8.7%, 20.1%), diarrhea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%).
 
Among the study's limitations, the researchers noted that the study population was restricted to patients with intravaginal ejaculatory latency time under two minutes with moderate to severe premature ejaculation. Therefore, they said, the results cannot be generalized to men with milder forms of the disorder.
 
The study, they said, also failed to assess patients excluded from the trial (those with coexisting erectile dysfunction, for example). Finally, they noted that because of the predominance of Caucasian and young patients, the results cannot be extended to other ethnic or age groups.
 
In conclusion, Dr. Pryor said that in view of the distress and interpersonal difficulties generally associated with this condition, availability of effective treatment "might encourage men with premature ejaculation to seek a physician diagnosis, and could provide a substantial benefit for men and their partners."
 
Several study authors served as consultants for Johnson & Johnson, and two said they were Alza employees. Dr. Pryor and another author reported having served on advisory boards for Alza.
 
In a commentary in the same Lancet issue, Francesco Montorsi, M.D., and Andrea Salonia, M.D., wrote that a main limitation of chronic administration of an SSRI is the need to continue it, lest premature ejaculation recur.
 
On the other hand, they wrote, dapoxetine with its short duration makes it appealing for on-demand use. Although its three- to four-fold increase in intravaginal ejaculatory latency time is less than that typically seen with chronic SSRIs, "in our experience, most patients would clearly prefer on-demand treatment compared with being placed on a drug long-term," they wrote.
 
"Our hope is that on-demand dapoxetine will become an important drug to offer patients with premature ejaculation," they concluded.
 
Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials
 
The Lancet, Current Issue, Volume 368, Number 9539, 09 September 2006
 
Prof Jon L Pryor MD a , Prof Stanley E Althof PhD b, Christopher Steidle MD c, Prof Raymond C Rosen PhD d, Prof Wayne JG Hellstrom MD e, Ridwan Shabsigh MD f, Maja Miloslavsky PhD g and Sherron Kell MD g, for the Dapoxetine Study Group
a. University of Minnesota, Minneapolis, MN, USA
b. Case Medical School, Cleveland, OH, USA
c. Northeast Indiana Research, LLC, Fort Wayne, IN, USA
d. Robert Wood Johnson Medical School, Piscataway, NJ, USA
e. Tulane University Health Sciences Center, New Orleans, LA, USA
f. New York Center for Human Sexuality, Columbia University, New York, NY, USA g. ALZA Corporation, Mountain View, CA, USA
 
Summary
Background

No drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation.
 
Methods
We determined the efficacy of dapoxetine in a prospectively predefined integrated analysis of two 12-week randomised, double-blind, placebo-controlled, phase III trials of identical design done independently, in parallel, at 121 sites in the USA. Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity). The primary endpoint was intravaginal ejaculatory latency time (IELT) measured by stopwatch. Safety and tolerability were assessed. All analyses were done on an intention-to-treat basis. The trials are registered at ClinicalTrials.gov, numbers NCT00211107 and NCT00211094.
 
Findings
672, 676, and 610 patients completed in the placebo, 30 mg dapoxetine, and 60 mg dapoxetine groups, respectively. Dapoxetine significantly prolonged IELT (p<0-0001, all doses vs placebo). Mean IELT at baseline was 0-90 (SD 0-47) minute, 0-92 (0-50) minute, and 0-91 (0-48) minute, and at study endpoint (week 12 or final visit) was 1-75 (2-21) minutes for placebo, 2-78 (3-48) minutes for 30 mg dapoxetine, and 3-32 (3-68) minutes for 60 mg dapoxetine. Both dapoxetine doses were effective on the first dose. Common adverse events (30 mg and 60 mg dapoxetine, respectively) were nausea (8-7%, 20-1%), diarrhoea (3-9%, 6-8%), headache (5-9%, 6-8%), and dizziness (3-0%, 6-2%).
 
Interpretation
On-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation.
 
Patients who received dapoxetine perceived an overall improvement in symptoms of premature ejaculation, and partners of patients with premature ejaculation had a significant increase in satisfaction with sexual intercourse (table 4). A significant improvement in patient ratings of severity of premature ejaculation was also seen in patients who received dapoxetine (table 4).
 
Accidental injuries-eg, sprained ankle, car accident-were reported in 17 (1-9%) patients receiving placebo, in 28 (3-2%) patients receiving 30 mg dapoxetine, and in 26 (3-0%) on 60 mg dapoxetine. Dizziness and somnolence were the most common neurocognitive adverse events reported (table 5). Individual categories of cardiovascular adverse events each occurred in less than 2% of patients; the most clinically significant event reported was syncope. Syncope was reported in two individuals (0-2%) receiving placebo, three (0-3%) receiving 30 mg dapoxetine, and two (0-2%) receiving 60 mg dapoxetine. Mean blood pressure and heart rate throughout the study were much the same for active treatment and placebo.
 
The incidence of severe adverse events was low-2-9% (n=25) for placebo, 2-3% (20) for 30 mg dapoxetine, and 4-3% (37) for 60 mg dapoxetine. The incidence of serious adverse events was also low-0-9% (8) for placebo, 0-3% (3) for 30 mg dapoxetine, and 0-6% (16) for 60 mg dapoxetine. No deaths, suicides, suicide attempts, suicidal ideations, or SSRI withdrawal syndromes were reported.
 
Introduction
Premature ejaculation is thought to be the most common male sexual dysfunction, with a prevalence of 21-33%.1-3 It can be a source of distress for many men, although some are less affected or cope more effectively with the condition.1-5 In men who are affected by this problem, premature ejaculation can adversely affect self-image, interfere with sexual satisfaction and the sexual relationship,1,2,4,5 and negatively affect the overall quality of life of men and their partners.6,7
 
Although the condition is highly undertreated, selective serotonin reuptake inhibitors (SSRIs), which were developed to treat depression and other psychiatric disorders, are used increasingly as off-label treatment for premature ejaculation, on the basis of their side-effect of delayed ejaculation.5,8-12 However, these compounds were not developed to treat premature ejaculation, are long acting, and are associated with drawbacks.5 SSRI adverse effects include psychiatric and neurological issues, dermatological reactions, anticholinergic side-effects, changes in bodyweight, cognitive impairment, drug-drug interactions, and sexual side-effects (eg, erectile dysfunction and loss of libido).13-19 The rate and mean duration of each type of adverse event varies with the SSRI agent. Conventional SSRIs have longer half-lives and generally take longer to reach peak concentrations.13 Overdose of SSRIs (and drug-drug interactions between SSRIs and other agents that enhance central nervous system serotonergic activity) can lead to the serotonin syndrome.20 Patients receiving continuous-dose SSRI therapy are more likely to have drug-drug interactions with concomitant medications and must adjust their SSRI doses accordingly.18
 
The underlying pathophysiology of premature ejaculation is not completely understood, although both physiological and psychological components could contribute to the condition. Psychopharmacological studies suggest that premature ejaculation might be related to diminished serotonergic neurotransmission through pathways that control ejaculation.21,22 Dapoxetine is a short acting SSRI developed specifically for the treatment of premature ejaculation.23 The drug's mechanism of action is thought to be related to inhibition of neuronal reuptake of serotonin and subsequent potentiation of serotonin activity.23 By contrast with SSRIs approved for depression, which take 2 weeks or longer to reach steady-state concentration,13 dapoxetine has a unique pharmacokinetic profile, with a short time to maximum serum concentration (about 1 h) and rapid elimination (initial half-life of 1-2 h). By 24 h, plasma concentrations are less than 5% of peak values.24 These attributes make dapoxetine suitable for on-demand therapy.
 
We report results from a prespecified integrated analysis of two identically designed clinical trials to determine the efficacy and tolerability of on-demand dapoxetine at two doses in patients with premature ejaculation.
 
Discussion
Our analyses show that dapoxetine, given 1-3 h before intercourse, increased IELT significantly, even after administration of the first dose. Dapoxetine also improved patients' perception of control over ejaculation, satisfaction with sexual intercourse, and overall impression of change in condition. Partners benefited through improved satisfaction with sexual intercourse. Thus, dapoxetine seems to lead to improvements in ejaculatory function that have meaning for men with premature ejaculation and their partners. For many men, premature ejaculation is associated with substantial psychological effects-eg, interpersonal distress,1,2,4,5,26 decreased self-confidence, and relationship difficulties.2,4 Thus, an effective treatment that can be used as needed will offer an important new option for men with premature ejaculation and their partners.
 
In the absence of an approved treatment for premature ejaculation, conventional SSRIs are increasingly used to treat premature ejaculation. Such agents could also delay ejaculation when taken on a daily basis. Waldinger's meta-analysis32 of pharmacological agents that delay ejaculation reported IELT delays ranging from two-fold to nine-fold above baseline when the drugs were taken on a daily basis. He also described IELT delays for on-demand agents in the two-fold to eight-fold range, but noted that these studies were difficult to interpret because of methodological difficulties. Dapoxetine, given on-demand, delays ejaculation roughly three-fold to four-fold in the overall population, with greater increases seen in men with lower baseline IELTs (eg, baseline IELT <30 s, 5-fold increase with 30 mg dapoxetine and 6-7-fold increase with 60 mg dapoxetine), which is consistent with previously reported studies.32
 
With the baseline IELTs of the population studied (mean of 0-90-0-92 minute and all ≦2 minutes), the overall 2-minutes or more (3-fold to 3-7-fold) improvement in IELT with dapoxetine is clinically meaningful, as evidenced by other more subjective measures of the condition. Improvements in control over ejaculation, satisfaction with sexual intercourse, and self-reported severity in this population of more severely affected individuals are highly relevant to confirming the clinical benefit of treatment. An observational study showed that patient ratings of the severity of premature ejaculation had a strong positive correlation with distress (r=0-61).26
 
The effect of dapoxetine on the single-item patient-reported outcome measures also showed clinically important differences. At baseline, 3% of patients reported fair or better than fair control over ejaculation. By the end of study, only about a quarter of placebo-treated individuals achieved fair or better control over ejaculation. By contrast, at least twice as many achieved that level with dapoxetine. Moreover, although about half of individuals in all groups had fair or better satisfaction with sexual intercourse at baseline, placebo treatment yielded negligible change-about half of individuals who received placebo achieved fair or better than fair satisfaction, compared with about three-quarters of individuals on dapoxetine. The finding that satisfaction with sexual intercourse was not as severely impaired as IELT or control over ejaculation at baseline is unsurprising, since IELT and control over ejaculation are more direct symptoms of premature ejaculation, whereas satisfaction with sexual intercourse is a broader notion that incorporates other aspects of the sexual encounter. Although a placebo effect was apparent for IELT and control over ejaculation, a corresponding improvement in satisfaction with sexual intercourse with placebo treatment was not.
 
One should note that the study population was restricted to patients with IELT consistently 2 minutes or less and who described their premature ejaculation as moderate to severe. Therefore, the results cannot be generalised to men with milder forms of premature ejaculation. Additionally, the effects of dapoxetine on patient types excluded from these trials-those with coexisting erectile dysfunction or premature ejaculation of other cause-are not known. Finally, because of the predominance of caucasian and young patients, robust conclusions in other ethnic groups and older men could not be established.
 
Generally, a chronic daily dosing schedule has been used when conventional SSRI antidepressants have been prescribed for premature ejaculation.5,8-12,33 However, in addition to the inconvenience of such a schedule, long-term daily dosing with conventional SSRIs could be a contributing factor to the increased frequency of sexual side-effects in individuals receiving such treatment-eg, erectile dysfunction (5-9%), decreased libido (2-5-5-0%), and high incidences of problems with orgasm (4-9%) and non-ejaculation (2-5-8-2%).34 In the trials analysed here, sexual side-effects were reported in 1-5% or less of patients on placebo, 2-9% of those on 30 mg dapoxetine, and 3-8% of those on 60 mg dapoxetine. Thus, dapoxetine on-demand is effective in delaying ejaculation when used as needed and is well tolerated, with a low incidence of sexual side-effects.
 
Non-sexual side-effects with dapoxetine were transient and characteristic of compounds with serotoninergic effects.5,8-12 Some of the side-effects-nausea, diarrhoea, and dizziness-seemed dependent on dose. The most commonly reported side-effect was nausea. Most of these events were mild and transient, and resulted in study discontinuation in only a few cases. Cardiovascular and central nervous system side-effects were reported at a low incidence. The most clinically important cardiovascular adverse event reported was syncope, which occurred at a low incidence that was much the same in all groups of patients in this combined analysis, but at a higher rate than placebo in other studies. The occurrence of syncope is not unexpected and is likely to be drug related, since syncope is reported as an infrequent adverse event (1 in 100-1000) with SSRIs approved for the treatment of depression;35 much the same rate that has been noted with dapoxetine in other, as yet unpublished studies.
 
Accidental injury is a recognised adverse event reported with many drug classes, especially with agents that modulate the central nervous system. Accidental injury is reported with some SSRIs36 and phosphodiesterase-5 inhibitors.37,38 Events should be examined qualitatively for details of circumstances surrounding the reported accidental injury. Such an assessment of the accidental injuries in these trials showed that there was no clinical signal to suggest that the accidental injuries were masking any other important adverse events-eg, syncope and suicidality. Neurocognitive adverse events-eg, dizziness and somnolence-seemed to be dose dependent. Both accidental injuries and neurocognitive adverse events could be drug related. The relation between the occurrence of these two types of adverse events needs further investigation. The discontinuation rate due to adverse events with dapoxetine (about 7%) was much the same as or less than that of other SSRI compounds when used in men with premature ejaculation.12
 
These trials have shown that dapoxetine is effective and generally well tolerated for the treatment of premature ejaculation when given on demand. Dapoxetine improves multiple patient-reported and partner-reported variables as well as the rigorous objective assessment of IELT. In view of the distress and interpersonal difficulties generally associated with this condition, availability of an effective treatment, especially for those with the most severe premature ejaculation, might encourage men with premature ejaculation to seek a physician diagnosis, and could provide a substantial benefit for men and their partners.
 
 
 
 
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