Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: A. Menarini Farmaceutica Internazionale SRL, Menarini House, Mercury Park, Wycombe Lane, Wooburn Green, Buckinghamshire, HP10 0HH
Pharmacotherapeutic group: Other Urologicals
ATC code: G04BX14
Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with an IC50 of 1.12 nM, while its major human metabolites, desmethyldapoxetine (IC50<1.0 nM) and didesmethyldapoxetine (IC50=2.0 nM) are equivalent or less potent (dapoxetine-N-oxide (IC50=282 nM)).
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.
In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level within the lateral paragigantocellular nucleus (LPGi). Post ganglionic sympathetic fibers that innervate the seminal vesicles, vas deferens, prostate, bulbourethral muscles and bladder neck cause them to contract in a coordinated fashion to achieve ejaculation. Dapoxetine modulates this ejaculatory reflex in rats.
The effectiveness of Priligy in the treatment of premature ejaculation has been established in five double-blind, placebo-controlled clinical trials, in which a total of 6081 subjects were randomized. Subjects were 18 years of age or older and had a history of PE in the majority of intercourse experiences in the 6-month period prior to enrolment. Premature ejaculation was defined according to the DSM-IV diagnostic criteria: short ejaculatory time (an intravaginal ejaculatory latency time [IELT; time from vaginal penetration to the moment of intravaginal ejaculation] of ≤2 minutes measured using a stopwatch in four studies), poor control over ejaculation, marked distress or interpersonal difficulty due to the condition.
Subjects with other forms of sexual dysfunction, including erectile dysfunction, or those using other forms of pharmacotherapy for the treatment of PE were excluded from all studies.
Results of all randomized studies were consistent. Efficacy was demonstrated after 12 weeks of treatment. One study enrolled patients both outside and within the EU and had a treatment duration of 24 weeks. In the study, 1162 subjects were randomized, 385 to placebo, 388 to Priligy 30 mg as needed, and 389 to Priligy 60 mg as needed. The mean and median Average IELT at study end are presented in Table 2 below and the cumulative distribution of subjects who achieved at least a specific level in Average IELT at study end are presented in Table 3 below. Other studies and pooled analysis of the data at Week 12 gave consistent results.
Table 2. Least squares mean and median Average IELT at study end:
| Average IELT | Placebo | Priligy 30 mg | Priligy 60 mg |
|---|---|---|---|
| Median | 1.05 min | 1.72 min | 1.91 min |
| Difference from placebo [95% CI] | 0.6 min** [0.37, 0.72] | 0.9 min** [0.66, 1.06] | |
| Least Squares Mean | 1.7 min | 2.9 min | 3.3 min |
| Difference from placebo [95% CI] | 1.2 min** [0.59, 1.72] | 1.6 min** [1.02, 2.16] |
* Baseline value carried forward for subjects with no post-baseline data.
** Difference was statistically significant (p-value ≤ 0.001).
Table 3. Subjects achieving at least a specific level in Average IELT at study end:
| IELT (mins) | Placebo % | Priligy 30 mg % | Priligy 60 mg % |
|---|---|---|---|
| ≥1.0 | 51.6 | 68.8 | 77.6 |
| ≥2.0 | 23.2 | 44.4 | 47.9 |
| ≥3.0 | 14.3 | 26.0 | 37.4 |
| ≥4.0 | 10.4 | 18.4 | 27.6 |
| ≥5.0 | 7.6 | 14.3 | 19.6 |
| ≥6.0 | 5.0 | 11.7 | 14.4 |
| ≥7.0 | 3.9 | 9.1 | 9.8 |
| ≥8.0 | 2.9 | 6.5 | 8.3 |
* Baseline value carried forward for subjects with no post-baseline data.
The magnitude of IELT prolongation was related to baseline IELT and was variable between individual subjects. The clinical relevance of Priligy treatment effects was further demonstrated in terms of various patient reported outcome measures and a responder analysis.
A responder was defined as a subject who had at least a 2-category increase in control over ejaculation plus at least a 1-category decrease in ejaculation-related distress. A statistically significantly greater percentage of subjects responded in each of the Priligy groups versus placebo at the end of the study Week 12 or 24. There was a higher percentage of responders in the dapoxetine 30 mg (11.1%-95% CI [7.24; 14.87]) and 60 mg (16.4%-95% CI [13.01; 19.75]) groups compared with the placebo group at Week 12 (pooled analysis).
The clinical relevance of Priligy treatment effects is represented by treatment group for the subject’s Clinical Global Impression of Change (CGIC) outcome measure, in which patients were asked to compare their premature ejaculation from the start of the study, with response options ranging from much better to much worse. At study end (Week 24), 28.4% (30 mg group) and 35.5% (60 mg group) of subjects reported their condition to be “better” or “much better”, compared to 14% for placebo, while 53.4% and 65.6% of subjects treated with dapoxetine 30 mg and 60 mg, respectively, reported their condition to be at least “slightly better”, compared to 28.8% for placebo.
Dapoxetine is rapidly absorbed with maximum plasma concentrations (Cmax) occurring approximately 1-2 hours after tablet intake. The absolute bioavailability is 42% (range 15-76%), and dose proportional increases in exposure (AUC and Cmax) are observed between the 30 and 60 mg dose strengths. Following multiple doses, AUC values for both dapoxetine and the active metabolite desmethyldapoxetine (DED) increase by approximately 50% when compared to single dose AUC values.
Ingestion of a high fat meal modestly reduced the Cmax (by 10%) and modestly increased the AUC (by 12%) of dapoxetine and slightly delayed the time for dapoxetine to reach peak concentrations. These changes are not clinically significant. Priligy can be taken with or without food.
More than 99% of dapoxetine is bound in vitro to human serum proteins. The active metabolite desmethyldapoxetine (DED) is 98.5% protein bound. Dapoxetine has a mean steady state volume of distribution of 162 L.
In vitro studies suggest that dapoxetine is cleared by multiple enzyme systems in the liver and kidneys, primarily CYP2D6, CYP3A4, and flavin monooxygenase (FMO1). Following oral dosing of 14C-dapoxetine, dapoxetine was extensively metabolized to multiple metabolites primarily through the following biotransformational pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation and sulfation. There was evidence of presystemic first-pass metabolism after oral administration.
Intact dapoxetine and dapoxetine-N-oxide were the major circulating moieties in the plasma. In vitro binding and transporter studies show that dapoxetine-N-oxide is inactive. Additional metabolites including desmethyldapoxetine and didesmethyldapoxetine account for less than 3% of the total circulating drug–related materials in plasma. In vitro binding studies indicate that DED is equipotent to dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of dapoxetine (see section 5.1). The unbound exposures (AUC and Cmax) of DED are approximately 50% and 23%, respectively, of the unbound exposure of dapoxetine.
The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged active substance was not detected in the urine. Following oral administration, dapoxetine has an initial (disposition) half-life of approximately 1.5 hours, with plasma levels less than 5% of peak concentrations by 24 hours post-dose, and a terminal half-life of approximately 19 hours. The terminal half-life of DED is approximately 19 hours.
The metabolite DED contributes to the pharmacological effect of Priligy, particularly when the exposure of DED is increased. Below, in some populations, the increase in active fraction parameters is presented. This is the sum of the unbound exposure of dapoxetine and DED. DED is equipotent to dapoxetine. The estimation assumes equal distribution of DED to the CNS but it is unknown whether this is the case.
Analyses of single dose clinical pharmacology studies using 60 mg dapoxetine indicated no statistically significant differences between Caucasians, Blacks, Hispanics and Asians. A clinical study conducted to compare the pharmacokinetics of dapoxetine in Japanese and Caucasian subjects showed 10% to 20% higher plasma levels (AUC and peak concentration) of dapoxetine in Japanese subjects due to lower body weight. The slightly higher exposure is not expected to have a meaningful clinical effect.
Analyses of a single dose clinical pharmacology study using 60 mg dapoxetine showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly males and healthy young adult males. The efficacy and safety has not been established in this population (see section 4.2).
A single-dose clinical pharmacology study using a 60 mg dapoxetine dose was conducted in subjects with mild (CrCL 50 to 80 mL/min), moderate (CrCL 30 to <50 mL/min), and severe renal impairment (CrCL<30 mL/min) and in subjects with normal renal function (CrCL>80 mL/min). No clear trend for an increase in dapoxetine AUC with decreasing renal function was observed. AUC in subjects with severe renal impairment was approximately 2-fold that of subjects with normal renal function, although there are limited data in patients with severe renal impairment. Dapoxetine pharmacokinetics have not been evaluated in patients requiring renal dialysis (see sections 4.2 and 4.4).
In patients with mild hepatic impairment, unbound Cmax of dapoxetine is decreased by 28% and unbound AUC is unchanged. The unbound Cmax and AUC of the active fraction (the sum of the unbound exposure of dapoxetine and desmethyldapoxetine) were decreased by 30% and 5%, repectively. In patients with moderate hepatic impairment, unbound Cmax of dapoxetine is essentially unchanged (decrease of 3%) and unbound AUC is increased by 66%. The unbound Cmax and AUC of the active fraction were essentially unchanged and doubled, respectively.
In patients with severe hepatic impairment, the unbound Cmax of dapoxetine was decreased by 42% but the unbound AUC was increased by approximately 223%. The Cmax and AUC of the active fraction had similar changes (see sections 4.2 and 4.3).
In a single dose clinical pharmacology study using 60 mg dapoxetine, plasma concentrations in poor metabolizers of CYP2D6 were higher than in extensive metabolizers of CYP2D6 (approximately 31% higher for Cmax and 36% higher for AUCinf of dapoxetine and 98% higher for Cmax and 161% higher for AUCinf of desmethyldapoxetine). The active fraction of Priligy may be increased by approximately 46% at Cmax and by approximately 90% at AUC. This increase may result in a higher incidence and severity of dose dependent adverse events (see section 4.2). The safety of Priligy in poor metabolizers of CYP2D6 is of particular concern with concomitant administration of other medicinal products that may inhibit the metabolism of dapoxetine such as moderate and potent CYP3A4 inhibitors (see sections 4.2 and 4.3).
A full assessment of the safety pharmacology, repeat dose toxicology, genetic toxicology, carcinogenicity, dependence/withdrawal liability, phototoxicity and developmental reproductive toxicology of dapoxetine was conducted in preclinical species (mouse, rat, rabbit, dog and monkey) up to the maximum tolerated doses in each species. Due to the more rapid bioconversion in the preclinical species than in man, pharmacokinetic exposure indices (Cmax and AUC0-24hr) at the maximum tolerated doses in some studies approached those observed in man. However, the body weight normalized dose multiples were greater than 100-fold. There were no clinically relevant safety hazards identified in any of these studies.
In studies with oral administration, dapoxetine was not carcinogenic to rats when administered daily for approximately two years at doses up to 225 mg/kg/day, yielding approximately twice the exposures (AUC) seen in human males given the Maximum Recommended Human Dose (MRHD) of 60 mg. Dapoxetine also did not cause tumors in Tg.rasH2 mice when administered at the maximum possible doses of 100 mg/kg for 6 months and 200 mg/kg for 4 months. The steady state exposures of dapoxetine in mice following 6-months oral administration at 100 mg/kg/day were less than the single dose exposures observed clinically at 60 mg.
There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats and no adverse signs of embryotoxicity or fetotoxicity in the rat or rabbit. Reproductive toxicity studies did not include studies to assess the risk of adverse effects after exposure during the peri-post-natal period.
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