DAPOXETINE
Dapoxetine ((+)-(S)-N,N-dimethyl-(a)-[2(lnaphthalenyloxy)ethyl]-benzenemethanamine hydrochloride) is the first compound specifically developed for the treatment of PE. Dapoxetine, structurally similar to fluoxetine is a potent SSRI. Reported equilibrium radioligand binding studies using human cells demonstrate that dapoxetine binds to 5-HT, norepinephrine (NE) and dopamine (DA) reuptake transporters and inhibits uptake in the following order of potency: NE < 5-HT » DA (McMahon CG, 2010).
Dapoxetine: Current Regulatory Status
Oral dapoxetine has been approved in various European countries, including Finland, Germany and Sweden, under the decentralized procedure and in several other countries worldwide for the treatment of men aged 18-64 years with premature ej aculation (Hoy SM et al 2010).
PHARMACOKINETICS AND METABOLISM
Absorption: Reported evidence suggest that 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%). 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. Dapoxetine can be taken with or without food (Dapoxetine SPC). Distribution: Reported evidence suggests that more than 99% of dapoxetine is bound to human serum proteins. The active metabolite desmethyldapoxetine (DED) is 98.5% protein bound. Dapoxetine appears to have a rapid distribution with a mean steady state volume of distribution of 162 L. Following intravenous administration in humans, mean estimated initial, intermediate, and terminal half life values for dapoxetine were 0.10, 2.19, and 19.3 hours respectively (Dapoxetine SPC). Biotransformation: Reported evidence suggest that dapoxetine is cleared by multiple enzyme systems in the liver and kidneys, primarily CYP2D6, CYP3A4, and flavin monooxygenase (FMO1). There was evidence of presystemic first pass metabolism after oral administration. Intact dapoxetine and Dapoxetine-N-oxide were the major circulating species in the plasma. Additional metabolites include desmethyldapoxetine and didesmethyldapoxetine, which account for less than 3% of the circulating medicinal product related material (Dapoxetine SPC). Elimination: The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged active substance was not detected in the urine. Dapoxetine has a rapid elimination, as evidenced by a low concentration (less than 5% of peak) 24 hours after dosing. There was minimal accumulation of dapoxetine following daily dosing. The terminal half-life is approximately 19 hours following oral administration (Dapoxetine SPC).
Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride was evaluated in a randomized, 2-sequence, 2-treatment crossover study which assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5 % of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea (Modi NB et al 2006).
CLINICAL EFFICACY OF DAPOXETINE
1) Efficacy and tolerability of dapoxetine in treatment of premature ejaculation
Pryor JL et al (2006) 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.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, 13 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.
Improvement in IELT:
At baseline, 1623 men (62%) had IELT of 1 minute or less, with mean IELT values much the same across groups. At week 12, both dapoxetine doses were better than placebo (p< 0.0001, each dose vs. placebo), and 60 mg Dapoxetine was better than 30 mg dapoxetine (p=0.0007; figure 6) Overall, IELT increased in all three groups, but the increase was greatest in those on dapoxetine (table 2). At the study endpoint, 109 (14%) of 787 patients on placebo, 232 (29%) of 801 on 30 mg dapoxetine, and 261 (34%) of 763 on 60 mg dapoxetine had an IELT of 3 minutes or more (table 2). The p values for the tests of difference of proportions between placebo and the 30 mg group, as well as between placebo and the 60 mg group, were both p< 0.0001.
Table 2: IELT at baseline and end of study mstmasmiimiies&m'xs:'::'',-'. : •.•
All patients n=870 n=874 n=870
Baseline 0.90(0.47) 0.92(0.50) 0.91(0.48) :
End of study 1.75(2.21) 2.78(3.48)* 3.32(3.68)*f
Least-square mean difference vs placebo (95% Cl) _ 1.11(0.80-1.43) 1.66(1.35-1.98)
Patients with baseline IELT > 1
to ^ 2 min n=328 n=332 n=328
Baseline 1.39(0.31) 1.14(0.31) 1.38(0.32)
End of study 2.51(2.72) 3.79(3.14)* 4.43(4.12)*$
Least-square mean difference vs placebo (95% Cl) - 1.27(0.72-1.82) 1.95(1.39-2.51)
Patients with baseline lELTsl min n=541 n=542 n=540
Baseline 0.61(0.26) 0.62(0.32) 0.61(0.29)
End of study 1.28(1.67) 2.19(3.54)* 2.67(3.24)*§
Least-square mean difference vs placebo (95% Cl) - 0.91 (0.54-1.27) 1.39 (1.02-1.76)
Patients with baseline
lELT^SOs (post-hoc analysis) n=200 n=184 n=187
Baseline 0.34(0.12) 0.32(0.14) 0.32(0.14)
End of study 0.86(1.48) 1.63(3.53)11 2.17(3.64)*1
Least-square mean difference vs placebo (95%C1) _ 0.84(0.17-1.52) 1.53(0.85-2.20)
Distribution of IELT at
study endpoint n=787 n=801 n=763
0 to < Imin 342 (44%) 203 (25%) 157(21%) I'
1 to <2 min 251(32%) 250(31%) 216(28%)
2 to < 3 min 85(11%) 116 (15%) 129(17%) ;
3 to < 4 min 42(5%) 90(11%) 59(8%) ;
>4 min 67 (9%) 142 (18%) 202 (27%)
Missing 17 21 38
Data are minutes (SD) or number (%), unless otherwise indicated. All percentages rounded. *P < 0.0001 vs placebo. tp= 0.0007
vs30mg. tp=0.018vs30mg. §p=0.0094vs30mg. | p=0. 014 vs placebo. tP=0.056vs30mg.
Improvement in Premature Ejaculation Profile
The study-specified secondary endpoints also showed that both dapoxetine doses were better than placebo (p< 0.0001, each dose vs placebo). Improvements in patient perception of control over ejaculation and satisfaction with sexual intercourse were achieved with both doses of dapoxetine at all time points (table 3). 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 3). A significant improvement in patient ratings of severity of premature ejaculation was also seen in patients who received Dapoxetine
Table 4: Adverse events reported in this study
Placebo (n=872)* 30 mg dapoxetine (n=876)* Occurred more frequently on dapoxetine than placebo
Nauseal? ( 1.9%)76 ( 8.7%)175 ( 20.1%)
Diarrhoea 12 ( 1.4%)
Headache 35 (4.0%)
Dizziness 7 (0.8%)
Somnolence 2 (0.2%)
60 mg dapoxetine (n=870)
34 (3.9%)59 (6.8%) 52 (5.9%)59 (6.8%) 26 ( 3.0%)54 (6.2%) 28( 3.2%)32 ( 3.7%)
Reasons for study discontinuation
Nausea
Dizziness
Diarrhoea
Headache
Erectile dysfunction
Insomnia
Vomiting
Anxiety
Nervousness
Sweating
Sexual function
Erectile Dysfunction Abnormal ejaculation Libido decreased Sexual function abnormal
11 (1.3%)33(3.8%) 8 (0.9%)13 (1.5%)
1(0.1%)
0
1(0.1%)
2(0.2%)
1 (0.1%)
0
0
0
0
0
4(0.5%)9 5 ( 0.6%)8 4(0.5%)6 3(0.3%)6 1 (0.1%)6 3(0.3%)5 1 (0.1%)5
(1.0%)
(0.9%)
(0.7%)
(0.7%)
(0.7%)
(0.6%)
(0.6%)
25 ( 2.9%)33 ( 3.8%) 6(0.7%)7(0.8%) 6(0.7%)3 (0.3%) 2(0.2%)4(0.5%)
13 ( 1.5%)
2(0.2%)
0
2 ( 0.2%)
Data presented as mean (SD) or number (%). Percentages are rounded. *p<0- 0001 vs placebo.
Conclusion of this study
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.
2) Overall treatment benefit of dapoxetine for premature ejaculation (PE), with specific emphasis on improvements in personal distress and interpersonal difficulty related to ejaculation
Kaufman JM et al (2009) evaluated the overall treatment benefit of dapoxetine for premature ejaculation (PE), with specific emphasis on improvements in personal distress and interpersonal difficulty related to ejaculation. In this randomized, double-blind, placebo-controlled, phase III trial Kaufman JM et al enrolled men aged > or =18 years, from the USA and Canada, who had a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, diagnosis of PE (1238 men). Men were randomized to receive placebo or dapoxetine 60 mg as needed or once daily for 9 weeks. The once-daily treatment arm was included for analysis of withdrawal symptoms (primary endpoint; presented elsewhere). Patients completed the Premature Ejaculation Profile (PEP) on day 1 (before dosing), and on days 28 and 63 (or study endpoint), which comprised the outcome measures for perceived control over ejaculation, satisfaction with sexual intercourse, and personal distress and interpersonal difficulty related to ejaculation. The patient-reported global impression of change in PE was reported on day 63 (or study endpoint). Treatment benefit measures included the composite criteria of at least a two-category increase in perceived control over ejaculation and at least a one-category decrease in personal distress related to ejaculation from baseline at study endpoint. Their results revealed that at baseline, approximately 5% of patients in any treatment group reported 'not at all1 or 'a little bit' of personal distress related to ejaculation, which increased to 54.3% of those receiving dapoxetine (vs 35.3% with placebo; P < 0.001). Similarly, 43.0% and 40.9% of men in the placebo and dapoxetine groups, respectively, reported 'not at all' or 'a little bit' of interpersonal difficulty related to ejaculation at baseline, which increased to 76.8% and 64.2% of those with dapoxetine and placebo, respectively (P < 0.001). The percentage of men who achieved the composite criteria with dapoxetine 'as needed' was 47.6%, vs 21.7% with placebo (difference from placebo, 25.9%; P < 0.001). The distribution of responses for the PEP among men who achieved the composite criteria was similar to that reported for men without PE in a previous observational study in the USA. The most common adverse events were nausea, dizziness, headache, diarrhoea and insomnia, which were more common with dapoxetine than with placebo. Authors concluded that dapoxetine reduced the personal distress and interpersonal difficulty associated with PE, and was associated with patient-reported improvements in their condition. The percentage of patients who achieved a composite of a two-category or greater increase in perceived control over ejaculation and a one-category or greater decrease in personal distress related to ejaculation was substantially greater than with placebo, as were all outcome measures.
3) Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries
This trial evaluated the efficacy and safety of long-term (6 month) treatment with as needed dapoxetine 30 mg and dapoxetine 60 mg in men with PE. This was a randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N = 1162) > 18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for > 6 mo, with an intravaginal ejaculatory latency time (IELT) <2 min in >75% of intercourse episodes at baseline. All enrolled patient received dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (13 h before intercourse) for 24 wk. Stop watch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs) were efficacy and safety variables.
Intravaginal ejaculatory latency time
Mean average IELT was greater with Dapoxetine than with placebo after the first dose and at all subsequent time points (all p < 0.001; Fig. 7). Mean (SD) IELT increased significantly from 0.9 min at baseline to 1.9 min (SD = 2.89 min), 3.1min (SD = 4.88 min), and 3.5min (SD = 3.80 min) with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, at the week 24 end point (both p < 0.001 vs placebo; week 24 end point and change from baseline.
Patient reported outcome for premature ejaculation profile
Because many factors influence IELT, the clinical relevance of PE treatments may best be evaluated using Patient reported outcome (PRO) that assess unobservable feelings known only to the man and his partner. All PRO measures improved significantly with dapoxetine versus placebo. Further, significantly more subjects receiving dapoxetine achieved a composite PRO-defined assessment of therapeutic benefit (an increase greater than or equal to two categories in control and a decrease of greater than or equal to one category in distress) compared with placebo. This composite definition of treatment benefit may be useful to clinicians because it captures changes in both patient functioning (control) and feeling (distress), rather than simply reporting a measure of biologic response (IELT)
Adverse event reported in this study:
Adverse events (AE) were reported by 38.4%, 56.2%, and 68.1 % of men receiving placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. The most common treatment emergent AEs with dapoxetine were nausea, dizziness, diarrhea, and headache.
Conclusion of this study:
Dapoxetine prolonged IELT, was well tolerated over 24 wk in men from a wide range of cultural backgrounds, and significantly improved all PROs, including control, satisfaction, distress, and interpersonal difficulty. These results demonstrate that the benefit of dapoxetine encompasses the overall and relational sexual experience.
4) Safety and Efficacy of Dapoxetine in the Treatment of Premature Ejaculation: A Double-Blind, Placebo-Controlled, Fixed-Dose, Randomized Study
Safarinejad MR (2008) evaluated the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) drug dapoxetine in delaying ejaculation in patients with premature ejaculation (PE). A total of 212 potent men with PE were randomly assigned to receive 30 mg orally dapoxetine (group 1, N= 106) twice daily or similar regimen of placebo (group 2, N = 106) during a 12-week period for each agent. Pretreatment evaluation included history and physical examination, geometric mean intravaginal ejaculatory latency time (IELT, primary outcome measure), and International Index of Erectile Function (IIEF). The efficacy of two treatments was assessed every 2 weeks during treatment, at the end of study, and in 3-month follow-up after cessation of treatment. We measured geometric mean IELT. Thus, the IELT values were logarithmically transformed before statistical analysis, and the results are reported as fold increases from baseline with associated 95 % confidence intervals (CI). The independent sample two-tailed t-test was used to compare the lELTs. At the end of 12-week treatment, the dapoxetine group had a 2.9- (95 % CI, 1.84-4.16) fold increase of the geometric mean IELT, while after placebo the geometric mean IELT did not increase significantly (1.4-fold increase; 95% CI, 0.84-1.63) (p=0.001). The mean weekly intercourse episodes increased from pretreatment values of 1.16 and 1.14 to 2.2 and 1.4, for dapoxetine and placebo, respectively (p=0.04). Baseline mean intercourse satisfaction domain values of IIEF, 12 and 11, reached to 16 and 10 at the 12-week treatment in groups 1 and 2, respectively (p=0.04). At the end of 3-month follow-up period, the geometric mean IELT in dapoxetine and placebo group demonstrated 1.4- (95% CI, 0.66-1.46) and 1.3-(95% CI, 0.77-1.63) fold increase, respectively (p=0.1). Three-month intercourse satisfaction domain value of IIEF was 11 in group 1 and 10 in group 2 (p=0.1). Mean number of adverse events was 19 for
DOSAGE AND ADMINISTRATION OF DAPOXETINE
Oral dapoxetine is indicated for the treatment of men aged 18-64 years with premature ejaculation. The recommended starting dosage is 30 mg (administered with water) as needed 1-3 hours prior to sexual intercourse (maximum dosing frequency of once every 24 hours); the dose may be increased to 60 mg (the maximum recommended dose) based on efficacy and tolerability. Dapoxetine may be administered with or without food(Hoy SM et al 2010).
Dapoxetine is contraindicated in men with moderate to severe hepatic impairment and in those receiving concomitant therapy with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, telithromycin), thioridazine, MAOIs, serotonin reuptake inhibitors (e.g. SSRIs, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants) or other medicinal/herbal products with serotonergic effects (e.g. hypericum [St John's wort]) (Hoy SM et al 2010).
Therapy with dapoxetine is not recommended in men with severe renal impairment; caution is advised with the administration of dapoxetine to men with mild or moderate renal impairment and in those men receiving concomitant therapy with a potent CYP2D6 inhibitor or a moderate CYP3A4 inhibitor. Concomitant dapoxetine therapy and alcohol or recreational drags should also be avoided (Hoy SM et al 2010).
Place in Therapy
Dapoxetine is an effective, safe and well-tolerated on-demand treatment for PE and is likely to fulfill the treatment needs of most patients. At present, Dapoxetine has the largest database for use in men with PE, and it is the only agent for which SSRI class-related effects have been studied in PE population.
PRESCRIBING INFORMATION
For the use of a registered medical practitioner or a hospital or a laboratory only Dapoxetine hydrochloride Tablet
Sustinex
Composition:
Each film-coated tablet contains:
Dapoxetine hydrochloride equivalent to Dapoxetine.... 30 mg / 60 mg
Indication:
Dapoxetine hydrochloride Tablet is indicated for the treatment of premature ejaculation in men 18 to 64 years of age.
Pharmacology:
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.
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). In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level with the lateral paragigantocellular nucleus (LPGi) as a necessary brain structure for the effect. 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, causing an increase in pudendal motoneuron reflex discharge (PMRD) latency and a reduction in PMRD duration.
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%). 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. Dapoxetine 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 appears to have a rapid distribution with a mean steady state volume of distribution of 162 L. Following intravenous administration in humans, mean estimated initial, intermediate, and terminal half-life values for
dapoxetine were 0.10,2.19, and 19.3 hours respectively. 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 in a clinical study designed to explore the metabolism 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 species in the plasma. In vitro studies show that Dapoxetine-N-oxide was inactive in a battery of in vitro binding and transporter studies. Additional metabolites include desmethyldapoxetine and didesmethyldapoxetine, which account for less than 3% of the circulating medicinal product-related material. In vitro binding studies indicate that DED is equipotent to dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of dapoxetine. The unbound exposure of DED is 1/3 of the free exposure of dapoxetine, The unbound Cmax of DED is estimated to be 20-25 % of dapoxetine Cmax in the absence of intrinsic or extrinsic factors that may change exposure levels. The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged active substance was not detected in the urine. Dapoxetine has a rapid elimination, as evidenced by a low concentration (less than 5 % of peak) 24 hours after dosing. There was minimal accumulation of dapoxetine following daily dosing. The terminal half-life is approximately 19 hours following oral administration. The metabolite DED contributes to the pharmacological effect of dapoxetine, 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 a single dose clinical pharmacology study using 60 nig dapoxetine showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly males and healthy young adult males. Dapoxetine pharmacokinetics have not been evaluated in patients requiring renal dialysis. There are limited data in patients with severe renal impairment. The pharmacokinetics of dapoxetine and DED are unchanged in patients with mild hepatic impairment. In patients with moderate hepatic impairment (Child-Pugh Class B), unbound Cmax of dapoxetine is increased by 55 % and unbound AUC is increased by 120%. The unbound Cmax and AUC of the active fraction were unchanged and doubled, respectively. In severe hepatic impairment, the unbound Cmax of dapoxetine was unchanged but the unbound AUC was increased more than 3-fold. The AUC of the active fraction was increased several-fold. 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 AUC inf of dapoxetine and 98 % higher for Cmax and 161 % higher for AUC inf of desmethyldapoxetine). The active fraction of dapoxetine 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 dapoxetine 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. Plasma concentrations of dapoxetine and DED in CYP2D6 ultra-rapid
metabolizers are expected to be decreased. Dosage and administration:
For oral use. Tablets should be swallowed whole to avoid the bitter taste. It is recommended that tablets be taken with at least one full glass of water. Patients should be cautioned to avoid situations where injury could result, including driving or operating hazardous machinery, should syncope or its prodromal symptoms such as dizziness or lightheadedness occur. Dapoxetine may be taken with or without food.
The physician who elects to use dapoxetine for the treatment of premature ejaculation should evaluate the risks and patient-reported benefits of the medicinal product after the first four weeks of treatment or after 6 doses to assess the patient risk-benefit balance and to determine whether continuing treatment with dapoxetine is appropriate.
Adult men (18 to 64 years of age: Before treatment is initiated, the physician should obtain a careful medical history focusing on past orthostatic events and also perform an orthostatic test (blood pressure and pulse rate, supine and standing). If the patient discloses a history suggestive of orthostatic reactions or an orthostatic test shows this kind of reaction, treatment with dapoxetine should be avoided. The recommended starting dose for all patients is 30 mg, taken as needed approximately 1 to 3 hours prior to sexual activity. The maximum recommended dosing frequency is once every 24 hours. If the effect of 30 mg is insufficient and the side effects are acceptable, the dose may be increased to the maximum recommended dose of 60 mg. If the patient has had orthostatic reactions on the starting dose, no dose escalation to 60 mg should be performed.
Elderly (age 65 years and over: Safety and efficacy of dapoxetine have not been established in patients age 65 years and over as limited data are available in this population.
Children and adolescents: dapoxetine should not be used in individuals below 18 years of age.
Patients with renal impairment: Caution is advised in patients with mild or moderate renal impairment. Dapoxetine is not recommended for use in patients with severe renal impairment.
Patients with hepatic impairment: dapoxetine is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C).
Known CYP2D6 poor metabolizers or patients treated with potent CYP2D6 inhibitors: Caution is advised if increasing the dose to 60 mg in patients known to be of CYP2D6 poor metabolizer genotype or in patients concomitantly treated with potent CYP2D6 inhibitors.
Patients treated with moderate or potent inhibitors of CYP3A4: Concomitant use of potent CYP3A4 inhibitors is contraindicated. The dose is restricted to 30 mg in patients concomitantly treated with moderate CYP3A4 inhibitors and caution is advised.
Contraindications:
Hypersensitivity to the active substance or to any of the excipients. Significant pathological cardiac conditions such as:
• Heart failure (NYHA class II-IV)
• Conduction abnormalities (second- or third-degree AV block or sick sinus syndrome) not treated with a permanent pacemaker
• Significant ischemic heart disease
• Significant valvular disease.
Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after dapoxetine has been discontinued.
Concomitant treatment with thioridazine, or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after dapoxetine has been discontinued.
Concomitant treatment with serotonin reuptake inhibitors [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs)] or other medicinal/herbal products with serotonergic effects [e.g., L-tryptophan, triptans, tramadol, linezolid, lithium, St. John's Wort (Hypericum perforatum)] or within 14 days of discontinuing treatment with these medicinal/herbal products. Similarly, these medicinal/herbal products should not be administered within 7 days after dapoxetine has been discontinued.
Concomitant treatment of potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazadone, nelfinavir, atazanavir, etc.
Moderate and severe hepatic impairment.
Warnings And Precautions:
General: dapoxetine is only indicated in men with PE. Safety has not been established and there are no data on the ejaculation-delaying effects in men without PE.
Use with recreational drugs: Patients should be advised not to use dapoxetine in combination with recreational drugs. Recreational drugs with serotonergic activity such as ketamine, methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD) may lead to potentially serious reactions if combined with dapoxetine. These reactions include, but are not limited to, arrhythmia, hyperthermia, and serotonin syndrome. Use of dapoxetine with recreational drugs with sedative properties such as narcotics andbenzodiazepines may further increase somnolence and dizziness.
Ethanol: Combining alcohol with dapoxetine may increase alcohol-related neurocognitive effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking dapoxetine.
Syncope: The frequency of syncope characterized as loss of consciousness in the dapoxetine clinical development program varied depending on the population studied and ranged from 0.06% (30 mg) to 0.23% (60 mg) for subjects enrolled in the Phase 3 placebo-controlled clinical trials to 0.64% (all doses combined) for Phase 1 non-PE healthy volunteer studies. Possibly prodromal symptoms such as nausea, dizziness/lightheadedness, and diaphoresis were reported more frequently among patients treated with dapoxetine compared to placebo. In patients receiving 30 mg dapoxetine in Phase 3 clinical trials, nausea was reported in 11.0%, dizziness in 5.8% and hyperhidrosis/diaphoresis in 0.8%. In patients receiving 60 mg dapoxetine in Phase 3 clinical trials, nausea was reported in 21.2%, dizziness in 11.7% and hyperhidrosis/diaphoresis in 1.5%. In addition, the occurrence of syncope and possibly prodromal symptoms appears dose dependent as demonstrated by higher incidence among patients treated with higher than recommended doses in Phase 3 clinical trials. Cases of syncope characterized as loss of consciousness observed in the clinical trials were considered vasovagal in etiology and the majority occurred during the first 3 hours after dosing, after the first dose, or associated with study-related procedures in the clinic setting (such as blood draw and orthostatic maneuvers and blood pressure measurements). Possibly prodromal symptoms, such as nausea, dizziness, lightheadedness, palpitations, asthenia, confusion and diaphoresis generally occurred within the first 3 hours following dosing, and often preceded the syncope. Patients need to be made aware that they could experience syncope at any time with or without prodromal symptoms during their treatment with dapoxetine. Prescribers should counsel patients about the importance of maintaining adequate hydration and about how to recognize prodromal signs and symptoms to decrease the likelihood of serious injury associated with falls due to loss of consciousness. If the patient experiences possibly prodromal symptoms, the patient should immediately lie down so his head is lower than the rest of his body or sit down with his head between his knees until the symptoms pass, and be cautioned to avoid situations where injury could result, including driving or operating hazardous machinery, should syncope
or other CNS effects occur. Combining alcohol with dapoxetine may enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking dapoxetine. Subjects with underlying cardiovascular disease were excluded from Phase 3 clinical trials. The risk of adverse cardiovascular outcomes from syncope (cardiac syncope and syncope from other causes) is increased in patients with underlying structural cardiovascular disease (e.g., documented outflow obstruction, valvular heart disease, carotid stenosis and coronary artery disease). There are insufficient data to determine whether this increased risk extends to vasovagal syncope in patients with underlying cardiovascular disease.
Orthostatic hypotension: An orthostatic test should be performed before initiating therapy. In case of a history of documented or suspected orthostatic reaction, treatment with dapoxetine should be avoided. Orthostatic hypotension has been reported in clinical trials. The prescriber should counsel the patient in advance that if he experiences possibly prodromal symptoms, such as lightheadedness soon after standing, he should immediately lie down so his head is lower than the rest of his body or sit down with his head between his knees until the symptoms pass. The prescriber should also inform the patient not to rise quickly after prolonged lying or sitting. In addition, dapoxetine should be prescribed with caution in patients taking medicinal products with vasodilatation properties (such as alpha adrenergic receptor antagonists, nitrates, PDE5 inhibitors) due to possible reduced orthostatic tolerance.
Moderate CYP3A4 inhibitors: Caution is advised in patients taking moderate CYP3A4 inhibitors and the dose is restricted to 30 mg.
Potent CYP2D6 inhibitors: Caution is advised if increasing the dose to 60 mg in patients taking potent CYP2D6 inhibitors or if increasing the dose to 60 mg in patients known to be of CYP2D6 poor metabolizer genotype, as this may increase exposure levels, which may result in a higher incidence and severity of dose dependent adverse events.
Suicide/suicidal thoughts: Antidepressants, including SSRIs, increased the risk compared to placebo of suicidal thinking and suicidality in short-term studies in children and adolescents with Major Depressive Disorder and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24. In clinical trials with dapoxetine for the treatment of premature ejaculation, there was no clear indication of treatment-emergent suicidality.
Mania: dapoxetine should not be used in patients with a history of mania/hypomania or bipolar disorder and
should be discontinued in any patient who develops symptoms of these disorders.
Seizure: Due to the potential of SSRIs to lower the seizure threshold, dapoxetine should be discontinued in
any patient who develops seizures and avoided in patients with unstable epilepsy. Patients with controlled
epilepsy should be carefully monitored.
Use in children and adolescents under age 18: dapoxetine should not be used in individuals below 18 years
ofage.
Co-morbid depression and psychiatric disorders: Men with underlying signs and symptoms of depression should be evaluated prior to treatment with dapoxetine to rule out undiagnosed depressive disorders. Concomitant treatment of dapoxetine with antidepressants, including SSRIs and SNRIs, is contraindicated. Discontinuation of treatment for ongoing depression or anxiety in order to initiate dapoxetine for the treatment of PE is not recommended. Dapoxetine is not indicated for psychiatric disorders and should not be used in men with these disorders, such as schizophrenia, or in those suffering with co-morbid depression, as worsening of symptoms associated with depression cannot be excluded. This could be the result of underlying psychiatric disorder or might be a result of medicinal product therapy. Physicians should encourage patients to report any distressing thoughts or feelings at any time and if signs and symptoms of depression develop during treatment, dapoxetine should be discontinued.
Haemorrhage: There have been reports of bleeding abnormalities with SSRIs. Caution is advised in patients taking dapoxetine, particularly in concomitant use with medicinal products known to affect platelet function (e.g., atypical antipsychotics andphenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs [NSAIDs], anti-platelet agents) or anticoagulants (e.g., warfarin), as well as in patients with a history of bleeding or coagulation disorders.
Renal impairment: dapoxetine is not recommended for use in patients with severe renal impairment and caution is advised in patients with mild or moderate renal impairment.
Withdrawal effects: Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disorders has been reported to result in the following symptoms: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. However, a double-blind clinical trial in subjects with PE designed to assess the withdrawal effects of 62 days of daily or as needed dosing with 60 mg dapoxetine showed no evidence of withdrawal syndrome and little evidence of withdrawal symptoms with only a slightly higher incidence of mild or moderate insomnia and dizziness reported in subjects switched to placebo after daily dosing. Consistent results were seen in a second double-blind clinical trial with a 24-week treatment phase of 30 and 60 mg doses as needed followed by a 1-week withdrawal assessment period.
Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Potential for interaction with monoamine oxidase inhibitors: In patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital
signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Animal data on the effects of combined use of an SSRI and MAOIs suggest that these medicinal products may act synergistically to elevate blood pressure and evoke behavioural excitation. Therefore, dapoxetine should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after dapoxetine has been discontinued.
Potential for interaction with thioridazine: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias. Medicinal products such as dapoxetine that inhibit the CYP2D6 isoenzyme appear to inhibit the metabolism of thioridazine and the resulting elevated levels of thioridazine are expected to augment the prolongation of the QTc interval. Dapoxetine should not be used in combination with thioridazine or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after dapoxetine has been discontinued.
Medicinal/herbal products with serotonergic effects: As with other SSRIs, co-administration with serotonergic medicinal/herbal products (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium and St. John's Wort(Hypericum perforatum) preparations) may lead to an incidence of serotonin associated effects. Dapoxetine should not be used in combination with other SSRIs, MAOIs or other serotonergic medicinal/herbal products or within 14 days of discontinuing treatment with these medicinal/herbal products. Similarly, these medicinal/herbal products should not be administered within 7 days after dapoxetine has been discontinued.
CNS active medicinal products: The use of dapoxetine in combination with CNS active medicinal products has not been systematically evaluated in patients with premature ejaculation. Consequently, caution is advised if the concomitant administration of dapoxetine and such medicinal products is required.
Effects of co-administered medicinal products on the pharmacokinetics of Dapoxetine: In vitro studies in human liver, kidney, and intestinal microsomes indicate dapoxetine is metabolized primarily by CYP2D6, CYP3A4 and flavin monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may reduce dapoxetine clearance.
CYP3A4 inhibitors: Potent CYP3A4 inhibitors - Administration of ketoconazole (200 mg twice daily for 7 days) increased the C-max and AUC(inf) of dapoxetine (60 mg single dose) by 35 % and 99 %, respectively. Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 25 % and the AUC of the active fraction may be doubled if taken with potent CYP3A4 inhibitors. The increases in the Cmax and AUC of the active fraction may be markedly increased in a part of the
population which lack a functional CYP2D6 enzyme, i.e., CYP2D6 poor metabolizers, or in combination with potent inhibitors of CYP2D6.
Therefore, concomitant use of dapoxetine and potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir, is contraindicated.
Moderate CYP3A4 inhibitors: Concomitant treatment with moderate CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also give rise to significantly increased exposure of dapoxetine and desmethyldapoxetine, especially in CYP2D6 poor metabolizers. The maximum dose of dapoxetine should be 30 mg if dapoxetine is combined with any of these drugs.
These two measures apply to all patients unless the patient has been verified to be a CYP2D6 extensive metabolizer by geno- or phenotyping. In patients verified to be CYP2D6 extensive metabolizers, a maximum dose of 30 mg is advised if dapoxetine is combined with a potent C YP3 A4 inhibitor and caution is advised if dapoxetine in 60 mg doses is taken concomitantly with a moderate CYP3A4 inhibitor.
Potent CYP2D6 inhibitors: The Cmax and AUC(inf) of dapoxetine (60 mg single dose) increased by 50% and 88%, respectively, in the presence of fluoxetine (60 mg/day for 7 days). Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 50% and the AUC of the active fraction may be doubled if taken with potent CYP2D6 inhibitors. These increases in the Cmax and AUC of the active fraction are similar to those expected for CYP2D6 poor metabolizers and may result in a higher incidence and severity of dose dependent adverse events.
PDE5 inhibitors: The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were evaluated in a single dose crossover study. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused slight changes in dapoxetine pharmacokinetics (22% increase in AUCinf and 4% increase in Cmax), which are not expected to be clinically significant. However, dapoxetine should be prescribed with caution in patients who use PDE5 inhibitors due to possible reduced orthostatic tolerance.
Tamsulosin: Concomitant administration of single or multiple doses of 30 mg or 60 mg dapoxetine to patients receiving daily doses of tamsulosin did not result in changes in the pharmacokinetics of tamsulosin. The addition of dapoxetine to tamsulosin did not result in a change in the orthostatic profile and there were no differences in orthostatic effects between tamsulosin combined with either 30 or 60 mg dapoxetine and tamsulosin alone; however, dapoxetine should be prescribed with caution in patients who use alpha adrenergic receptor antagonists due to possible reduced orthostatic tolerance.
Medicinal products metabolized by CYP2D6: Multiple doses of dapoxetine (60 mg/day for 6 days) followed by a single 50 mg dose of desipramine increased the mean Cmax and AUCinf of desipramine by approximately 11 % and 19%, respectively, compared to desipramine administered alone. Dapoxetine may give rise to a similar increase in the plasma concentrations of other drugs metabolized by CYP2D6. The clinical relevance is likely to be small.
Medicinal products metabolized by CYP3A4: Multiple dosing of dapoxetine (60 mg/day for 6 days) decreased the AUCinf of midazolam (8 mg single dose) by approximately 20 % (range -60 to +18 %). The clinical relevance of the effect on midazolam is likely to be small in most patients. The increase in CYP3A activity may be of clinical relevance in some individuals concomitantly treated with a medicinal product mainly metabolized by CYP3A and with a narrow therapeutic window.
Medicinal products metabolized by CYP2C19: Multiple dosing of dapoxetine (60 mg/day for 6 days) did not inhibit the metabolism of a single 40 mg dose of omeprazole. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.
Medicinal products metabolized by CYP2C9: Multiple dosing of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of a single 5 mg dose of glyburide. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.
Warfarin: There are no data evaluating the effect of chronic use of warfarin with dapoxetine; therefore, caution is advised when dapoxetine is used in patients taking warfarin chronically. In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics (PT or INR) of warfarin following a single 25 mg dose.
Ethanol: Coadministration of a single dose of ethanol, 0.5 g/kg (approximately 2 drinks), did not affect the pharmacokinetics of dapoxetine (60 mg single dose); however, dapoxetine in combination with ethanol increased somnolence and significantly decreased self-rated alertness. Pharmacodynamic measures of cognitive impairment (Digit Vigilance Speed, Digit Symbol Substitution Test) also showed an additive effect when dapoxetine was coadministered with ethanol. Concomitant use of alcohol and dapoxetine increases the chance or severity of adverse reactions such as dizziness, drowsiness, slow reflexes, or altered judgment. Combining alcohol with dapoxetine may increase these alcohol-related effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking dapoxetine.
Pregnancy and lactation:
Dapoxetine is not indicated for use by women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development. It is not known if either dapoxetine or
its metabolites are excreted in human breast milk.
Effects on ability to drive and use machines:
Dapoxetine has minor or moderate influence on the ability to drive and use machines. Dizziness, disturbance in attention, syncope, blurred vision and somnolence have been reported in subjects receiving dapoxetine in clinical trials. Therefore, patients should be warned to avoid situations where injury could result, including driving or operating hazardous machinery.
Combining alcohol with dapoxetine may increase alcohol-related neurocognitive effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking dapoxetine.
Adverse effects:
The safety of dapoxetine was evaluated in 4224 subjects with premature ejaculation who participated in five double-blind, placebo-controlled clinical trials. Of the 4224 subjects, 1616 received dapoxetineSO mg as needed and 2608 received 60 mg, either as needed or once daily.
Syncope characterized as loss of consciousness has been reported in clinical trials and is considered medicinal product-related. The majority of cases occurred during the first 3 hours after dosing, after the first dose or associated with study-related procedures in the clinic setting (such as blood draw and orthostatic maneuvers and blood pressure measurements). Prodromal symptoms often preceded the syncope.
Orthostatic hypotension has been reported in clinical trials.
The most common adverse drug reactions reported during clinical trials were headache, dizziness, nausea, diarrhoea, insomnia and fatigue. The most common adverse events leading to discontinuation were nausea (2.2% of dapoxetine-treated subjects) and dizziness (1.2% of dapoxetine-treated subjects).
Overdose:
No case of overdose has been reported. There were no unexpected adverse events in a clinical pharmacology study of dapoxetine with daily doses up to 240 mg (two 120 mg doses given 3 hours apart). In general, symptoms of overdose with SSRIs include serotonin-mediated adverse reactions such as somnolence, gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremor, agitation and dizziness. In cases of overdose, standard supportive measures should be adopted as required. Due to high protein binding and large volume of distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for dapoxetine are known.
Presentation:
Blister strip of 6 tablets
Storage:
Store in a cool, dry place