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Fortacin™ Spray for the Treatment of Premature Ejaculation

Authors:
  • Private Institute for Urology, Andrology and Sexual Medicine , Hamburg, Germany

Abstract and Figures

Premature ejaculation (PE) is a common complaint of male sexual dysfunction affecting men and their partners and consequently causing significant personal and interpersonal distress. Increased sensitivity of the glans penis and abnormalities of the afferent-efferent reflex pathway within the ejaculatory process are involved in the occurrence of PE. Drugs that either selectively reduce penile sensitization or modify the afferent-efferent reflex are well established therapeutic options for PE. Fortacin™ is the first topical treatment to be officially approved for the treatment of primary PE in adult men, and is mentioned as an experimental aerosol (as TEMPE) in the current European Association of Urology guidelines. It was approved for use in the European Union and launched in the United Kingdom in November 2016. Fortacin™ is a eutectic-like mixture of lidocaine 150 mg/mL and prilocaine 50 mg/mL that meets the requirements of an ideal treatment for PE because it is fast acting (within 5 minutes), has durable effects, can be easily used “on-demand”, and shows minimal side-effects. The metered-dose spray delivery system allows the desensitizing agents to be deposited in a dose-controlled, concentrated film onto the glans penis consequently reducing its sensitivity. This is translated into a delaying of the ejaculatory latency time without adversely affecting the sensation of ejaculation and orgasmic pleasure. The efficacy and safety of Fortacin™ have been proven by means of increased ejaculatory latency, control, and sexual satisfaction in large scale studies demonstrating the significant benefits for both patients and their partners.
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ISSN 0391-5603
Urologia 2017; 84 (Suppl 2): S1-S10
UJ
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REVIEW
most include the three main accepted dimensions of this
condion: short IELT, inability to control ejaculaon, and both
personal and interpersonal distress.
In 2014, the Internaonal Society for Sexual Medicine
(ISSM) introduced a new denion of lifelong and acquired
PE, represenng the rst evidence-based, in contrast to pure-
ly expert-based, denion (4). According to this denion, PE
(lifelong or acquired) is a male sexual dysfuncon character-
ized by: (1) ejaculaon that always or nearly always occurs
prior to or within about 1 minute of vaginal penetraon start-
ing at me of the rst sexual experience (lifelong PE) or a clin-
ically signicant and bothersome reducon in IELT, oen to
about 3 minutes or less (acquired PE); (2) the inability to delay
ejaculaon during all or nearly all vaginal penetraons; and,
(3) negave personal consequences, such as distress, bother,
frustraon, and/or the avoidance of sexual inmacy (4, 5).
Epidemiology of PE and quality of life
PE is more than just a short me to ejaculaon and the
determinants of PE are complex and mulfactorial (6). IELT,
control over ejaculaon, and the sexual sasfacon of the
man and his partner have been idened as important inter-
related determinants of PE (7). By causing signicant personal
and interpersonal distress for both the paent and partner, a
vicious cycle can develop where the emoonal reacons to
DOI: 10.5301/uj.5000275
Fortacin™ spray for the treatment of premature
ejaculaon
Hartmut Porst, Andrea Burri
Private Instute for Urology, Andrology and Sexual Medicine, Hamburg - Germany
Introducon
Premature ejaculaon (PE) is a frequent complaint of
male sexual dysfuncon and a major source of sexual distress
(1). Increased sensivity of the glans penis and abnormali-
es of the aerent-eerent reex pathway within the ejacula-
tory process are implicated in the occurrence of PE and may
contribute to penile hypersensivity and PE (2). Therefore, a
reducon in penile sensivity is ancipated to prolong intra-
vaginal ejaculaon latency me (IELT) without aecng the
sensaon of ejaculaon and orgasmic feelings (3).
There are several denions of PE and how to accurately
capture the phenomenon remains a major debate. Although
there is lile consensus amongst dierent organizaons and
sociees regarding the denion and classicaon of PE,
ABSTRACT
Premature ejaculaon (PE) is a common complaint of male sexual dysfuncon aecng men and their partners
and consequently causing signicant personal and interpersonal distress. Increased sensivity of the glans penis
and abnormalies of the aerent-eerent reex pathway within the ejaculatory process are involved in the oc-
currence of PE. Drugs that either selecvely reduce penile sensizaon or modify the aerent-eerent reex are
well established therapeuc opons for PE. Fortacin™ is the rst topical treatment to be ocially approved for
the treatment of primary PE in adult men, and is menoned as an experimental aerosol (as TEMPE) in the current
European Associaon of Urology guidelines. It was approved for use in the European Union and launched in the
United Kingdom in November 2016. Fortacin™ is a eutecc-like mixture of lidocaine 150 mg/mL and prilocaine
50 mg/mL that meets the requirements of an ideal treatment for PE because it is fast acng (within 5 minutes),
has durable eects, can be easily used “on-demand”, and shows minimal side-eects. The metered-dose spray
delivery system allows the desensizing agents to be deposited in a dose-controlled, concentrated lm onto the
glans penis consequently reducing its sensivity. This is translated into a delaying of the ejaculatory latency me
without adversely aecng the sensaon of ejaculaon and orgasmic pleasure. The ecacy and safety of Forta-
cin™ have been proven by means of increased ejaculatory latency, control, and sexual sasfacon in large scale
studies demonstrang the signicant benets for both paents and their partners.
Keywords: Fortacin™, Intravaginal ejaculatory latency me, Lidocaine/Prilocaine, Premature ejaculaon, Topical
anesthesia
Accepted: November 24, 2017
Published online: December 18, 2017
Corresponding author:
Hartmut Porst
Private Instute for Urology
Andrology and Sexual Medicine
Neuer Jungfernseg 6a
20354 Hamburg, Germany
Porst20354@aol.com
Fortacin™ for premature ejaculaon
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© 2017 The Authors. Published by Wichg Publishing
PE by both pares can exacerbate or perpetuate the problem
(6). Indeed, men with PE report having more interpersonal
dicules and higher levels of personal distress than men
without PE, and partners of men with PE report having higher
levels of relaonship problems compared with partners of
men without PE (5). Importantly, men with PE feel they are
“leng their partner down” and that the quality of their rela-
onship would improve without PE (8).
Apart from interpersonal fricon and distress, PE is also
associated with signicant sexual and psychological comor-
bidies. The Premature Ejaculaon Prevalence and Atudes
(PEPA) survey (9), a comprehensive Internet-based survey
conducted on 12,133 men aged 18-70 years in the United
States, Germany, and Italy, for example, found that the per-
centage of men self-reporng comorbid condions including
sexual dysfuncons (e.g., anorgasmia, low libido, erecle dys-
funcon) and psychological disturbances (e.g., depression,
anxiety, excessive stress), was signicantly higher in men with
PE (22.7% of the total sample) than in men without PE (all
p<0.05) (9). In the survey, men were classied as having PE
based on self-reporng of low or absent control over ejacu-
laon, resulng in distress for them, their sexual partner, or
both, with similar prevalence rates among the parcipang
countries (United States 24%, Germany 20.3 %, Italy 20%).
Despite the fact that PE can have serious eects on the
psychological well-being and overall quality of life of the suf-
ferer and his partner, only a minority of men seek profes-
sional help. The PEPA survey, for example, showed that only
9% of men with self-reported PE had consulted a doctor (9).
Embarrassment and a belief that there is no eecve treat-
ment available are the main reasons for not discussing PE
with their physician (10).
Neurophysiology of ejaculaon
The male sexual-response cycle consists of four phases:
desire, arousal (erecon), orgasm (ejaculaon), and resoluon
(Fig. 1) (11). The process of ejaculaon is classied by two dis-
nct phases, “emission” and “expulsion”. Sympathec, para-
sympathec, and somac nervous systems are involved in the
Fig. 1 - Nor ma l male sexu al response
compared with premature ejacu-
laon. Figure adapted from Kirby
2014 (11).
ejaculatory response and are coordinated by the spinal ejacula-
tory generator (SEG) (12, 13). Sensory aerents received by the
SEG are coordinated with inhibitory and excitatory inuences
from supra-spinal sites, as well as biochemical or mechanical
informaon from the accessory sex organs (14). The ejaculato-
ry process starts with the emission of semen into the posterior
urethra, induced by increased acvity of the sympathec ef-
ferent bers causing sequenal contracons of the epididymis,
vas deferens, seminal vesicles, and prostate, alongside the clo-
sure of the bladder neck (15). Emission of the semen with dila-
on of the posterior urethra results in the forceful expulsion of
semen out of the urethral orice induced by acvaon of the
somac pudendal nerve with subsequent contracons of the
bulbospongiosus, bulbocavernosus, and perineal muscles (16).
The rhythmical expulsion is mainly inuenced by the somac
nervous system and represents an involuntary spinal cord re-
ex (13). Various neurotransmiers also play a major role in
the control of ejaculaon, such as the excitatory role of dopa-
mine and the inhibitory role of serotonin or nitric oxide (13).
Although numerous preclinical and clinical studies in re-
cent years have been able to provide a beer understand-
ing of the ejaculatory process, many details remain unknown
regarding the exact physiology of the ejaculatory process. At
present, it is commonly accepted that PE is the result of a
dysregulaon of the normal ejaculatory process with either
over-acvaon of ejaculaon smulatory or inhibion of
ejaculaon delaying 5-HT (serotonin) receptors, leading to
an involuntary lack of control over ejaculaon (17). Clearly,
a more in-depth understanding of the normal physiological
ejaculatory reex (Fig. 2) is essenal in order to determine
the exact underlying pathophysiology of PE.
Raonale for the use of topical anesthecs
The use of drugs that selecvely reduce penile sensiza-
on or which modify the aerent-eerent reex could pro-
vide eecve therapy for PE, as has been shown with the
o-label use of topical desensizing creams (2). Due to the
variable nature of sexual intercourse, spontaneity is an im-
portant factor in the treatment of PE. The ideal treatment
Porst and Burri S3
© 2017 The Authors. Published by Wichg Publishing
for PE should therefore be characterized, among others, by a
rapid on-set of acon, which is eecve for “on-demand” use
from the rst dose, and which is reversible (18). An ideal PE
medicaon should also demonstrate high ecacy on IELT re-
ected in paent-reported outcomes and, in addion, should
show a good safety prole with minimal side-eects and no
undesirable eects on the sexual partner.
The use of topical anesthecs to reduce sensivity of the
glans penis has been shown to improve ejaculatory latency
without having any adverse eects on the sensaon of ejacu-
laon and impairment of orgasmic capacity (19, 20). Unlike the
majority of systemic treatments for PE, topical treatments can
be used “on-demand” and are unlikely to have systemic side-
eects (20). There are, however, a number of disadvantages to
some topical treatments including dicult dosing with the po-
tenal of either over- or under-dosing causing either erecle
dicules or lack of ecacy, which may interfere with sponta-
neity (20). Some topical treatments may also need to be used
with a condom or washed o prior to intercourse, and again
may potenally interfere with spontaneity and arousal.
The paucity of approved pharmacological treatments for
PE, has led to an increased “o-label” use of oral andepres-
sants and local anesthecs.
Clearly, an approved treatment that can be used “on-
demand” and which is eecve from rst use with minimal
systemic side-eects is essenal (2, 21).
Exisng treatments for PE
Of the oral and locally acng topical therapies currently
used to manage PE in Europe, only Fortacin™ and dapoxene
have been ocially approved for the treatment of PE.
Oral therapies
Dapoxene, a short-acng selecve serotonin reuptake
inhibitor (SSRI), was the rst oral pharmacological agent de-
veloped for the treatment of PE and ocially approved for
“on-demand” use in adult men aged 18 to 64 years (22). Its
mechanism of acon in the treatment of PE is presumed to
be linked to the inhibion of neuronal reuptake of serotonin
and the subsequent potenaon of the neurotransmier’s
acon at pre- and post-synapc receptors (23). The recom-
mended starng dose for all paents is 30 mg, taken approxi-
mately 1 to 3 hours prior to sexual acvity, with no more than
one dose taken every 24 hours (23).
Dapoxene was shown to signicantly improve all as-
pects of PE, including prolonging stopwatch-measured IELT
(as primary outcome) and increasing paent-reported out-
come measures (i.e. the Premature Ejaculaon Prole [PEP]
quesonnaire and the clinical global impression of change
[CGIC] as secondary outcomes), in four randomized, double-
blind, placebo-controlled, mulcenter, phase III studies of
12-24 weeks’ duraon in men with PE (n = 4,843) (24-26).
A pooled analysis of these studies showed that oral dapox-
ene 30 mg or 60 mg (taken as needed) induced signicantly
greater improvements from baseline in the geometric mean
IELT at all me points measured, compared with placebo (27).
At week 12, the geometric mean IELT increased from a base-
line of approximately 0.8 minutes to 2.0 and 2.3 minutes with
dapoxene 30 mg and 60 mg, respecvely, compared with
1.3 minutes for placebo (both p<0.001), corresponding to a
2.5-fold and 3.0-fold increase in the geometric mean IELT re-
specvely (vs. a 1.6-fold increase for placebo; p<0.0001 for
both) (27). Signicant improvements in PEP items and CGIC
Fig. 2 - The physiological ejacula-
tory reex. Ejaculaon results from
coordinated contracle acvity
organized by the spinal ejaculatory
generator (SEG). Sensory aerent
informaon is received by the SEG
which, alongside supra-spinal infor-
maon arising from specic brain
regions, triggers the ejaculatory
mechanism during sexual acvity.
Topical anesthecs applied to the
glans penis inhibit penile sensory re-
ceptors. Figure adapted from Saitz
and Serefoglu 2015 (12).
Fortacin™ for premature ejaculaon
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© 2017 The Authors. Published by Wichg Publishing
were also shown with both doses of dapoxene (all p<0.001
vs. placebo) (27).
Despite its ecacy in the treatment of PE, dapoxene
has also been associated with dose-related systemic adverse
eects (AEs), with nausea, dizziness, headache, diarrhea,
insomnia, and fague as the most frequently reported drug-
related adverse events in ve randomized, double-blind, pla-
cebo-controlled, mulcenter, phase III studies in men with PE
(n = 6,081) (24-26, 28). Indeed, an integrated analysis of these
studies showed that AEs were reported in 47.0% and 60.3% of
paents receiving 30 mg and 60 mg dapoxene, respecvely,
with AE-related disconnuaon occurring in 3.5% and 8.8%
of these paents (27). In addion, the Summary of Product
Characteriscs states that orthostac vital signs (blood pres-
sure and heart rate) must be measured prior to starng
dapoxene, which should not be used in paents using PDE5
inhibitors due to possible reduced orthostac tolerance (23).
High disconnuaon rates of this drug have also been
reported in the seng of real clinical pracce. In a study
by Mondaini et al. (n = 120), 20% of paents decided not
to start dapoxene with fear of using a “drug” being the
most frequently reported reason (29). Moreover, of the 80%
who started therapy, 26% stopped taking dapoxene aer
1 month due to side eects and lack of ecacy. Only 10.4% of
paents connued the treatment for over one year. The main
reasons for disconnuing the treatment were: eect below
expectaon, costs, side eects, loss of interest in sex, and lack
of ecacy.
The o-label use of other SSRIs (including paroxene, ser-
traline, and citalopram) in the treatment of PE is based on
the side-eect of delayed ejaculaon that was observed in
depressed paents with normal sexual funcon who were
treated with SSRIs for their depression. This increase in IELT
is most likely the consequence of increased concentraons
of serotonin in the synapc cle, causing an inhibion in the
ejaculatory reex and therefore a delay or even absence of
ejaculaon (2). Although doses of prescribed SSRIs tend to be
generally lower for PE than for depression, the AEs are simi-
lar and there is also the potenal for serious drug interacon
that may result in rare cases of the so-called serotonin syn-
drome and suicidal ideaon (30).
Locally acng topical therapies
Topical therapies that can be applied directly to the glans
penis in order to produce some degree of penile desensiza-
on are directed to the hypersensivity aspect of PE. These
topical treatments can be used “on-demand” with minimal
systemic eects but may interfere with sexual spontaneity
and have dosing dicules with the potenal of either over-
or under-dosing, which may either cause penile hypoesthe-
sia with subsequent erecle dysfuncon and/or transvaginal
transmission resulng in vaginal numbness and anorgasmia
or lack of ecacy, respecvely (20). Their ease of applicaon
and tolerability is further limited by the presence of a number
of excipients in the formulaon of the majority of creams and
topical products causing dicules in applying the correct
measured dose.
Creams/ointments that have been frequently used in
clinical pracce, but that have not been specically approved
for the management of PE, include a local anesthec cream
containing lidocaine and prilocaine (2.5% each) that was de-
veloped for the topical anesthesia of intact skin. Although
studies have shown some ecacy of lidocaine/prilocaine
cream 5% in prevenng PE (31, 32), it is slow-acng and cum-
bersome to use, with genital hypoesthesia reported in both
sexual partners (20). In addion, dicules in applying the
cream have been reported along with a decrease in penile
and vaginal sensivity, penile hypoesthesia and loss of erec-
on, and penile irritaon (31, 32). Local anesthec creams
may also contain a mixture of base and ionized forms of local
anesthecs where only the uncharged base forms are able to
penetrate skin or mucous membranes (33).
Fortacin™ (Lidocaine/Prilocaine, Recorda) is the rst of-
cially approved topical therapy for PE. It is indicated for the
treatment of primary PE in adult men and was approved for
use in the European Union in 2013 and launched in the United
Kingdom in November 2016 (34, 35). During its clinical devel-
opment, Fortacin™ was referred to by two separate names,
Topical Eutecc Mixture for Premature Ejaculaon (TEMPE)
and PSD502, with both names having been used in the pub-
lished literature. Notably, Fortacin™ (denoted as TEMPE) is
menoned as an experimental aerosol in current European
Associaon of Urology Guidelines (10).
Overview of Fortacin™
Fortacin™ is a metered-dose aerosol spray that delivers
topical anesthesia to the glans penis. It contains purely base
(uncharged) forms of the local anesthecs lidocaine 150 mg/
mL and prilocaine 50 mg/mL, with no excipients except the
spray propellant (norurane) (34). This oers a potenal ad-
vantage over other exisng topical anesthecs in terms of a
reduced risk of allergic reacon due to excipients. Although
lidocaine and prilocaine are crystalline solids at room tem-
perature, they form a eutecc mixture when mixed together,
resulng in an oily liquid that remains in liquid form at tem-
peratures that are lower than their individual melng points
(33). Deployment of the metered-dose chamber causes the
instant vaporizaon of the propellant forcing the lidocaine
and prilocaine out of the soluon and into a eutecc-like mix-
ture. This forms a slightly oily substance that enhances ad-
herence to the penile surface by creang a thin layer of local
anesthec molecules on the glans mucosa. Consequently, the
absorpon of the acve components in their free-base form
through the non- or poorly-keranized ssue of the glans pe-
nis can be opmized (33, 36), the extent of neural blockage
maximized, and the onset of numbness minimized.
Furthermore, in contrast to the applicaon of creams, the
metered-dose spray delivery system allows the desensizing
agents to be deposited in a dose-controlled, concentrated
lm onto the glans penis (33). Due to its formulaon, the
uncharged base forms of lidocaine and prilocaine are read-
ily absorbed through the glans penis mucous membrane, but
not through normal keranized skin (i.e. the sha of the pe-
nis); this minimizes absorpon through normal skin so that
a full sensaon can be maintained in the sha of the penis
(33, 36). Furthermore, by reducing the permeability of the
neuronal membranes to sodium ions, Fortacin™ produces
localized reversible inhibion of nerve conducon (33). The
Porst and Burri S5
© 2017 The Authors. Published by Wichg Publishing
acve substances, lidocaine and prilocaine, block transmis-
sion of nerve impulses in the glans penis, reducing its sensi-
vity, which is then translated into a delaying of the ejacula-
tory latency me without adversely aecng the sensaon
of ejaculaon and orgasm (34).
Ecacy of Fortacin™
The clinical ecacy of Fortacin™ in the treatment of pri-
mary PE in adult men has been evaluated in ve studies: one
proof-of-concept phase II study (3); one supporve phase II
study (37); two pivotal phase III studies (38, 39); and, com-
bined data from the two pivotal phase III studies, including
the open-label extension of 5 and 9 months (2, 40).
Posive outcomes in terms of increased IELT, sexual sat-
isfacon, and minimal local AEs were inially shown from
the proof-of-concept and supporve phase II studies. In the
prospecve, open-label, proof-of-concept study, a signicant
increase in IELT (p = 0.008 versus baseline), improved sexual
sasfacon, and minimal local AEs were demonstrated in
11 men with self-reported PE who applied Fortacin™ to the
glans penis 15 minutes prior to intercourse (3). Similarly, the
supporve phase II study (37) conducted on 54 men with
PE (according to DSM-IV criteria) also showed posive out-
comes with an increased IELT, beer ejaculatory control, and
improved sexual quality of life compared with the placebo
group (41).
Primary evidence for the ecacy of Fortacin™ in the treat-
ment of paents with PE was derived from two pivotal phase
III, mulcenter, randomized, double-blind, placebo-controlled
studies, with open-label follow-up in paents with lifelong
PE and their sexual partners (38, 39). In both studies, the
3-month treatment phase with 30 mg Fortacin™ was followed
by a 9-month open-label treatment phase in the rst study
(39) and a 5-month open-label treatment phase in the second
study (38). Inclusion criteria for both studies were heterosex-
ual men aged ≥18 years in stable, monogamous relaonships
with lifelong PE diagnosed according to both the DSM-IV cri-
teria (41) and the ISSM denion (42), and a baseline IELT of
≤1 minute for at least two of the rst three sexual encounters
during the 4-week screening period. Men taking tricyclic an-
depressants, monoamine oxidase inhibitors or short- acng
SSRIs, in which the dose had changed within the 4-week
screening period or was expected to change, were excluded
from the trials, as were those with erecle dysfuncon.
Fortacin™ (or matched placebo) was applied to the glans
penis (aer retracng any foreskin) approximately 5 minutes
before intercourse with excess spray wiped o prior to pen-
etraon. Paents recorded stop-watch measured IELT during
each sexual encounter and completed the Index of Prema-
ture Ejaculaon (IPE) and PEP quesonnaires at study entry
and monthly visits.
The 10-item IPE quesonnaire assesses subjecve as-
pects of PE, covering three domains: ejaculatory control (four
quesons), sexual sasfacon (four quesons), and distress
(two quesons) (43). Each queson is answered on a 6-point
Likert-type scale with nal scores for control/sasfacon
and distress ranging from 4-20 points and 2-10 points, re-
specvely (38). The PEP quesonnaire consists of four ques-
ons relang to perceived control over ejaculaon, personal
distress related to ejaculaon, sasfacon with sexual inter-
course, and interpersonal diculty related to ejaculaon.
Each queson is answered on a 5-point Likert-type scale (44).
Primary ecacy outcome variables for the pivotal studies
included the change from baseline to study end in mean IELT
and in the IPE quesonnaire domains of ejaculatory control,
sexual sasfacon, and distress (distress was a primary e-
cacy variable for the second study only). Secondary ecacy
outcome variables included the proporon of paents with a
mean IELT of >1 minute and >2 minutes during the 3-month
double-blind treatment period, the change in the IPE domain
of distress from baseline to month 3 (rst study only), and
the PEP quesonnaire at months 1, 2, and 3. As drug-induced
ejaculatory performance has been shown to disclose a posi-
vely skewed IELT distribuon, the geometric mean IELT and
the fold increase of the geometric mean IELT were used in
order to avoid overesmaon of treatment ecacy (45).
The rst pivotal phase III study (n = 290; 191 paents
treated with Fortacin™ and 99 with placebo) produced sig-
nicant, clinically meaningful improvements in ejaculatory
latency, control, and sexual sasfacon with acve treatment
(39). The geometric mean IELT increased from a baseline
of 0.6 minutes in both treatment groups to 3.8 minutes in
the Fortacin™ group vs. 1.1 minutes in the placebo group at
study end aer 3 months (Fig. 3). Aer adjusng for treat-
ment-group imbalances, these numbers eecvely represent
a 6.3-fold and 1.7-fold increase in adjusted geometric mean
IELT, demonstrang a signicant between-treatment dier-
ence in favor of the acve treatment (p<0.001), which was
also ecacious in restoring control with signicantly greater
increases from baseline to month 3 for the IPE domain scores
of ejaculatory control, sexual sasfacon, and distress (7.0,
5.9, and 2.8 point dierence between acve treatment and
placebo, respecvely; all p<0.001) (Fig. 4).
Fortacin™ was well received with 65.9% (of 182) paents
rang the medicaon as “good” or “excellent”, as opposed to
14.6% (of 96) paents in the placebo group. In addion, the
topical spray improved sexual sasfacon for both paents
and their partners at the end of the 3-month double-blind
phase, with signicantly more paents and partners report-
ing improvements of at least one point in each of the PEP
domains compared with those using placebo (p<0.001 for all
between-treatment comparisons) (Fig. 5).
The advantageous eects of Fortacin™ were replicated
and reinforced by the ndings from the second pivotal phase
III study (n = 249; 167 paents with acve treatment and 82
with placebo) (38). In this study, greater improvements in the
geometric mean IELT from baseline to month 3 were observed
for the acve treatment group compared with placebo (0.56
to 2.6 minutes vs. 0.53 to 0.8 minutes, respecvely), with a
signicant between-treatment dierence in the adjusted
geometric mean IELT in favor of the acve treatment (4.7 vs.
1.5 for placebo; p<0.0001) (Fig. 3). Scores for the IPE domains
of ejaculatory control, sexual sasfacon, and distress in the
acve treatment group were also signicantly higher than in
the placebo group (all p<0.001) (Fig. 4) (38). Similarly, signi-
cantly more paents and partners reported improvements of
at least one point for all four domains of the PEP queson-
naire at 3 months with use of the topical spray (all p<0.0001
vs. the placebo group) (Fig. 5).
Fortacin™ for premature ejaculaon
S6
© 2017 The Authors. Published by Wichg Publishing
A higher proporon of paents treated with Fortacin™ had
a mean IELT of >1 minute, >2 minutes, >3 minutes or >4 min-
utes compared with placebo based on combined data of the
intent-to-treat populaon during the 3-month double-blind
treatment period from both pivotal studies (Fig. 6) (40). Most
paents (85.2%) in the acve treatment group achieved a mean
IELT of >1 minute versus only 46.4% in the placebo group.
Parcipants in both pivotal studies had the opon to enter
the open-label treatment phase in which all paents received
Fortacin™. In total, 497 paents (98.4% of those compleng
the double-blind phase) entered the open-label extension; of
these, 326 subjects had received acve treatment and 171
had received placebo in the double-blind phase (40).
Fortacin™ was shown to be as eecve for the treatment
of PE at the end of the open-label phase as it was at the end of
the double-blind treatment phase, with no evidence of tachy-
phylaxis despite repeated use. The posive changes in the geo-
metric mean IELT observed during the double-blind phase were
maintained and augmented during the open-label phase, with
a marked improvement in geometric mean IELT in paents who
converted from placebo to acve treatment (Fig. 7) (2). The ef-
fecveness of the topical spray increased with repeated use over
me (Fig. 8), and improvements could be observed for all IPE
domain scores (mean change from baseline for ejaculatory con-
trol, sexual sasfacon, and distress scores were 12.3, 10.9, and
5.3 points, respecvely, at the end of the open-label phase) (40).
Fig. 3 - Geometric mean intravagi-
nal ejaculaon latency me (IELT)
at baseline and at the end of the
3-month treatment period in pa-
ents treated with For tacin™ or
placebo. *p<0.001 versus baseline.
Figure adapted from Dinsmore and
Wyllie 2009 (39) and Carson and
Wyllie 2010 (38).
Fig. 4 - Change from baseline to
month 3 in the adjusted mean Index
of Premature Ejaculaon (IPE) do-
main scores for ejaculatory control,
sexual sasfac on, and distress in
paents treated with Fortacin™ or
placebo. *p<0.001 versus placebo.
Figure adapted from Dinsmore and
Wyllie 2009 (39) and Carson and
Wyllie 2010 (38).
Porst and Burri S7
© 2017 The Authors. Published by Wichg Publishing
Tolerability of Fortacin™
In all studies, Fortacin™ has shown a good safety prole
with only a low incidence of mild-to-moderate local AEs ac-
cording to a combined evaluaon of 596 male paents and
584 female partners who parcipated in the clinical trials
(40). In general, most treatment-related AEs occurred imme-
diately or within 24 hours and most were mild or moderate
in intensity (40). The incidence of treatment-related AEs was
low in both paents (9.6%) and their female partners (6.0%)
(40). The most frequent adverse reacons reported in male
paents were local eects of genital hypoesthesia (4.5%) and
erecle dysfuncon (4.4%), with disconnuaon of treatment
in 0.2% and 0.5% of paents, respecvely. The most frequent
adverse reacons reported in female partners were vulvo-
vaginal burning sensaon (3.9%), and genital hypoesthesia
Fig. 5 - Percentage of paents (A)
and female sexual partners (B) re-
porng an improvement of at least
one point in Premature Ejacula-
on Prole (PEP) domains aer
3 months’ treatment with Forta-
cin™ or placebo. *p<0.001 for all
between-treatment comparisons.
**p<0.0001 for all between-treat-
ment comparisons. Figure adapted
from Dinsmore and Wyllie 2009 (39)
and Carson and Wyllie 2010 (38).
Fortacin™ for premature ejaculaon
S8
© 2017 The Authors. Published by Wichg Publishing
(1.0%). Vulvovaginal discomfort or burning sensaon caused
disconnuaon of treatment in 0.3% of subjects. In addion
to moderate-to-low AEs, there was lile or no desensizaon
of the genitalia neither in the paent nor in their partner with
the topical spray, which did not detract from sexual sasfac-
on as evidenced by the increase in IPE and PEP scores aer
3-months’ treatment compared with baseline. It is also note-
worthy that the topical spray was unlikely to be associated
with systemic AEs (46).
Posioning Fortacin™ in the treatment of PE
Due to the easy applicaon of Fortacin™ and short me to
ecacy (i.e. within 5 minutes) this new treatment is unlikely to
interfere with spontaneity of sexual acvies. Aer retracon
of the foreskin, the topical spray is applied to the glans penis
5 minutes before intercourse using three successive actua-
ons of the aerosol to deliver the approved dose and ensure
complete coverage, with any excess spray easily removed pri-
or to sexual intercourse minimizing transmission to the sexual
partner (27, 28). A maximum of 3 doses can be used within
24 hours, with a minimum interval of 4 hours between doses.
Based on results from clinical trials, which have shown sig-
nicant benets for both paents and their female partners in
ejaculatory latency, control, and sexual sasfacon, Fortacin™
should be recommended as a rst-line topical treatment of PE.
It is also noteworthy that the pivotal phase III studies demon-
strated increased eecveness of the topical spray over me,
Fig. 6 - Proporon of paents with
mean intravaginal ejaculaon laten-
cy me (IELT) >1 minute, >2 minutes,
>3 minutes, or >4 minutes during
the 3 month double-blind treatment
with Fortacin™ or placebo [com-
bined data of the intent-to-treat
populaon from both pivotal phase
III studies (38, 39)]. Figure adapt-
ed from the 2013 Commiee for
Medicinal Products for Human Use
assessment report on Lidocaine/Pri-
locaine (40).
Fig. 7 - Change in the geometric
mean intravaginal ejaculaon la-
tency me (IELT) over 12 months in
paents treated with Fortacin™ or
placebo [combined data from the
double-blind and open-label phases
of both pivotal phase III studies (38,
39)]. Figure adapted from Wyllie and
Powell 2012 (2).
Porst and Burri S9
© 2017 The Authors. Published by Wichg Publishing
which was most likely due to improved sexual condence (2).
By prolonging IELT with repeated use of the topical spray, pre-
sumably via acvity on neuro-biogenic factors, a paent’s psy-
chological mindset may be posively inuenced, which may
improve his condence and ability to control ejaculaon with
further improvement in the signs and symptoms of PE (2).
PE involves a complex sensory pathway controlled by the
SEG, which can be targeted for the treatment of PE at two
main sites: in the CNS, where SSRIs increase serotonin levels,
leading to a delay in the transmission of ejaculaon process-
ing neural smuli, and at the level of penile sensory receptors,
where topical anesthecs can reduce penile sensivity and af-
ferent sensory neural smuli. Hence, Fortacin™ could be con-
sidered not only as an alternave therapy to SSRIs but also,
because of their dierent site of acon, as an adjuncve ther-
apy to oral SSRIs in severe PE paents. It is also apparent that
paents with PE are somemes not sased when treated
regularly with SSRIs and therefore the addion of Fortacin™
to a paents’ regular SSRI regimen may be advantageous.
Conclusions
PE can have detrimental eects on the quality of life of the
paent and his partner with a negave impact on emoons,
habits, and behavior, ulmately aecng the relaonship and
even leading to relaonship break-ups. It is obvious that ad-
equate and ecient medical help is needed to address this
debilitang condion. Fortacin™ is the rst ocially approved
topical prescripon therapy for the treatment of primary PE in
adult men. Its formulaon opmizes fast penetraon through
the glans surface while the metered-dose spray delivery sys-
tem allows the desensizing agents, lidocaine and prilocaine,
to be deposited in a dose-controlled, concentrated lm onto
the glans penis. This leads to a reducon in penile sensivity,
thus delaying the ejaculatory latency me without adversely
aecng the sensaon of ejaculaon. The ecacy and safety
of Fortacin™ have been proven in numerous large scale studies
with improvements demonstrated in ejaculatory latency, con-
trol, and sexual sasfacon. The topical spray has a good safety
prole with only a low incidence of mild-to-moderate local AEs
seen in paents and partners, and is unlikely to be associated
with systemic side eects. Overall, Fortacin™ signicantly im-
proves the quality of the sexual performance, has a durable
eect over me, and may help break the vicious cycle of PE.
Disclosures
Financial support: Medical wring assistance was provided by
Dr. Melanie Ga, PhD, on behalf of Health Publishing & Services Srl.
This was funded by Recorda.
Conict of interest: AB is an advisory board member and consultant
for A. Menarini Pharmaceucals. Hartmut Porst is a consultant and
speaker for Berlin Chemie/Menarini group and Recorda.
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2009;103(3):358-364.
45. Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. Geo-
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Cod. 37700162 - AIFA Filing Date: December 18, 2017
... Ejaculation consists of two phases: emission and expulsion [13,16,43,44]. ...
... Expulsion follows emission, where semen is pushed out as the consequence of the rhythmic contractions of the striated muscles of the pelvis and the ischiocavernosus, bulbospongiosus, and perineal muscles [43]. Electromyographic [EMG] studies of the bulbocavernosus or bulbospongiosus have reported evidence of ejaculation or expulsion in animals following electrical or mechanical stimulation of genital structures or of the dorsal nerve of the penis [32,50], which is controlled by lumbar spinothalamic cells. ...
... Factors include anxiety, depression, guilt, stress, history of sexual suppression, lack of poor body image, sexual abuse, problems in understanding among partners, and early sexual experience [43,48,[69][70][71][72]. Anxiety is considered the primary cause of rapid ejaculation. ...
Article
Full-text available
Ejaculation is a reflex and the last stage of intercourse in male mammals. It consists of two coordinated phases, emission and expulsion. The emission phase consists of secretions from the vas deferens, seminal vesicle, prostate, and Cowper’s gland. Once these contents reach the posterior urethra, movement of the contents becomes inevitable, followed by the expulsion phase. The urogenital organs are synchronized during this complete event. The L3–L4 (lumbar) segment, the spinal cord region responsible for ejaculation, nerve cell bodies, also called lumbar spinothalamic (LSt) cells, which are denoted as spinal ejaculation generators or lumbar spinothalamic cells [Lst]. Lst cells activation causes ejaculation. These Lst cells coordinate with [autonomic] parasympathetic and sympathetic assistance in ejaculation. The presence of a spinal ejaculatory generator has recently been confirmed in humans. Different types of ejaculatory dysfunction in humans include premature ejaculation (PE), retrograde ejaculation (RE), delayed ejaculation (DE), and anejaculation (AE). The most common form of ejaculatory dysfunction studied is premature ejaculation. The least common forms of ejaculation studied are delayed ejaculation and anejaculation. Despite the confirmation of Lst in humans, there is insufficient research on animals mimicking human ejaculatory dysfunction.
... 2 Several treatments have been considered for the management of PE. 5 Dapoxetine, a shortacting selective serotonin reuptake inhibitor (SSRI) derived from fluoxetine, 6,7 is the gold standard of medical treatment for lifelong and acquired PE. 5,[8][9][10] In cases of acquired PE, treatment of the underlying contributing factor, when identifiable, is the priority (eg, by treating thyrotoxicosis or prostate inflammation). [10][11][12][13] Local anesthetics have also been considered a possible alternative for lifelong PE. 14,15 Although such medications have proven effective to a large extent, several factors contribute to their limited success in clinical practice, such as their side effects, high sale price, and limited support given to manage patients' expectations. [16][17][18][19] In a meta-analysis, treatments based on traditional Chinese medicine (TCM) theory were shown to be effective in improving PE. 20 Acupuncture is an important treatment method based on the theory of TCM and is applied in the treatment of many diseases. ...
Article
Full-text available
Background Although acupuncture is widely used to treat premature ejaculation (PE), its effectiveness remains highly controversial. Aim To evaluate the efficacy and safety of acupuncture on PE. Methods According to the relevant keywords, 11 major English and Chinese databases were searched for randomized controlled trials (RCTs) of acupuncture alone or in combination with other treatments for PE. The quality of evidence across studies was assessed by the GRADEpro tool. Outcomes Study outcome measures included the intravaginal ejaculation latency time (IELT), the Premature Ejaculation Diagnostic Tool (PEDT), the Chinese Index of Premature Ejaculation–5 (CIPE-5), treatment success rate, and adverse events. Results Seven trials were included in this review for a total of 603 participants. A low quality of evidence suggests that it is not possible to determine whether acupuncture, as compared with a selective serotonin reuptake inhibitor, has an advantage in improving the IELT (standardized mean difference [SMD], −1.75; 95% CI, −6.12 to 2.63; P = .43, I2 = 98%), PEDT scores (SMD, 0.32; 95% CI, −0.68 to 1.32; P = .53, I2 = 85%), and treatment success rate (risk ratio, 0.69; 95% CI, 0.41-1.14; P = .15). However, participants receiving acupuncture had a lower CIPE-5 (SMD, −1.06; 95% CI, −1.68 to −0.44; P < .01). As compared with sham acupuncture, acupuncture significantly improved the IELT (SMD, 1.47; 95% CI, 1.01-1.92; P < .01, I2 = 0%) and PEDT scores (SMD, −1.23; 95% CI, −1.78 to −0.67; P < .01, I2 = 37%). When compared with other treatments alone, a combined treatment with acupuncture can significantly improve the IELT (SMD, 7.06; 95% CI, 2.53-11.59; P < .01, I2 = 97%), CIPE-5 (SMD, 0.84; 95% CI, 0.45-1.22; P < .01, I2 = 0%), and treatment success rate (SMD, 1.60; 95% CI, 1.18-2.16; P < .01, I2 = 53). Clinical Implications The results suggest a significant effect of acupuncture in the treatment of certain important indicators of PE; however, this finding needs to be treated with caution because of the quality of the RCTs included. Strengths and Limitations Comprehensive inclusion of available RCTs has been performed. However, limitations include a low number of studies and a lack of detailed information to allow subgroup analysis. Conclusion The present systematic review and meta-analysis show that acupuncture has a significant effect on several subjective PE parameters, such as improving the feeling of control over ejaculation and distress, particularly when used in an integrated way. However, due to the low quality of evidence, acupuncture still needs larger well-designed RCTs to be confirmed.
... However, its use is limited by the attenuated sensation and enjoyment of intercourse in the patient, and in the partner where there is vaginal absorption of the local anaesthetic (if a condom is not used). 139 The lidocaine/prilocaine metered dose spray (Fortacin) containing a pure mixture of lidocaine 150 mg/ml and prilocaine 50 mg/ml is the only EMA-approved topical anaesthetic agent approved for use in PE. 142 However, these topical agents should be avoided in couples wishing to conceive as they may have direct toxic effects on spermatozoa. 144 A proposed management algorithm for PE is shown in Figure 3. ...
Article
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Introduction: Diabetes mellitus (DM) is a rapidly rising metabolic disorder with important systemic complications. Global figures have demonstrated the prevalence of DM has almost quadrupled from 108 million in 1980 to 422 million in 2014, with a current prevalence of over 525 million. Of the male sexual dysfunction resulting from DM, significant focus is afforded to erectile dysfunction (ED). Nevertheless, ejaculatory dysfunction (EjD) constitutes important sexual sequelae in diabetic men, with up to 35-50% of men with DM suffering from EjD. Despite this, aspects of its pathophysiology and treatment are less well understood than ED. The main disorders of ejaculation include premature ejaculation (PE), delayed ejaculation (DE), anejaculation (AE) and retrograde ejaculation (RE). Background: Although EjD in DM can have complex multifactorial aetiology, understanding the pathophysiological mechanisms caused by DM has facilitated the development of therapies in the management of EjD. Most of our understanding of its pathophysiology is derived from diabetic animal models, however observational studies in humans have also provided useful information in elucidating important associative factors potentially contributing to EjD in diabetic men. These have provided the potential for more tailored treatment regimens in patients depending on the ejaculatory disorder, other co-existing sequelae of DM, specific metabolic factors as well as the need for fertility treatment. However, the evidence for treatment of EjD, especially DE and RE, is based on low-level evidence comprising small sample-size series and retrospective or cross-sectional studies. Whilst promising findings from large randomised controlled trials (RCTs) have provided strong evidence for the licensed treatment of PE, similar robust studies are needed to accurately elucidate factors predicting EjD in DM, as well as for the development of pharmacotherapies for DE and RE. Similarly, more contemporary robust data is required for fertility outcomes in these patients, including methods of sperm retrieval and assisted reproductive techniques (ART) in RE. This article is protected by copyright. All rights reserved.
... More recently, FORTACIN™ has been approved as the first officially topical therapy for lifelong PE [7]. In this context, Prost et al. found that FORTACIN™ increased ejaculatory latency, control and sexual satisfaction, demonstrating the significant benefits for both patients and their partners when using the drug [28]. Likewise, other groups confirmed the after mentioned findings making local anaesthetic a viable alternative for lifelong and acquired PE [10,29]. ...
Article
Full-text available
Topical anaesthetics are considered a first-line therapy option in men with premature ejaculation (PE). A cross-sectional retrospective analysis was performed to evaluate the real-life use of the eutectic mixture of prilocaine/lidocaine spray (FORTACIN™) in a cohort of 198 white-European men who had been consecutively and prospectively seen at a single tertiary-referral andrology centre for self-reported PE and naive for previous PE treatments. Descriptive statistics was used to describe the whole cohort and the paired t-test was applied to investigate potential differences throughout a 12-month follow-up (baseline, 1, 3, 6 and 12 months). Overall, mean (SD) age was 37 (6.5) years. Of all, lifelong, acquired and subjective PE were reported in 101 (51%), 59 (29.8%) and 38 (19.2%) patients at baseline, respectively. FORTACIN™ use increased up to 6 months, with 184 (92.9%) and 128 (66.4%) men who had tried and regularly used the compound, respectively. At 12-month follow-up, 53 (26.8%) men reported a regular use of the compound. Mean Premature Ejaculation Diagnostic Tool score significantly decreased at 6 and 12 months compared to baseline (all p < 0.05). Conversely, mean IELT significantly improved at 6-month follow-up compared to baseline (all p ≤ 0.04). Overall, FORTACIN™ emerged to be a safe and effective treatment option in PE patients of various types, with almost one fourth of patients still under treatment after 12 months. Timing and dosing of the drug can deserve to be adjusted according to patient’s needs and their sexual ecology.
Article
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Increasing the efficacy of currently available medications is one of the pharmaceutical industry's main objectives. It is far simpler to develop current medications or enhance their efficacy than to create novel therapeutic candidates. This can be accomplished by altering deep eutectic solvents are prepared for solubility in the formulation techniques improvements made to different Active Pharmaceutical Ingredients (APIs). Usually, to modify DES, compounds having hazardous profiles that were previously well-known determined. DESs are thought to function as solubilization carriers. The evolution Organic solvents such as ethanol and acetone ethers are typically needed for soluble medicines. The melting of APIs is improved as a result. Along with improving the solubility of currently available medications, DESs also has a number of other uses.
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Akademisyen Yayınevi yöneticileri, yaklaşık 30 yıllık yayın tecrübesini, kendi tüzel kişiliklerine aktararak uzun zamandan beri, ticarî faaliyetlerini sürdürmektedir. Anılan süre içinde, başta sağlık ve sosyal bilimler, kültürel ve sanatsal konular dahil 2000'i aşkın kitabı yayımlamanın gururu içindedir. Uluslararası yayınevi olmanın alt yapısını tamamlayan Akademisyen, Türkçe ve yabancı dillerde yayın yapmanın yanında, küresel bir marka yaratmanın peşindedir. Bilimsel ve düşünsel çalışmaların kalıcı belgeleri sayılan kitaplar, bilgi kayıt ortamı olarak yüzlerce yılın tanıklarıdır. Matbaanın icadıyla varoluşunu sağlam temellere oturtan kitabın geleceği, her ne kadar yeni buluşların yörüngesine taşınmış olsa da, daha uzun süre hayatımızda yer edineceği muhakkaktır.
Article
Objective: TheDES are formed by mixing a Hydrogen Bond Donor (HBD) and a Hydrogen Bond Acceptor (HBA) in appropriate molar ratios. These solvents have been shown to enhance drug solubility, permeability, and delivery. The main objective of the present article is to review these advantages of TheDES. Significance: TheDES show unique properties, such as low toxicity, biodegradability, improved bioavailability and enhanced drug delivery of poorly soluble active pharmaceutical ingredients. They are also biocompatible in nature which makes them a promising candidate for various therapeutic applications, including drug formulations, drug delivery and other biomedical uses. The development and utilization of TheDES shows significant advancement in pharmaceutical research, providing new opportunities for improving drug delivery. Methods: The current study was carried out by conducting a systematic literature review that identified relevant papers from indexed databases. Numerous studies and research are cited and quoted in this article to demonstrate the effectiveness of TheDES in enhancing drug solubility, permeability, and delivery. All chosen articles were selected considering their significance, quality, and approach to addressing issues. Result: As a result, various TheDES were identified that can be formulated in different ways: one component can act as a vehicle for an API, either HBD or HBA can be an API, both HBD and HBA can be APIs, or the individual components of DES are not therapeutically active but the resulting DES possesses therapeutic activity. Additionally, TheDES were also recognized to enhance drug delivery and solubility for different APIs, including NSAIDs, anesthetic drugs, antifungals, and others.
Article
: Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting Selective Serotonin Reuptake Inhibitor (SSRI) approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by Traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: while the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study - the largest in the field - shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies. This article is protected by copyright. All rights reserved.
Article
Ejaculation and orgasm are complex phenomena within the male sexual response cycle. Disordered ejaculation commonly presents as premature or delayed ejaculation, although issues with painful ejaculation, retrograde ejaculation, or postorgasmic illness syndrome are also seen. This article will review the pathophysiology of these conditions as well as the current pharmacologic treatments available.
Article
Introduction: Premature ejaculation (PE) is a sexual dysfunction of unknown etiology affecting a substantial number of males and deteriorating sexual health and quality of life of the patient and his partner. Treatment still remains challenging; however, pharmacotherapy is considered the mainstay of therapy with behavioral and psychosexual interventions being particularly important as adjudicate procedures, within the context of a holistic approach. Areas covered: The authors review the literature on the available medications for PE, both officially registered and non-registered. Currently, only dapoxetine and an anesthetic spray containing lidocaine and prilocaine (Fortacin™) are officially approved, with the rest being used off-label. Herein, updated data regarding the efficacy and safety of the pharmaceutical agents are presented. Expert opinion: On-demand dapoxetine is reportedly efficacious and safe in treating lifelong PE and is the first medication to be approved for this purpose. Fortacin has also shown considerable efficacy and may be reliably used on-demand. Phosphodiesterase type 5 inhibitors (PDE5Is) have been found to be effective in the treatment of PE and are therefore recommended either as monotherapy or combined with other therapies (i.e. dapoxetine). Adverse events of any therapy should be taken under consideration. Physicians should encourage patients to discuss their needs and expectations and grade any improvement of their condition with treatment.
Article
Full-text available
Premature ejaculation (PE) is a common sexual dysfunction affecting20% to 30% of men worldwide. Definitions of PE vary, but itis typically characterized by short intravaginal ejaculatory latencytime (IELT) with concomitant sexual dissatisfaction and distress.PE may be lifelong or acquired, but its etiology remains unclear.Treatment of PE typically involves pharmacotherapy, particularlywhen lifelong. Although there are numerous reports on the offlabeluse of selective serotonin reuptake inhibitors (SSRIs) andother compounds, only 2 treatments have been evaluated in randomizedcontrolled phase 3 clinical trials: PSD502 and dapoxetine(SSRI). Both significantly improved IELT and patient-reportedoutcome domains of ejaculatory control, sexual satisfaction, anddistress as measured by the index of premature ejaculation (IPE),compared with placebo. They constitute the focus of this review.Evidence demonstrated that PSD502, dapoxetine and other SSRIsall significantly improve the symptoms of PE. Systemic use of SSRIspresents risks associated with the known pharmacology of thisclass. PSD502 allows for topical on-demand treatment appliedapplied immediately before intercourse, and is not associated withsystemic adverse events.
Article
Full-text available
Introduction: In 2009, the International Society for Sexual Medicine (ISSM) convened a select panel of experts to develop an evidence-based set of guidelines for patients suffering from lifelong premature ejaculation (PE). That document reviewed definitions, etiology, impact on the patient and partner, assessment, and pharmacological, psychological, and combined treatments. It concluded by recognizing the continually evolving nature of clinical research and recommended a subsequent guideline review and revision every fourth year. Consistent with that recommendation, the ISSM organized a second multidisciplinary panel of experts in April 2013, which met for 2 days in Bangalore, India. This manuscript updates the previous guidelines and reports on the recommendations of the panel of experts. Aim: The aim of this study was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of PE for family practice clinicians as well as sexual medicine experts. Method: A comprehensive literature review was performed. Results: This article contains the report of the second ISSM PE Guidelines Committee. It offers a new unified definition of PE and updates the previous treatment recommendations. Brief assessment procedures are delineated, and validated diagnostic and treatment questionnaires are reviewed. Finally, the best practices treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with PE, in facilitating treatment of their patients. Conclusion: Development of guidelines is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to a more complete understanding of the pathophysiology as well as new efficacious and safe treatments for this sexual dysfunction. We again recommend that these guidelines be reevaluated and updated by the ISSM in 4 years. Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, Adaikan PG, Becher E, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An update of the International Society of Sexual Medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE). Sex Med 2014;2:60–90.
Article
Full-text available
Over the past several years, many advances have been made in our understanding of the epidemiology, pathophysiology, and management of premature ejaculation. Newly developed definitions of premature ejaculation are now available, and our perception of the classification, prevalence, aetiological factors, and treatment options for premature ejaculation have evolved. Despite ongoing research, there remains much to be learned about all aspects of this common sexual disorder, in particular effective clinical diagnosis and treatment options.
Chapter
Interest and research into the physiology of ejaculation began in the mid-1700s with the essays of the British surgeon John Hunter who wrote about the different compositions of semen at distinct points of ejaculation. He further reported on the anatomical organs that contributed to this process based upon his own human and animal dissections (Hendry, Ann R Coll Surg Engl 81(5):352–358, 1999). Over 200 years later, despite the prevalence of male sexual dysfunction and modern technological advancements, the intricacies of human ejaculation are still poorly understood. Neuroscientific studies on animals as well as brain imaging provide the bulk of what is understood today. This chapter provides the accepted gross anatomical and temporal progression models of ejaculation. The most current neuroanatomical and neurophysiological discoveries are also provided. An understanding of these processes will provide the foundation for approaching and understanding the disorders of ejaculation discussed later in this book.
Article
The ideal treatment for premature ejaculation – the most common male sexual dysfunction – would be an approved, discreet and on-demand therapy that is effective from the first dose and has no side-effects. The author takes a look at what is available. Copyright © 2010 Wiley Interface Ltd
Article
Mike Kirby discusses how various definitions of premature ejaculation have made it difficult to evaluate the prevalence and epidemiology of the condition. Copyright © 2014 John Wiley & Sons.
Article
IntroductionThe International Society for Sexual Medicine (ISSM) Ad Hoc Committee for the Definition of Premature Ejaculation developed the first evidence-based definition for lifelong premature ejaculation (PE) in 2007 and concluded that there were insufficient published objective data at that time to develop a definition for acquired PE.AimThe aim of this article is to review and critique the current literature and develop a contemporary, evidence-based definition for acquired PE and/or a unified definition for both lifelong and acquired PE.Methods In April 2013, the ISSM convened a second Ad Hoc Committee for the Definition of Premature Ejaculation in Bangalore, India. The same evidence-based systematic approach to literature search, retrieval, and evaluation used by the original committee was adopted.ResultsThe committee unanimously agreed that men with lifelong and acquired PE appear to share the dimensions of short ejaculatory latency, reduced or absent perceived ejaculatory control, and the presence of negative personal consequences. Men with acquired PE are older, have higher incidences of erectile dysfunction, comorbid disease, and cardiovascular risk factors, and have a longer intravaginal ejaculation latency time (IELT) as compared with men with lifelong PE. A self-estimated or stopwatch IELT of 3 minutes was identified as a valid IELT cut-off for diagnosing acquired PE. On this basis, the committee agreed on a unified definition of both acquired and lifelong PE as a male sexual dysfunction characterized by (i) ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration from the first sexual experience (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about 3 minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy.Conclusion The ISSM unified definition of lifelong and acquired PE represents the first evidence-based definition for these conditions. This definition will enable researchers to design methodologically rigorous studies to improve our understanding of acquired PE. Serefoglu EC, McMahon CG, Waldinger MD, Althof SE, Shindel A, Adaikan G, Becher EF, Dean J, Giuliano F, Hellstrom WJG, Giraldi A, Glina S, Incrocci L, Jannini E, McCabe M, Parish S, Rowland D, Segraves RT, Sharlip I, and Torres LO. An evidence-based unified definition of lifelong and acquired premature ejaculation: Report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. J Sex Med **;**:**–**.
Article
To assess both the acceptance and the discontinuation rates from dapoxetine, the first oral pharmacological agent indicated for the treatment of premature ejaculation (PE). One hundred twenty consecutive potent patients (mean age 40.3 years; range 18-63 years) seeking medical treatment for lifelong PE were enrolled in a prospective phase II study. Moreover, they were assessed regarding detailed medical and sexual history, intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and complete physical examination. The patients received a dapoxetine prescription (30 mg on demand) and unresponded cases received increased dose (60 mg after 3 months). The patients were evaluated at 1, 3, 6, and 12 months, and requested to complete a multiple-choice global assessment questionnaire regarding specific reasons for eventual therapy discontinuation. Twenty-four of the patients (20%) decided not to start dapoxetine. Fear of using a "drug" was the most frequently reported reason for treatment nonacceptance (50%) and the cost of treatment was the reason for 25% of the patients. Ninety-six patients (80%) started the therapy. Twenty-six percent dropped out after 1 month, 42.7% dropped out after 3 months, 18.7% dropped out at 6 months, 2% dropped out at 12 months, and 10.4% are continuing the therapy after 1 year. The main reasons were effect below expectations 24.4%, costs 22.1%, side effects 19.8%, loss of interest in sex 19.8%, and no efficacy 13.9%. Twenty percent of lifelong PE patients seeking medical treatment for early ejaculation freely decided not to start treatment with dapoxetine, and roughly 90% of the patients who started therapy discontinued after 1 year.
Article
Premature ejaculation (PE) is a common sexual dysfunction affecting 20% to 30% of men worldwide. Definitions of PE vary, but it is typically characterized by short intravaginal ejaculatory latency time (IELT) with concomitant sexual dissatisfaction and distress. PE may be lifelong or acquired, but its etiology remains unclear. Treatment of PE typically involves pharmacotherapy, particularly when lifelong. Although there are numerous reports on the off-label use of selective serotonin reuptake inhibitors (SSRIs) and other compounds, only 2 treatments have been evaluated in randomized controlled phase 3 clinical trials: PSD502 and dapoxetine (SSRI). Both significantly improved IELT and patient-reported outcome domains of ejaculatory control, sexual satisfaction, and distress as measured by the index of premature ejaculation (IPE), compared with placebo. They constitute the focus of this review. Evidence demonstrated that PSD502, dapoxetine and other SSRIs all significantly improve the symptoms of PE. Systemic use of SSRIs presents risks associated with the known pharmacology of this class. PSD502 allows for topical on-demand treatment applied applied immediately before intercourse, and is not associated with systemic adverse events.