Depojoy is indicated for the treatment of premature ejaculation (PE) in adult men aged 18 to 64
years. Depojoy should only be prescribed to patients who meet all the following criteria:
• An intravaginal ejaculatory latency time (IELT) of less than two minutes;and
Depojoy ® 30 mg, 60 mg film-coated Tablets
• Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortlyafter
penetration and before the patient wishes; and
• Marked personal distress or interpersonal difficulty as a consequence of PE;and
• Poor control over ejaculation; and
• A history of premature ejaculation in the majority of intercourse attempts over the prior 6 months.
Depojoy should be administered only as on-demand treatment before anticipated sexual activity.
Depojoy should not be prescribed to delay ejaculation in men who have not been diagnosed with PE
 

Posology
Adultmen(aged18to64years)
The recommended starting dose for all patients is 30 mg, taken as needed approximately 1 to 3 hours
prior to sexual activity. Treatment with Depojoy should not be initiated with the 60 mg dose.
Depojoy is not intended for continuous daily use. Depojoy should be taken only when sexual activity is
anticipated. Depojoy must not be taken more frequently than once every 24 hours.
If the individual response to 30 mg is insufficient and the patient has not experienced moderate or severe
adverse reactions or prodromal symptoms suggestive of syncope, the dose may be increased to a
maximum recommended dose of 60 mg taken as needed approximately 1 to 3 hours prior to sexual
activity. The incidence and severity of adverse events is higher with the 60 mg dose.
If the patient experienced orthostatic reactions on the starting dose, no dose escalation to 60 mg should
be performed (see section 4.4).
A careful appraisal of individual benefit risk of Depojoy should be performed by the physician after the
first four weeks of treatment (or at least after 6 doses of treatment) to determine whether continuing
treatment with Depojoy is appropriate.
Data regarding the efficacy and safety of Depojoy beyond 24 weeks are limited. The clinical need of
continuing and the benefit risk balance of treatment with Depojoy should be re-evaluated at least
everysix months.
Elderly (age 65 years and over)
The efficacy and safety of Depojoy have not been established in patients age 65 years and
over(see section 5.2).
Paediatric population
There is no relevant use of Depojoy in this population in the indication of premature ejaculation.
Patients with renal impairment
Caution is advised in patients with mild or moderate renal impairment. Depojoy is not recommended for
use in patients with severe renal impairment (see sections 4.4 and 5.2).
Patients with hepatic impairment
Depojoy is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh Class
B and C) (see sections 4.3 and 5.2).
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 poormetabolizer
genotype or in patients concomitantly treated with potent CYP2D6 inhibitors (see sections 4.4, 4.5 and
5.2).
Patients treated withmoderate or potent inhibitors of CYP3A4
Concomitant use of potent CYP3A4 inhibitors is contraindicated. The dose should be restricted to 30 mg
in patients concomitantly treated with moderate CYP3A4 inhibitors and caution is advised (see sections
4.3, 4.4 and 4.5).
Method of 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. Depojoy may be taken with or without food (see section
5.2). Precautionstobetakenbeforehandlingoradministeringthemedicinalproduct
Before treatment is initiated, see section 4.4 regarding orthostatichypotension
 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Significant pathological cardiac conditions such as:• Heart failure (NYHA class II-IV) • Conduction abnormalities such as AV block or sick sinussyndrome • Significant ischemic heart disease • Significant valvular disease • A history of syncope. A history of mania or severe depression. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days ofdiscontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after Depojoyhas been discontinued (see section4.5). Concomitant treatment with thioridazine, or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after Depojoy has been discontinued (see section 4.5). 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 Depojoy has been discontinued (see section4.5). Concomitant treatment of potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazadone, nelfinavir, atazanavir, etc. (see section 4.5). Moderate and severe hepatic impairment

General recommendations
Depojoy is only indicated in men with Premature Ejaculation who meet all the criteria listed in sections
4.1 and 5.1. Depojoy should not be prescribed to men who have not been diagnosed with Premature
Ejaculation. Safety has not been established and there are no data on the ejaculation-delaying effects in
men without Premature Ejaculation.
Other forms of sexual dysfunction
Before treatment, subjects with other forms of sexual dysfunction, including erectile dysfunction, should
be carefully investigated by physicians. Depojoy should not be used in men with erectile dysfunction
(ED) who are using PDE5 inhibitors (see section4.5).
Orthostatic hypotension
Before treatment initiation, a careful medical examination including history of orthostatic events should
be performed by the physician. An orthostatic test should be performed before initiating therapy(blood
pressure and pulse rate, supine and standing). In case of a history of documented or suspected
orthostatic reaction, treatment with Depojoy 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 downwith
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.
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 Depojoy for the
treatment of premature ejaculation, there was no clear indication of treatment-emergent suicidality in
evaluation of possibly suicide-related adverse events evaluated by the Columbia Classification Algorhythm
of Suicide Assessment (C-CASA), Montgomery-Asberg Depression Rating Scale, or Beck Depression
Inventory-II.
Syncope
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 (see section 4.8).
Possibly prodromal symptoms such as nausea, dizziness/lightheadedness, and diaphoresis werereported
more frequently among patients treated with Depojoy compared to placebo.
In the clinical trials, cases of syncope characterized as loss of consciousness, with bradycardia orsinus
arrest observed in patients wearing Holter monitors,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 Depojoy.
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
patientshould 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 (see section 4.7). Patients with cardiovascular risk factors
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.
Use with recreational drugs
Patients should be advised not to use Depojoy 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
Depojoy. These reactions include, but are not limited to, arrhythmia, hyperthermia, and serotonin
syndrome. Use of Depojoy with recreational drugs with sedative properties such as narcotics and
benzodiazepines may further increase somnolence anddizziness.
Ethanol
Patients should be advised not to use Depojoy in combination with alcohol.
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 Depojoy (see sections 4.5
and 4.7).
Medicinal products with vasodilatation properties
Depojoy should be prescribed with caution in patients taking medicinal products with
vasodilatation properties (such as alpha adrenergic receptor antagonists and nitrates) due to
possiblereduced orthostatic tolerance (see section 4.5).
Moderate CYP3A4 inhibitors
Caution is advised in patients taking moderate CYP3A4 inhibitors and the dose is restricted to 30 mg(see
sections 4.2 and 4.5).
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 (see sections 4.2, 4.5 and 5.2).
Mania
Depojoy 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, Depojoy should be discontinued in any patient
who develops seizures and avoided in patients with unstable epilepsy. Patients with controlled epilepsy
should be carefully monitored.
Paediatric population
Depojoy should not be used in individuals below 18 years of age.
Depression and/or psychiatric disorders
Men with underlying signs and symptoms of depression should be evaluated prior to treatment with
Depojoy to rule out undiagnosed depressive disorders. Concomitant treatment of Depojoy with
antidepressants, including SSRIs and SNRIs, is contraindicated (see section 4.3). Discontinuation of
treatment for ongoing depression or anxiety in order to initiate Depojoy for the treatment of PE is not
recommended. Depojoy 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, Depojoy should be discontinued.
Haemorrhage
There have been reports of bleeding abnormalities with SSRIs. Caution is advised in patients taking
Depojoy, particularly in concomitant use with medicinal products known to affect platelet function (e.g.,
atypical antipsychotics and phenothiazines, 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 (see section 4.5).
Renal impairment
Depojoy is not recommended for use in patients with severe renal impairment and caution is advised in
patients with mild or moderate renal impairment (see sections 4.2 and 5.2).
Withdrawal effects
Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disordershas
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 andhypomania.
A double-blind clinical trial in subjects with PE designed to assess the withdrawal effects of 62 daysof
daily or as needed dosing with 60 mg Depojoy showed mild withdrawal symptoms with a slightly higher
incidence of insomnia and dizziness in subjects switched to placebo after daily dosing (see section 5.1).
Eye disorders
The use of Depojoy has been associated with ocular effects such as mydriasis and eye pain.
Depojoyshould be used with caution in patients with raised intraocular pressure or those at risk of angle
closure glaucoma.
Lactose intolerance
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption should not take this medicine
 

Pharmacodynamic interactions
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 synergisticallyto
elevate blood pressure and evoke behavioural excitation. Therefore, Depojoy 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 Depojoy has been discontinued (see section 4.3).
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 Depojoy 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. Depojoy should not be used in combination
with thioridazine or within 14 days of discontinuing treatment with thioridazine. Similarly,
thioridazineshould not be administered within 7 days after Depojoy has been discontinued (see section
4.3).
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. Depojoy should not
be used in combination with other SSRIs, MAOIs or other serotonergic medicinal/herbal products
orwithin 14 days of discontinuing treatment with these medicinal/herbal products. Similarly, these
medicinal/herbal products should not be administered within 7 days after Depojoy has been
discontinued (see section 4.3).
CNS active medicinal products
The use of Depojoy in combination with CNS active medicinal products (e.g., antiepileptics,
antidepressants, antipsychotics, anxiolytics, sedative hypnotics) has not been systematically evaluated in
patients with premature ejaculation. Consequently, caution is advised if the concomitant administration of
Depojoy and such medicinal products is required.
Pharmacokinetic interactions
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 dapoxetineclearance.
CYP3A4 inhibitors
Potent CYP3A4 inhibitors. Administration of ketoconazole (200 mg twice daily for 7 days) increasedthe
Cmax and AUCinf 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 takenwith
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 Depojoy and potent CYP3A4 inhibitors, such as ketoconazole,
itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir, is
contraindicated (see section 4.3).
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 (see sections 4.2, 4.4 and below).
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 CYP3A4 inhibitor andcaution
is advised if dapoxetine in 60 mg doses is taken concomitantly with a moderate CYP3A4 inhibitor.
Potent CYP2D6 inhibitors
The Cmax and AUCinf 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 unbounddapoxetine
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 (see section 4.4).
PDE5 inhibitors
Depojoy should not be used in patients using PDE5 inhibitors due to possible reduced
orthostatictolerance (see section 4.4). 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.
Concomitant use of Depojoy with PDE5 inhibitors may result in orthostatic hypotension (see section 4.4).
The efficacy and safety of Depojoy in patients with both premature ejaculation and erectiledysfunction
concomitantly treated with Depojoy and PDE5 inhibitors have not been established.
Effects of dapoxetine on the pharmacokinetics of co -administered medicinal products
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, Depojoy should be prescribed with caution in patients who use alpha
adrenergic receptor antagonists due to possible reduced orthostatic tolerance (see section 4.4).
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 and medicinal products that are known to affect coagulation and/or platelet function
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 (see section 4.4). 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.
There have been reports of bleeding abnormalities with SSRIs (see section 4.4).
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 withethanol
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 anddapoxetine
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 Depojoy
(seesections 4.4 and 4.7)
 

Pregnancy category: NA
Depojoy is not indicated for use by women.
Animal studies do not indicate direct or indirect harmful effects with respect to fertility, pregnancy or
embryonal/foetal development (see section 5.3).
It is not known if either dapoxetine or its metabolites are excreted in human milk
 

Depojoy 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 ofaccidental
injury; therefore, patients should be advised to avoid alcohol while taking Depojoy (see sections 4.4 and
4.5)
 

Summary of the safety profile
Syncope and orthostatic hypotension have been reported in clinical trials (see section 4.4).
The following adverse drug reactions were reported during Phase 3 clinical trials most commonly and
were dose related: nausea (11.0% and 22.2% in 30 mg and 60 mg prn dapoxetine groups, respectively),
dizziness (5.8% and 10.9%), headache (5.6% and 8.8%), diarrhoea (3.5% and 6.9%), insomnia (2.1%
and 3.9%) and fatigue (2.0% and 4.1%). The most common adverse events leading to discontinuation
were nausea (2.2% of Depojoy-treated subjects) and dizziness (1.2% of Depojoy-treated subjects).
Tabulated list of adverse reactions
The safety of Depojoy was evaluated in 4224 subjects with premature ejaculation who participated in
five double-blind, placebo-controlled clinical trials. Of the 4224 subjects, 1616 received Depojoy 30
mg as needed and 2608 received 60 mg, either as needed or once daily.
Table 1 presents the adverse reactions that have been reported

Adverse drug reactions reported in the 9-month long-term open-label extension trial were consistent
with those reported in the double-blind studies and no additional adverse drug reactions were reported.
Description of selected adverse reactions
Syncope characterized as loss of consciousness, with bradycardia or sinus arrest observed in patients
wearing Holter monitors, has been reported in clinical trials and is considered medicinalproduct-related.
The majority of cases occurred during the first 3 hours after dosing, after the first dose or associatedwith
study-related procedures in the clinical setting (such as blood draw and orthostatic maneuvers andblood
pressure measurements). Prodromal symptoms often preceded the syncope (see section 4.4).
The occurrence of syncope and possibly prodromal symptoms appears dose dependent asdemonstrated
by higher incidence among patients treated with higher than recommended doses in Phase 3 clinical
trials.
Orthostatic hypotension has been reported in clinical trials (see section 4.4).The frequency ofsyncope
characterized as loss of consciousness in the Depojoy clinical development program varied depending
on the population studied and ranged from 0.06% (30 mg) to 0.23% (60 mg) for subjects enrolled
inthe Phase 3 placebo-controlled clinical trials to 0.64% (all doses combined) for Phase 1 non-PE
healthy volunteer studies.
Other special populations
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 (see sections
4.2, 4.4, 4.5 and 5.2).
Withdrawal effects
Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disordershas
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 andhypomania.
Results of a safety study showed a slightly higher incidence of withdrawal symptoms of mild or moderate
insomnia and dizziness in subjects switched to placebo after 62 days of dailydosing.
To report any side effect(s):

No case of overdose has been reported.
There were no unexpected adverse events in a clinical pharmacology study of Depojoy 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 anddizziness.
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 Depojoy
are known
 

Pharmacotherapeutic group: Other Urologicals, ATC code: G04BX14
Mechanism of action
Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with an IC50 of 1.12 nM, while its
major human metabolites, desmethyldapoxetine (IC50 < 1.0 nM) and didesmethyldapoxetine (IC50 = 2.0
nM) are equivalent or less potent (dapoxetine-N-oxide (IC50 = 282 nM)).
Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculatorypathway
originates from a spinal reflex centre, mediated by the brain stem, which is influenced initially bya
number of nuclei in the brain (medial preoptic and paraventricular nuclei).
The mechanism of action of dapoxetine in premature ejaculation is presumed to be linked to the
inhibition of neuronal reuptake of serotonin and the subsequent potentiation of theneurotransmitter's
action at pre- and postsynaptic receptors.
In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level within the
lateral paragigantocellular nucleus (LPGi). Post ganglionic sympathetic fibers that innervate theseminal
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.
Clinical efficacy and safety
The effectiveness of Depojoy in the treatment of premature ejaculation has been established in five
double-blind, placebo-controlled clinical trials, in which a total of 6081 subjects were randomized.
Subjects were 18 years of age or older and had a history of PE in the majority of intercourse experiences
in the 6-month period prior to enrolment. Premature ejaculation was defined according to the DSM-IV
diagnostic criteria: short ejaculatory time (an intravaginal ejaculatory latency time [IELT; time from
vaginal penetration to the moment of intravaginal ejaculation] of ≤ 2 minutes measured using a
o Please contact the relevant competent authority.
stopwatch in four studies), poor control over ejaculation, marked distress or interpersonal difficulty due to
the condition.
Subjects with other forms of sexual dysfunction, including erectile dysfunction, or those using otherforms
of pharmacotherapy for the treatment of PE were excluded from all studies.
Results of all randomized studies were consistent. Efficacy was demonstrated after 12 weeks of
treatment. One study enrolled patients both outside and within the EU and had a treatment duration of
24 weeks. In the study, 1162 subjects were randomized, 385 to placebo, 388 to Depojoy 30 mg
asneeded, and 389 to Depojoy 60 mg as needed. The mean and median Average IELT at study end are
presentedin Table 2 below and the cumulative distribution of subjects who achieved at least a specific
level in Average IELT at study end are presented in Table 3 below. Other studies and pooled analysis of
the data at Week 12 gave consistent results

The magnitude of IELT prolongation was related to baseline IELT and was variable between individual
subjects. The clinical relevance of Depojoy treatment effects was further demonstrated in terms of
various patient reported outcome measures and a responder analysis.
A responder was defined as a subject who had at least a 2-category increase in control over ejaculation
plus at least a 1-category decrease in ejaculation-related distress. A statistically significantly greater
percentage of subjects responded in each of the Depojoy groups versus placebo at the end of the study
Week 12 or 24. There was a higher percentage of responders in the dapoxetine 30 mg (11.1% - 95% CI
[7.24; 14.87]) and 60 mg (16.4% - 95% CI [13.01; 19.75]) groups compared with the placebo group at
Week 12 (pooled analysis).
The clinical relevance of Depojoy treatment effects is represented by treatment group for the subject's
Clinical Global Impression of Change (CGIC) outcome measure, in which patients were asked tocompare
their premature ejaculation from the start of the study, with response options ranging from muchbetter
to much worse. At study end (Week 24), 28.4% (30 mg group) and 35.5% (60 mg group) ofsubjects
reported their condition to be “better” or “much better”, compared to 14% for placebo, while 53.4% and
65.6% of subjects treated with dapoxetine 30 mg and 60 mg, respectively, reported their condition to be
at least “slightly better”, compared to 28.8% for placebo
 

Absorption
Dapoxetine is rapidly absorbed with maximum plasma concentrations (Cmax) occurring approximately 1-2
hours after tablet intake. The absolute bioavailability is 42% (range 15-76%), and dose proportional
increases in exposure (AUC and Cmax) are observed between the 30 and 60 mg dose strengths. Following
multiple doses, AUC values for both dapoxetine and the active metabolite desmethyldapoxetine (DED)
increase by approximately 50% when compared to single dose AUC values.
Ingestion of a high fat meal modestly reduced the Cmax (by 10%) and modestly increased the AUC (by
12%) of dapoxetine and slightly delayed the time for dapoxetine to reach peak concentrations. These
changes are not clinically significant. Depojoy can be taken with or without food.
Distribution
More than 99% of dapoxetine is bound in vitro to human serum proteins. The active metabolite
desmethyldapoxetine (DED) is 98.5% protein bound. Dapoxetine has a mean steady state volume of
distribution of 162 L.
Biotransformation
In vitro studies suggest that dapoxetine is cleared by multiple enzyme systems in the liver and kidneys,
primarily CYP2D6, CYP3A4, and flavin monooxygenase (FMO1). Following oral dosing of 14C-dapoxetine,
dapoxetine was extensively metabolized to multiple metabolites primarily through the following
biotransformational pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation
and sulfation. There was evidence of presystemic first-pass metabolism after oraladministration.
Intact dapoxetine and dapoxetine-N-oxide were the major circulating moieties in the plasma. Invitro
binding and transporter studies show that dapoxetine-N-oxide is inactive. Additional metabolites
including desmethyldapoxetine and didesmethyldapoxetine account for less than 3% of the total
circulating drug –related materials in plasma. In vitro binding studies indicate that DED is equipotent to
dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of dapoxetine (see section
5.1). The unbound exposures (AUC and Cmax) of DED are approximately 50% and 23%, respectively, of
the unbound exposure of dapoxetine.
Elimination
The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchangedactive
substance was not detected in the urine. Following oral administration, dapoxetine has an initial
(disposition) half-life of approximately 1.5 hours, with plasma levels less than 5% of peak concentrations
by 24 hours post-dose, and a terminal half-life of approximately 19 hours. The terminal half-life of DED
is approximately 19 hours.
Pharmacokinetics in special populations
The metabolite DED contributes to the pharmacological effect of Depojoy, particularly when the exposureof
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.
Race
Analyses of single dose clinical pharmacology studies using 60 mg dapoxetine indicated no statistically
significant differences between Caucasians, Blacks, Hispanics and Asians. A clinical study conducted to
compare the pharmacokinetics of dapoxetine in Japanese and Caucasian subjects showed 10% to 20%
higher plasma levels (AUC and peak concentration) of dapoxetine in Japanese subjects due to lowerbody
weight. The slightly higher exposure is not expected to have a meaningful clinical effect.
Elderly (age 65 years and over)
Analyses of a single dose clinical pharmacology study using 60 mg dapoxetine showed no significant
differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly males andhealthy
young adult males. The efficacy and safety has not been established in this population (see section 4.2).
Renal impairment
A single-dose clinical pharmacology study using a 60 mg dapoxetine dose was conducted in subjectswith
mild (CrCL 50 to 80 mL/min), moderate (CrCL 30 to < 50 mL/min), and severe renal impairment (CrCL <
6. Pharmaceutical particulars
6.1 List of excipients
30 mL/min) and in subjects with normal renal function (CrCL > 80 mL/min). No clear trend for an
increase in dapoxetine AUC with decreasing renal function was observed. AUC in subjects with severe
renal impairment was approximately 2-fold that of subjects with normal renal function, although there
are limited data in patients with severe renal impairment. Dapoxetine pharmacokinetics have not been
evaluated in patients requiring renal dialysis (see sections 4.2 and 4.4).
Hepatic impairment
In patients with mild hepatic impairment, unbound Cmax of dapoxetine is decreased by 28% and unbound
AUC is unchanged. The unbound Cmax and AUC of the active fraction (the sum of the unbound exposure
of dapoxetine and desmethyldapoxetine) were decreased by 30% and 5%, repectively. In patients with
moderate hepatic impairment, unbound Cmax of dapoxetine is essentially unchanged (decrease of 3%)
and unbound AUC is increased by 66%. The unbound Cmaxand AUC of the active fraction were essentially
unchanged and doubled,respectively.
In patients with severe hepatic impairment, the unbound Cmax of dapoxetine was decreased by 42% but
the unbound AUC was increased by approximately 223%. The Cmax and AUC of the active fraction had
similar changes (see sections 4.2 and 4.3).
CYP2D6 Polymorphism
In a single dose clinical pharmacology study using 60 mg dapoxetine, plasma concentrations in poor
metabolizers of CYP2D6 were higher than in extensive metabolizers of CYP2D6 (approximately 31%
higher for Cmax and 36% higher for AUCinf of dapoxetine and 98% higher for Cmax and 161% higher for
AUCinf of desmethyldapoxetine). The active fraction of Depojoy 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 Depojoy in poor metabolizers of CYP2D6
is of particular concern with concomitant administration of other medicinal products that may inhibit the
metabolism of dapoxetine such as moderate and potent CYP3A4 inhibitors (see sections 4.2 and 4.3)
 

A full assessment of the safety pharmacology, repeat dose toxicology, genetictoxicology,carcinogenicity,
dependence/withdrawal liability, phototoxicity and developmental reproductive toxicology of dapoxetine
was conducted in preclinical species (mouse, rat, rabbit, dog and monkey) up to the maximum tolerated
doses in each species. Due to the more rapid bioconversion in the preclinical species than in man,
pharmacokinetic exposure indices (Cmax and AUC0- 24 hr) at the maximum tolerated doses in some studies
approached those observed in man. However, the body weight normalized dose multiples were greater
than 100-fold. There were no clinically relevant safety hazards identified in any of these studies.
In studies with oral administration, dapoxetine was not carcinogenic to rats when administered dailyfor
approximately two years at doses up to 225 mg/kg/day, yielding approximately twice the exposures
(AUC) seen in human males given the Maximum Recommended Human Dose (MRHD) of 60 mg.
Dapoxetine also did not cause tumors in Tg.rasH2 mice when administered at the maximum possible
doses of 100 mg/kg for 6 months and 200 mg/kg for 4 months. The steady state exposures of
dapoxetine in mice following 6-months oral administration at 100 mg/kg/day were less than thesingle
dose exposures observed clinically at 60 mg.
There were no effects on fertility, reproductive performance or reproductive organ morphology in male or
female rats and no adverse signs of embryotoxicity or fetotoxicity in the rat or rabbit. Reproductive
toxicity studies did not include studies to assess the risk of adverse effects after exposure during the peripost-natal period
 

Tablet core:
Lactose Fast Flow (monohydrate)
Avicel PH 102
Croscarmellose Sodium
Colloidal Silicon dioxide
Magnesium stearate
Tablet coating:
Opadry Pink 31K34533
 

Not applicable
 

2 years

Store below 30°C.
This medicinal product does not require any special storage conditions
 

PVC/PVDC- Alu. Blisters: 6 tablets
 

No special requirements