Dapoxetine tablets is indicated for the treatment of premature ejaculation (PE) in adult men aged
18 to 64 years.
Dapoxetine tablets should only be prescribed to patients who meet all the following criteria:
• An intravaginal ejaculatory latency time (IELT) of less than two minutes; and
• Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after
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.
Dapoxetine tablets should be administered only as on-demand treatment before anticipated sexual
activity. Dapoxetine tablets should not be prescribed to delay ejaculation in men who have not
been diagnosed with PE.

Posology
Adult men (aged 18 to 64 years)
The recommended starting dose for all patients is 30 mg, taken as needed approximately 1 to 3
hours prior to sexual activity. Treatment with Dapoxetine tablets should not be initiated with the
60 mg dose.
Dapoxetine tablets is not intended for continuous daily use. Dapoxetine tablets should be taken
only when sexual activity is anticipated. Dapoxetine tablets 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 Dapoxetine tablets 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 Dapoxetine tablets is appropriate.
Data regarding the efficacy and safety of Dapoxetine tablets beyond 24 weeks are limited. The
clinical need of continuing and the benefit risk balance of treatment with Dapoxetine tablets
should be re-evaluated at least every six months.
Elderly (age 65 years and over)
The efficacy and safety of Dapoxetine tablets have not been established in patient’s age 65 years
and over (see section 5.2).
Paediatric population
There is no relevant use of Dapoxetine tablets in this population in the indication of premature
ejaculation.
Patients with renal impairment
Caution is advised in patients with mild or moderate renal impairment. Dapoxetine tablets is not
recommended for use in patients with severe renal impairment (see sections 4.4 and 5.2).

Patients with hepatic impairment
Dapoxetine tablets 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 poor
metabolizer genotype or in patients concomitantly treated with potent CYP2D6 inhibitors (see
sections 4.4, 4.5 and 5.2).
Patients treated with moderate 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. Dapoxetine tablets may be taken with or
without food (see section 5.2).
Precautions to be taken before handling or administering the medicinal product
Before treatment is initiated, see section 4.4 regarding orthostatic hypotension.

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 sinus syndrome • 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 of discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after Dapoxetine tablets has been discontinued (see section 4.5). Concomitant treatment with thioridazine, or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after Dapoxetine tablets 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 Dapoxetine tablets has been discontinued (see section 4.5). 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
Dapoxetine tablets is only indicated in men with Premature Ejaculation who meet all the criteria
listed in sections 4.1 and 5.1. Dapoxetine tablets 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. Dapoxetine tablets should not be used in men with
erectile dysfunction (ED) who are using PDE5 inhibitors (see section 4.5).
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 Dapoxetine tablets should be avoided.
Orthostatic hypotension has been reported in clinical trials. The prescriber should counsel the
patient in advance that if he experiences possibly prodromal symptoms, such as lightheadedness
soon after standing, he should immediately lie down so his head is lower than the rest of his body
or sit down with his head between his knees until the symptoms pass. The prescriber should also
inform the patient not to rise quickly after prolonged lying or sitting.
Suicide/suicidal thoughts
Antidepressants, including SSRIs, increased the risk compared to placebo of suicidal thinking and
suicidality in short-term studies in children and adolescents with Major Depressive Disorder and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality
with antidepressants compared to placebo in adults beyond age 24. In clinical trials with
Dapoxetine tablets 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 were
reported more frequently among patients treated with Dapoxetine tablets compared to placebo.
In the clinical trials, cases of syncope characterized as loss of consciousness, with bradycardia or
sinus 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 Dapoxetine tablets. Prescribers should counsel patients about the importance of maintaining
adequate hydration and about how to recognize prodromal signs and symptoms to decrease the
likelihood of serious injury associated with falls due to loss of consciousness. If the patient
experiences possibly prodromal symptoms, the patient should immediately lie down so his head is
lower than the rest of his body or sit down with his head between his knees until the symptoms pass,
and be cautioned to avoid situations where injury could result, including driving or operating
hazardous machinery, should syncope or other CNS effects occur (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 Dapoxetine tablets in combination with recreational drugs.
Recreational drugs with serotonergic activity such as ketamine, methylenedioxymethamphetamine
(MDMA) and lysergic acid diethylamide (LSD) may lead to potentially serious reactions if
combined with Dapoxetine tablets. These reactions include, but are not limited to, arrhythmia,
hyperthermia, and serotonin syndrome. Use of Dapoxetine tablets with recreational drugs with
sedative properties such as narcotics and benzodiazepines may further increase somnolence and
dizziness.
Ethanol
Patients should be advised not to use Dapoxetine tablets 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 Dapoxetine
tablets (see sections 4.5 and 4.7).

Medicinal products with vasodilatation properties
Dapoxetine tablets should be prescribed with caution in patients taking medicinal products with
vasodilatation properties (such as alpha adrenergic receptor antagonists and nitrates) due to possible
reduced 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
Dapoxetine tablets should not be used in patients with a history of mania/hypomania or bipolar
disorder and should be discontinued in any patient who develops symptoms of these disorders.
Seizure
Due to the potential of SSRIs to lower the seizure threshold, Dapoxetine tablets 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
Dapoxetine tablets 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
Dapoxetine tablets to rule out undiagnosed depressive disorders. Concomitant treatment of
Dapoxetine tablets with antidepressants, including SSRIs and SNRIs, is contraindicated (see section
4.3). Discontinuation of treatment for ongoing depression or anxiety in order to initiate Dapoxetine
tablets for the treatment of PE is not recommended. Dapoxetine tablets is not indicated for
psychiatric disorders and should not be used in men with these disorders, such as schizophrenia, or
in those suffering with co−morbid depression, as worsening of symptoms associated with depression
cannot be excluded. This could be the result of underlying psychiatric disorder or might be a result
of medicinal product therapy. Physicians should encourage patients to report any distressing
thoughts or feelings at any time and if signs and symptoms of depression develop during treatment,
Dapoxetine tablets should be discontinued.
Haemorrhage
There have been reports of bleeding abnormalities with SSRIs. Caution is advised in patients taking
Dapoxetine tablets , 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
Dapoxetine tablets 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 disorders
has been reported to result in the following symptoms: dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety,
confusion, headache, lethargy, emotional lability, insomnia and hypomania.
A double−blind clinical trial in subjects with PE designed to assess the withdrawal effects of 62 days
of daily or as needed dosing with 60 mg Dapoxetine tablets 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 Dapoxetine tablets has been associated with ocular effects such as mydriasis and eye
pain. Dapoxetine tablets should 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 synergistically to elevate blood pressure and evoke behavioural excitation. Therefore,
Dapoxetine tablets should not be used in combination with an MAOI, or within 14 days of
discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7
days after Dapoxetine tablets 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 Dapoxetine tablets that inhibit the
CYP2D6 isoenzyme appear to inhibit the metabolism of thioridazine and the resulting elevated
levels of thioridazine are expected to augment the prolongation of the QTc interval. Dapoxetine
tablets should not be used in combination with thioridazine or within 14 days of discontinuing
treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after
Dapoxetine tablets 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.
Dapoxetine tablets should not be used in combination with other SSRIs, MAOIs or other
serotonergic medicinal/herbal products or within 14 days of discontinuing treatment with these
medicinal/herbal products. Similarly, these medicinal/herbal products should not be administered
within 7 days after Dapoxetine tablets has been discontinued (see section 4.3).
CNS active medicinal products
The use of Dapoxetine tablets 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 Dapoxetine tablets 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 dapoxetine clearance.
CYP3A4 inhibitors
Potent CYP3A4 inhibitors. Administration of ketoconazole (200 mg twice daily for 7 days)
increased the 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 taken with potent CYP3A4 inhibitors.
The increases in the Cmax and AUC of the active fraction may be markedly increased in a part of
the population which lack a functional CYP2D6 enzyme, i.e., CYP2D6 poor metabolizers, or in
combination with potent inhibitors of CYP2D6.
Therefore, concomitant use of Dapoxetine tablets 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 and caution 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 unbound
dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by
approximately 50% and the AUC of the active fraction may be doubled if taken with potent
CYP2D6 inhibitors. These increases in the Cmax and AUC of the active fraction are similar to
those expected for CYP2D6 poor metabolizers and may result in a higher incidence and severity of
dose dependent adverse events (see section 4.4).
PDE5 inhibitors
Dapoxetine tablets should not be used in patients using PDE5 inhibitors due to possible reduced
orthostatic tolerance (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 Dapoxetine tablets with PDE5 inhibitors may result in orthostatic hypotension
(see section 4.4). The efficacy and safety of Dapoxetine tablets in patients with both premature
ejaculation and erectile dysfunction concomitantly treated with Dapoxetine tablets 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, Dapoxetine tablets 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 with
ethanol increased somnolence and significantly decreased self−rated alertness. Pharmacodynamic
measures of cognitive impairment (Digit Vigilance Speed, Digit Symbol Substitution Test) also
showed an additive effect when dapoxetine was coadministered with ethanol. Concomitant use of
alcohol and dapoxetine increases the chance or severity of adverse reactions such as dizziness,
drowsiness, slow reflexes, or altered judgment. Combining alcohol with dapoxetine may increase
these alcohol−related effects and may also enhance neurocardiogenic adverse events such as
syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to
avoid alcohol while taking Dapoxetine tablets (see sections 4.4 and 4.7).

Dapoxetine tablets 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.
 

Dapoxetine tablets has minor or moderate influence on the ability to drive and use machines.
Dizziness, disturbance in attention, syncope, blurred vision and somnolence have been reported in
subjects receiving dapoxetine in clinical trials. Therefore, patients should be warned to avoid
situations where injury could result, including driving or operating hazardous machinery.
Combining alcohol with dapoxetine may increase alcohol−related neurocognitive effects and may
also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of
accidental injury; therefore, patients should be advised to avoid alcohol while taking Dapoxetine
tablets (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 Dapoxetine tablets −treated subjects) and dizziness (1.2%
of Dapoxetine tablets −treated subjects).
Tabulated list of adverse reactions
The safety of Dapoxetine tablets was evaluated in 4224 subjects with premature ejaculation who
participated in five double−blind, placebo−controlled clinical trials. Of the 4224 subjects, 1616
received Dapoxetine tablets 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 medicinal productrelated.
The majority of cases occurred during the first 3 hours after dosing, after the first dose or
associated with study-related procedures in the clinical setting (such as blood draw and orthostatic
maneuvers and blood pressure measurements). Prodromal symptoms often preceded the syncope
(see section 4.4).
The occurrence of syncope and possibly prodromal symptoms appears dose dependent as
demonstrated by higher incidence among patients treated with higher than recommended doses in
Phase 3 clinical trials.
Orthostatic hypotension has been reported in clinical trials (see section 4.4).The frequency of
syncope characterized as loss of consciousness in the Dapoxetine tablets clinical development
program varied depending on the population studied and ranged from 0.06% (30 mg) to 0.23% (60
mg) for subjects enrolled in the Phase 3 placebo-controlled clinical trials to 0.64% (all doses
combined) for Phase 1 non-PE healthy volunteer studies.
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 disorders
has been reported to result in the following symptoms: dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety,
confusion, headache, lethargy, emotional lability, insomnia and hypomania.
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 daily dosing.

No case of overdose has been reported.
There were no unexpected adverse events in a clinical pharmacology study of Dapoxetine tablets
with daily doses up to 240 mg (two 120 mg doses given 3 hours apart). In general, symptoms of overdose with SSRIs include serotonin−mediated adverse reactions such as somnolence,
gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremor, agitation and
dizziness.
In cases of overdose, standard supportive measures should be adopted as required. Due to high
protein binding and large volume of distribution of dapoxetine hydrochloride, forced diuresis,
dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific
antidotes for Dapoxetine tablets 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 ejaculatory
pathway originates from a spinal reflex centre, mediated by the brain stem, which is influenced
initially by a number of nuclei in the brain (medial preoptic and paraventricular nuclei).
The mechanism of action of dapoxetine in premature ejaculation is presumed to be linked to the
inhibition of neuronal reuptake of serotonin and the subsequent potentiation of the
neurotransmitter's action at pre− and postsynaptic receptors.
In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level
within the lateral paragigantocellular nucleus (LPGi). Post ganglionic sympathetic fibers that
innervate the seminal vesicles, vas deferens, prostate, bulbourethral muscles and bladder neck
cause them to contract in a coordinated fashion to achieve ejaculation. Dapoxetine modulates this
ejaculatory reflex in rats.
Clinical efficacy and safety
The effectiveness of Dapoxetine tablets in the treatment of premature ejaculation has been
established in five double−blind, placebo−controlled clinical trials, in which a total of 6081
subjects were randomized. Subjects were 18 years of age or older and had a history of PE in the
majority of intercourse experiences in the 6−month period prior to enrolment. Premature
ejaculation was defined according to the DSM-IV diagnostic criteria: short ejaculatory time (an
intravaginal ejaculatory latency time [IELT; time from vaginal penetration to the moment of
intravaginal ejaculation] of ≤ 2 minutes measured using a stopwatch in four studies), poor control
over ejaculation, marked distress or interpersonal difficulty due to the condition.
Subjects with other forms of sexual dysfunction, including erectile dysfunction, or those using
other forms of pharmacotherapy for the treatment of PE were excluded from all studies.

Results of all randomized studies were consistent. Efficacy was demonstrated after 12 weeks of
treatment. One study enrolled patients both outside and within the EU and had a treatment duration
of 24 weeks. In the study, 1162 subjects were randomized, 385 to placebo, 388 to Dapoxetine
tablets 30 mg as needed, and 389 to Dapoxetine tablets 60 mg as needed. The mean and median
Average IELT at study end are presented in Table 2 below and the cumulative distribution of
subjects who achieved at least a specific level in Average IELT at study end are presented in Table
3 below. Other studies and pooled analysis of the data at Week 12 gave consistent results.

The magnitude of IELT prolongation was related to baseline IELT and was variable between
individual subjects. The clinical relevance of Dapoxetine tablets 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 Dapoxetine tablets 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 Dapoxetine tablets treatment effects is represented by treatment group for
the subject's Clinical Global Impression of Change (CGIC) outcome measure, in which patients were asked to compare their premature ejaculation from the start of the study, with response
options ranging from much better to much worse. At study end (Week 24), 28.4% (30 mg group)
and 35.5% (60 mg group) of subjects reported their condition to be “better” or “much better”,
compared to 14% for placebo, while 53.4% and 65.6% of subjects treated with dapoxetine 30 mg
and 60 mg, respectively, reported their condition to be at least “slightly better”, compared to
28.8% for placebo.

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. Dapoxetine tablets 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 oral administration.
Intact dapoxetine and dapoxetine−N−oxide were the major circulating moieties in the plasma. In
vitro binding and transporter studies show that dapoxetine−N−oxide is inactive. Additional
metabolites including desmethyldapoxetine and didesmethyldapoxetine account for less than 3% of
the total circulating drug –related materials in plasma. In vitro binding studies indicate that DED is
equipotent to dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of
dapoxetine (see section 5.1). The unbound exposures (AUC and Cmax) of DED are approximately
50% and 23%, respectively, of the unbound exposure of dapoxetine.
Elimination
The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged
active substance was not detected in the urine. Following oral administration, dapoxetine has an
initial (disposition) half-life of approximately 1.5 hours, with plasma levels less than 5% of peak concentrations by 24 hours post-dose, and a terminal half-life of approximately 19 hours. The
terminal half−life of DED is approximately 19 hours.
Pharmacokinetics in special populations
The metabolite DED contributes to the pharmacological effect of Dapoxetine tablets, particularly
when the exposure of DED is increased. Below, in some populations, the increase in active fraction
parameters is presented. This is the sum of the unbound exposure of dapoxetine and DED. DED is
equipotent to dapoxetine. The estimation assumes equal distribution of DED to the CNS but it is
unknown whether this is the case.
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 lower body 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 and healthy 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
subjects with mild (CrCL 50 to 80 mL/min), moderate (CrCL 30 to < 50 mL/min), and severe renal
impairment (CrCL < 30 mL/min) and in subjects with normal renal function (CrCL > 80 mL/min).
No clear trend for an increase in dapoxetine AUC with decreasing renal function was observed.
AUC in subjects with severe renal impairment was approximately 2-fold that of subjects with
normal renal function, although there are limited data in patients with severe renal impairment.
Dapoxetine pharmacokinetics have not been evaluated in patients requiring renal dialysis (see
sections 4.2 and 4.4).
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
Cmax and AUC of the active fraction were essentially unchanged and doubled, respectively.
In patients with severe hepatic impairment, the unbound Cmax of dapoxetine was decreased by 42%
but the unbound AUC was increased by approximately 223%. The Cmax and AUC of the active
fraction had similar changes (see sections 4.2 and 4.3).
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 Dapoxetine
tablets may be increased by approximately 46% at Cmax and by approximately 90% at AUC. This
increase may result in a higher incidence and severity of dose dependent adverse events (see section
4.2). The safety of Dapoxetine tablets in poor metabolizers of CYP2D6 is of particular concern with
concomitant administration of other medicinal products that may inhibit the metabolism of
dapoxetine such as moderate and potent CYP3A4 inhibitors (see sections 4.2 and 4.3).

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

 Lactose Monohydrate
 Microcrystalline Cellulose
 Croscarmellose Sodium
 Colloidal Silicon Dioxide
 Magnesium Stearate

 Opadry II Grey
 Purified Water

Not applicable.

36 Months

Do not store above 30 °C.
Keep out of reach and sight of children.

Immediate Container: Alu-PVC/PVDC Blister pack
Secondary Container: Carton & PIL

No special requirements.