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DAPOXEM 30/ 60 (Dapoxetine film-coated tablets 30 mg/ 60 mg)

DAPOXEM 30/ 60 (Dapoxetine film-coated tablets 30 mg/ 60 mg)

Pharmacotherapeutic group: Other Urologicals, ATC code: G04BX14

Dapoxetine is a potent selective serotonin reuptake inhibitor (SSRI) with an IC50of 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.

DAPOXEM Therapeutic indications

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.

DAPOXEM Posology and method of administration

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.

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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.

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 patients age 65 years and over.

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.

Patients with hepatic impairment: Dapoxetine Tablets is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C).

Known CYP2D6 poor metabolizers or patients treated with potent CYP2D6 inhibitors: Caution is advised if increasing the dose to 60 mg in patients known to be of CYP2D6 poor metabolizer genotype or in patients concomitantly treated with potent CYP2D6 inhibitors.

Patients treated with moderate or potent inhibitors of CYP3A4: Concomitant use of potent CYP3A4 inhibitors is contraindicated. The dose should be restricted to 30 mg in patients concomitantly treated with moderate CYP3A4 inhibitors and caution is advised.

DAPOXEM 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.

DAPOXEM Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Significant pathological cardiac conditions such as:

  • Heart failure (NYHA class II-IV)
  • Conduction abnormalities 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.

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.

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., Ltryptophan, 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.

Concomitant treatment of potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazadone, nelfinavir, atazanavir, etc.

Moderate and severe hepatic impairment.

DAPOXEM Special warnings and precautions for use

Dapoxetine Tablets is only indicated in men with Premature Ejaculation. 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.

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.

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.

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.

Eye disorders:

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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.

DAPOXEM Effects on ability to drive and use machines

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.

DAPOXEM Undesirable effects

Syncope and orthostatic hypotension have been reported in clinical trials.

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).

DAPOXEM Overdose

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.

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