Dapoxetine is a Western medicine. The common dosage form is tablets. It is used to treat male patients with premature ejaculation (PE) aged 18-64 who meet all of the following conditions: continuous or repeated ejaculation due to only minimal sexual stimulation before, during or shortly after the penis is inserted into the vagina, and before sexual satisfaction is achieved; significant personal distress or interpersonal communication difficulties caused by premature ejaculation (PE); poor ejaculation control ability.
Element
The main ingredient of this product is dapoxetine hydrochloride.
Characteristics
Dapoxetine hydrochloride tablets: gray film-coated tablets, appearing white or off-white after removing the coating.
Indications
This product is used to treat premature ejaculation (PE) in men aged 18 to 64 years who meet all of the following conditions:
1. Continuous or repeated ejaculation occurs before, during, or shortly after the penis penetrates the vagina, and before sexual satisfaction is achieved, due to only minimal sexual stimulation.
2. Significant personal distress or interpersonal communication difficulties caused by premature ejaculation (PE).
3. Poor ejaculation control ability.
Specification
Dapoxetine hydrochloride tablets: 30 mg.
Dosage
The usage and dosage of this product in different dosage forms and specifications may vary. Please read the specific drug instructions for use, or follow the doctor’s advice.
Dapoxetine Hydrochloride Tablets:
1. For oral administration, the tablet should be swallowed whole. Patients are advised to take the drug with at least a full glass of water. Patients should try to avoid injuries caused by prodromal symptoms such as syncope or dizziness.
2. Adult males (18-64 years old): The recommended first dose for all patients is 30 mg, which needs to be taken about 1-3 hours before sexual intercourse. If the effect after taking 30 mg is not satisfactory and the side effects are still within the acceptable range, the dose can be increased to the maximum recommended dose of 60 mg. The recommended maximum dose frequency is once every 24 hours. This product can be taken before or after meals (see [Pharmacokinetics]). If the doctor chooses this product to treat premature ejaculation, the risks and patient-reported benefits should be evaluated in the first 4 weeks after the use of this drug, or the patient’s risk-benefit balance should be evaluated after 6 treatment doses and a decision should be made whether to continue the treatment with this product.
3. Elderly (65 years and above): The safety and efficacy of this product in patients aged 65 years and above have not been evaluated. The main reason is that the data on the use of this product in this population is extremely limited (see the pharmacokinetics section).
4. Children and adolescents: This product is not for use in people under 18 years of age.
5. Patients with renal impairment: Patients with mild or moderate renal impairment do not need to adjust the dose of this product, but should take it with caution. This product is not recommended for patients with severe renal impairment (see the pharmacokinetics section).
6. Patients with liver damage: Patients with mild liver damage do not need to adjust the dose of this product; this product is contraindicated for use in patients with moderate and severe liver damage (Child-Pugh Class C patients) (see the pharmacokinetics section).
Adverse Reactions
Dapoxetine hydrochloride tablets: The safety of this product was evaluated in 6081 subjects with premature ejaculation who participated in 5 double-blind, placebo-controlled clinical trials. Among these evaluated subjects, 4222 subjects received treatment with this product: 1615 of them received 30 mg of this product as needed, and 2607 received 60 mg of this product, either as needed or once a day.
Syncope (characterized by loss of consciousness) has been reported in clinical trials and is considered to be drug related. Most cases occurred within 3 hours of dosing, after the first dose, or in conjunction with study-related procedures performed in the clinic (e.g., blood draws, upright maneuvers, and blood pressure measurements). Syncope is often preceded by prodromal symptoms.
Orthostatic hypotension has been reported in clinical trials.
The most common adverse drug reactions (≥5%) in clinical trials included headache, dizziness, nausea, diarrhea, insomnia, and fatigue. The most common events leading to discontinuation included nausea (2.2% of subjects treated with tamoxifen) and dizziness (1.2% of subjects treated with tamoxifen).
Adverse drug reactions reported in the long-term open-label extension clinical trial were consistent with those observed in the double-blind study, and no other adverse drug reactions were reported.
Taboo
1. It is forbidden to use in patients who are known to be allergic to dapoxetine hydrochloride or any excipients.
2. It is forbidden to use in patients with obvious cardiac pathological conditions, such as heart failure (NYHA II-IV), conduction abnormalities not treated with permanent pacemakers (grade 2 or 3 atrioventricular block or sick sinus syndrome), obvious myocardial ischemia and valvular disease.
3. This product cannot be used together with monoamine oxidase inhibitors (MAOIs), nor can it be used within 14 days after stopping monoamine oxidase inhibitor treatment. Similarly, monoamine oxidase inhibitors cannot be used within 7 days after stopping this product (see the drug interactions section).
4. This product cannot be used together with thioridazine, nor can it be used within 14 days after cessation of thioridazine treatment. Similarly, thioridazine cannot be taken within 7 days after discontinuation of this product (see the drug interactions section).
5. This product should not be used together with selective serotonin reuptake inhibitors [selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA)] or other drugs/herbal medicines with serotonin effects [such as L-tryptophan, triptans, tramadol, linezolid, lithium, Hypericum perforatum extract (Hypericum)], nor should it be taken within 14 days after discontinuation of these drugs/herbal medicines. Similarly, these drugs/herbal medicines should not be taken within 7 days after discontinuation of this product (see the drug interactions section).
6. It is contraindicated for patients who are taking strong cytochrome P4503A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nafinavir, and atazanavir at the same time.
7. It is prohibited to use in patients with moderate and severe liver damage.
Precautions
1. General precautions: This product is only for male patients with premature ejaculation. The safety of this product in men who do not suffer from premature ejaculation is not yet clear, and there is no data on the effect of this product in delaying ejaculation in this population. It is recommended that patients should not take this product at the same time as “entertainment drugs” because the effects are unknown and serious adverse events may occur.
2. Patients are advised not to take psychotropic drugs with stimulant effects while taking this product. Psychotropic drugs with serotonergic activity, such as ketamine, methylenedioxymethamphetamine and lysergic acid diethylamide, may cause serious adverse reactions if taken with this product. These adverse reactions include but are not limited to arrhythmia, hyperthermia, and serotonin syndrome. Taking sedative psychotropic drugs, such as narcotics and benzodiazepines, while taking this product may aggravate drowsiness and dizziness.
3. The simultaneous use of this product with alcohol may aggravate alcohol-related neurorecognition effects and may also aggravate neurocardiovascular adverse reactions (such as syncope), thereby increasing the risk of accidental injury; therefore, patients are advised to avoid taking alcohol when taking this product.
4. Using this product may cause fainting or dizziness.
5. Subjects with underlying cardiovascular disease did not participate in Phase III clinical trials. Patients with underlying organic cardiovascular disease (such as documented outflow tract obstruction, valvular heart disease, carotid artery stenosis, and coronary heart disease) have an increased risk of adverse cardiovascular reactions caused by syncope (cardiogenic syncope and syncope from other causes). There is not enough data to prove whether this increased risk can develop into the risk of vasovagal syncope in patients with underlying diseases.
6. Orthostatic hypotension has been reported in clinical trials. Prescribers should inform patients in advance that if possible prodromal symptoms occur (such as dizziness shortly after standing up), they should immediately lie down with their head lower than the rest of the body, or sit down and place their head between their knees until the symptoms disappear.
7. When taking moderate cytochrome P450 3A4 inhibitors such as erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil and diltiazem, the dosage of this product is limited to 30 mg and it is recommended to be used with caution.
8. Patients taking strong cytochrome P450 2D6 inhibitors or known cytochrome P450 2D6 poor metabolizers should be cautious when increasing the dose to 60 mg, as this may result in increased exposure and ultimately lead to a high incidence and severity of dose-dependent adverse reactions.
9. Short-term studies conducted in children and adolescents with severe depression and other mental illnesses have found that antidepressants (including selective serotonin reuptake inhibitors) can increase the risk of suicidal thinking and behavior compared with placebo. Short-term studies have not confirmed that antidepressants can increase the risk of suicidal behavior in adults over 24 years old compared with placebo. In clinical trials of this product for the treatment of premature ejaculation, no suicidal behavior with clear emergency treatment has occurred.
10. This product should not be used in patients with a history of mania/hypomania or bipolar disorder. At the same time, any patient who develops symptoms of the above diseases should discontinue use of this product.
11. Since selective serotonin reuptake inhibitors may lower the threshold of epilepsy, any patient who has an epileptic seizure should stop using this product. At the same time, patients with unstable epilepsy should avoid using this product. Patients whose epilepsy has been controlled should be closely monitored.
12. Children and adolescents: This product is not for use in people under 18 years of age.
13. Men with signs and symptoms of depression should be evaluated before taking this product to rule out undiagnosed depressive diseases. It is forbidden to take antidepressants at the same time, including selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. It is not recommended to interrupt the treatment of depression and anxiety to take this product to treat premature ejaculation. This product is not suitable for mental disorders and should not be used in male patients with mental illness (such as schizophrenia) or patients with mental illness and depression because it cannot be ruled out that depression-related symptoms may be aggravated. This may be the result of underlying mental illness, or it may be the result of drug treatment. Physicians should encourage patients to report any painful thoughts or feelings at any time, and if the signs and symptoms of depression worsen, they should stop taking this product.
14. There have been reports of bleeding abnormalities during treatment with selective serotonin reuptake inhibitors. Patients should be cautious when taking this product, especially those who are taking drugs known to affect platelet function (such as atypical antipsychotics and phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet drugs) or anticoagulants (such as warfarin), as well as patients with a history of bleeding or coagulation disorders.
15. This product is not recommended for patients with severe renal damage. Patients with mild or moderate renal damage should use this product with caution.
16. It has been reported that abrupt discontinuation of long-term selective serotonin reuptake inhibitor treatment for chronic depression can cause the following symptoms: anxious mood, irritability, excitement, dizziness, paresthesias (i.e. sensory confusions, such as electroconvulsive sensations), anxiety, confusion, headache, drowsiness, mood lability, insomnia and hypomania.
17. Like other selective serotonin reuptake inhibitors, the use of this product is associated with some eye reactions, such as pupil dilation and eye pain. Patients with increased intraocular pressure or at risk of angle-closure glaucoma should use this product with caution.
18. Please keep out of reach of children.
Pregnant and lactating women
1. Pregnant women: No evidence of teratogenicity, embryotoxicity or fetotoxicity was found when rats or rabbits received up to 100 mg/kg (rats) or 75 mg/kg (rabbits). Based on the limited observational data from the clinical trial database, there is no evidence that taking dapoxetine will affect the mother’s pregnancy. There are currently no adequate and well-controlled studies on pregnant women.
2. Breastfeeding women: It is not clear whether dapoxetine or its metabolites can be secreted in human milk.
Children’s medication
This product should not be used by people under 18 years of age.
Medication for the elderly
The safety and efficacy of this product in patients aged 65 years and above have not been evaluated, mainly because the data on the use of this product in this population are very limited.
Analysis of a single-dose clinical pharmacology study using 60 mg of dapoxetine hydrochloride showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly men and healthy young men.
Drug interactions
1. Possibility of interaction with monoamine oxidase inhibitors: Severe (sometimes fatal) reactions have been reported in patients taking a selective serotonin reuptake inhibitor plus a monoamine oxidase inhibitor (MAOI) at the same time. These reactions include hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs and changes in mental status, including extreme excitement and progression to delirium and coma. These reactions have also been reported in patients who recently discontinued a selective serotonin reuptake inhibitor and started treatment with a monoamine oxidase inhibitor. Some cases showed features similar to neuroleptic malignant syndrome. Data on the combination of selective serotonin reuptake inhibitors and monoamine oxidase inhibitors in animal models suggest that these drugs may have synergistic effects in increasing blood pressure and inducing behavioral excitement. Therefore, this product cannot be used in combination with monoamine oxidase inhibitors or within 14 days of stopping monoamine oxidase inhibitor treatment. Similarly, monoamine oxidase inhibitors cannot be used within 7 days of stopping this product (see contraindications).
2. Possibility of interaction with thioridazine: Thioridazine used alone can prolong the QTc interval, which is accompanied by severe ventricular arrhythmias. Some drugs that can inhibit the cytochrome P450 2D6 isoenzyme, such as this product, can inhibit the metabolism of thioridazine, resulting in an increase in thioridazine concentration, which will increase the prolongation of the QTc interval. This product cannot be used in combination with thioridazine, nor can it be used within 14 days after stopping thioridazine treatment. Similarly, thioridazine cannot be used within 7 days after stopping this product (see contraindications).
3. Drugs/herbal medicines with serotonin effects: Like other selective serotonin reuptake inhibitors, the combined use of this product with drugs/herbal medicines with serotonin effects (including monoamine oxidase inhibitors, L-tryptophan, triptans, tramadol, linezolid, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, lithium and Hypericum perforatum extract (Hypericum wilfordii)) may lead to the occurrence of serotonin effects. This product should not be used in combination with other selective serotonin reuptake inhibitors, monoamine oxidase inhibitors or other drugs/herbal medicines with serotonin-related effects, nor should it be taken within 14 days after discontinuation of these drugs/herbal medicines. Similarly, these drugs/herbal medicines should not be taken within 7 days after discontinuation of this product (see contraindications).
4. Central nervous system active drugs: The combination of this product with CNS active drugs has not been systematically evaluated in patients with premature ejaculation. Therefore, if this product needs to be used concomitantly with such drugs, patients should be treated with caution.
5. Effect of combined drugs on dapoxetine hydrochloride: In vitro studies conducted in human liver, kidney and intestinal microsomes have shown that dapoxetine is mainly metabolized by cytochrome P450 2D6, cytochrome P450 3A4 and flavin monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may reduce the clearance rate of dapoxetine.
6. Strong cytochrome P450 3A4 inhibitors: Ketoconazole (200 mg, twice a day for 7 days) can increase the Cmax and AUCinf of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the effects of free dapoxetine and demethyl dapoxetine, if a strong cytochrome P450 3A4 inhibitor is taken, the blood concentration of the active part (the sum of free dapoxetine and demethyl dapoxetine) may increase by about 25%, and the AUC may double. Such an increase will be obvious in some patients, mainly including those who lack the functional enzyme of cytochrome P450 2D6, that is, those who are poor metabolizers of cytochrome P450 2D6 or those who are taking strong cytochrome P450 2D6 inhibitors. Therefore, this product is contraindicated for patients who are taking ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nafinavir, atazanavir, etc. at the same time.
7. Strong inhibitors of cytochrome P450 2D6: When fluoxetine (60 mg/day for 7 days) is combined with dapoxetine (60 mg single dose), the Cmax and AUCinf of dapoxetine increase by 50% and 88%, respectively. Considering the effects of free dapoxetine and demethyl dapoxetine, if a strong inhibitor of cytochrome P450 2D6 is taken, the blood concentration of the active portion (the sum of free dapoxetine and demethyl dapoxetine) may increase by approximately 50%, and the AUC may double. This increase in the blood concentration and AUC of the active portion is similar to that expected in cytochrome P450 2D6 poor metabolizers, and may increase the incidence and severity of dose-dependent adverse events. Therefore, for patients taking strong inhibitors of cytochrome P450 2D6 and known cytochrome P450 2D6 poor metabolizers, careful consideration should be given when increasing the dose to 60 mg.
8. Phosphodiesterase type 5 inhibitors: A single-dose crossover study evaluated the pharmacokinetics of dapoxetine (60 mg) when used in combination with tadalafil (20 mg) and sildenafil (100 mg). Tadalafil does not affect the pharmacokinetics of dapoxetine. Sildenafil can slightly change the pharmacokinetics of dapoxetine (AUCinf increased by 22, Cmax increased by 4%), but this effect is not clinically significant. However, due to the possibility of reduced orthostatic tolerance, this product should be used with caution in patients who are currently taking phosphodiesterase type 5 inhibitors.
9. Tamsulosin: Patients who are receiving tamsulosin daily will not change the pharmacokinetics of tamsulosin if they take this product (single or multiple times) at the same time. Adding this product to tamsulosin will not lead to changes in orthostatic tolerance. The orthostatic effect of tamsulosin combined with this product 30 mg or 60 mg is no different from that of tamsulosin alone; however, due to the possibility of reduced orthostatic tolerance, this product should be used with caution in patients receiving α-adrenergic receptor antagonists.
10. Drugs metabolized by cytochrome P450 2D6: A single dose of 50 mg of desipramine followed by multiple doses of this product (60 mg/day for 6 days) can increase the average Cmax and AUCinf of desipramine by approximately 11% and 19%, respectively, compared to desipramine alone. Dapoxetine can also increase the plasma concentration of drugs metabolized by cytochrome P450 2D6 to a similar degree. The clinical significance of this increase is small.
11. Drugs metabolized by cytochrome P450 3A: Multiple doses of this product (60 mg/day for 6 days) can reduce the AUCinf of midazolam (8 mg single dose) by approximately 20% (-60 to +18%). The clinical relevance of this effect of midazolam is small for most patients. The enhancement of cytochrome P450 3A activity may be clinically relevant for patients who are taking drugs that rely on cytochrome P450 3A metabolism and have a narrow therapeutic window.
12. Drugs metabolized by cytochrome P450 2C19: Multiple administration of this product (60 mg/day for 6 days) will not affect the pharmacokinetics of omeprazole (40 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other cytochrome P450 2C19 substrates.
13. Drugs metabolized by cytochrome P450 2C9: Multiple administration of this product (60 mg/day for 6 days) will not affect the pharmacokinetics and pharmacodynamics of glibenclamide (5 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other cytochrome P450 2C9 substrates.
14. Phosphodiesterase type 5 inhibitors: In a single-dose crossover study, dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) or sildenafil (100 mg).
15. Warfarin: There is currently no data to evaluate the effect of this product on long-term use of warfarin; therefore, this product should be used with caution in patients taking warfarin for a long time (see the precautions section). In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics and pharmacodynamics (PT or INR) of warfarin (single dose of 25 mg).
16. Alcohol: Consuming 0.5 g/kg of alcohol at the same time for a single dose will not affect the pharmacokinetics of dapoxetine (single dose of 60 mg) and alcohol; however, the combination of this product with alcohol can increase the incidence of dapoxetine and significantly reduce self-rated alertness. Pharmacodynamic measurements of cognitive impairment (digit alertness speed, digit symbol substitution test) also showed that there was no significant difference between alcohol or this product alone and placebo, but the combination of this product and alcohol was statistically significant compared with alcohol alone. The combination of alcohol and this product can increase the incidence or severity of the following adverse reactions: dizziness, drowsiness, slow reaction or change in judgment. The combination of alcohol and this product may also increase neurocardiovascular adverse reactions, such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol when taking this product.
Overdose
There were no reports of overdose during clinical trials.
In clinical pharmacology studies with up to 240 mg of this product per day (two 120 mg doses, 3 hours apart), no unexpected adverse events occurred. In general, symptoms of overdose of selective serotonin reuptake inhibitors include serotonin-mediated adverse reactions such as drowsiness, gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremors, excitement and dizziness.
In the event of an overdose, standard supportive measures should be taken as needed. Due to the high protein binding and large volume of distribution of dapoxetine hydrochloride, intensive diuresis, dialysis, hemoperfusion, and exchange transfusion therapy are unlikely to be effective. There is currently no specific antidote for this drug.
Pharmacological Action
The mechanism of action of dapoxetine in treating premature ejaculation may be related to its inhibition of the reabsorption of 5-hydroxytryptamine by neurons, thereby affecting the potential difference between the neurotransmitter acting on the pre- and post-synaptic receptors of the cell.
Human ejaculation is primarily mediated by the sympathetic nervous system. The reflex pathway for ejaculation originates from the spinal reflex center, which is mediated by the brainstem and is initially influenced by a number of brain nuclei (medial preoptic nucleus and inferior paraventricular nucleus). In rats, dapoxetine inhibits the ejaculation drive reflex by acting at the supraspinal level, of which the lateral paragigantocellular nucleus (LPGi) is an essential brain structure. Postganglionic sympathetic nerve fibers innervating the seminal vesicles, vas deferens, prostate, bulbar urethral muscles, and bladder neck enable the coordinated contraction of these organs to achieve ejaculation. Dapoxetine modulates this ejaculatory reflex in rats, thereby prolonging the latency of pudendal motor neuron reflex discharge (PMRD) and reducing the duration of PMRD.
Toxicological effects
In oral administration studies in rats, dapoxetine was not carcinogenic at doses up to 225 mg/kg/day daily for approximately two years, a dose that produced exposures approximately twice the exposure (AUC) observed in males receiving the recommended human dose (MRHD) of 60 mg. In Tg.rasH2 mice, dapoxetine did not cause tumors after administration at a potential dose of 100 mg/kg for 6 months and 200 mg/kg for 4 months. The steady-state exposure of 100 mg/kg of mice orally administered daily for 6 consecutive months is less than the exposure of a single clinical dose of 60 mg.
Tg.AC transgenic mice were topically dosed daily for 6 months at 375, 750, or 1500 mg/kg/day and some tumor initiator activity (papillomas at the administration site) was observed at 750 mg/kg/day or higher dose levels. Systemic drug exposures calculated as AUCs of dapoxetine and its major human metabolite were approximately 1 to 2 times the exposures observed in males receiving the recommended human dose (MRHD) of 60 mg. The local exposure model is not applicable to orally administered drug products.
Neither dapoxetine nor its major human metabolite was mutagenic in the in vitro bacterial Ames assay or in the forward mutation test in mouse lymphoma cells.Dapoxetine was not clastogenic in the in vitro chromosome aberration test in Chinese hamster ovary cells or in the in vitro mouse micronucleus assay.
Based on data from a two-year rat carcinogenicity study, a six-month Tg.rasH2 carcinogenicity study, and genetic toxicology studies, dapoxetine is not expected to present a carcinogenic hazard.
Dapoxetine did not affect fertility, reproductive function, or reproductive organ morphology in male or female rats, and did not cause adverse signs of embryotoxicity or fetotoxicity in rats or rabbits.
Pharmacokinetics
1. Absorption
After oral administration, dapoxetine is rapidly absorbed and reaches plasma concentration (Cmax) approximately 1-2 hours later. The bioavailability is 42% (range 15-76%). After a single oral dose of 30 mg and 60 mg dapoxetine in the fasting state, the peak plasma concentration is reached after 1.01 and 1.27 hours, respectively (297 ng/ml and 498 ng/ml, respectively).
Intake of a high-fat meal can moderately reduce the Cmax of dapoxetine (10%) and moderately increase the AUC (12%). At the same time, it can also slightly delay the time for dapoxetine to reach peak concentration; however, intake of a high-fat meal does not affect the degree of absorption. These changes are not clinically significant. This product can be taken with or without meals.
2. Distribution
In vitro, more than 99% of dapoxetine can bind to human serum proteins. The protein binding rate of the active metabolite demethyl dapoxetine is 98.5%. Dapoxetine can be distributed, and the average steady-state distribution volume is 162L. After intravenous administration to humans, the estimated average early, middle, and terminal half-lives of dapoxetine are 0.10, 2.19, and 19.3 hours, respectively.
3. Metabolism
In vitro studies have shown that dapoxetine can be cleared by multiple enzyme systems in the liver and kidneys, mainly cytochrome P450 2D6, cytochrome P450 3A4, and flavin-containing monooxygenase 1 (FMO1). In a clinical study observing the metabolism of 14C-dapoxetine, dapoxetine was extensively metabolized into a variety of metabolites after oral administration, mainly through the following biotransformation pathways: N-terminal oxidation, N-terminal demethylation, naphthyl hydroxylation, glucuronidation, and sulfation. There is evidence that first-pass metabolism occurs before absorption into the blood after oral administration.
Intact dapoxetine and dapoxetine-N-oxide are the major circulating forms in plasma. Other metabolites include desmethyl dapoxetine, which has an activity equal to that of dapoxetine, and bis-desmethyl dapoxetine, which has an activity approximately 50% that of dapoxetine. Considering the activity and unbound plasma concentrations, only desmethyl dapoxetine can increase the activity of dapoxetine in vivo.
4. Excretion
The metabolites of dapoxetine are eliminated primarily in the urine as conjugates. No parent active substance was detected in the urine. Dapoxetine is rapidly eliminated, as evidenced by low plasma concentrations 24 hours after administration (less than 5% of peak concentration). Dapoxetine has minimal drug accumulation with daily administration. The terminal half-life of oral administration is approximately 19 hours. The half-life of demethyl dapoxetine is similar to that of dapoxetine.
5. Pharmacokinetics in special populations
(1) Race
Analysis of clinical pharmacology studies using a single dose of 60 mg dapoxetine showed no statistically significant differences between whites, blacks, Hispanics, and Asians. A clinical study comparing the pharmacokinetics of dapoxetine in Japanese and white subjects showed that plasma concentrations (AUC and peak concentrations) of dapoxetine in Japanese subjects were 10% to 20% higher than those in white subjects due to their lower body weight. This slight increase in exposure is not expected to be clinically significant.
(2) Elderly people (65 years and above)
Analysis of clinical pharmacology studies using a single dose of 60 mg dapoxetine showed no significant differences in pharmacokinetic parameters (Cmax, AUCinf, Tmax) between healthy elderly men and healthy young men.
(3) Renal impairment
In a single-dose clinical pharmacology study using 60 mg of dapoxetine, no association was observed between creatinine clearance and dapoxetine Cmax or AUCinf in subjects with mild (creatinine clearance 50 to 80 mL/min), moderate (creatinine clearance 30 to <50 mL/min), and severe (creatinine clearance <30 mL/min) renal impairment. In all subjects, only a small portion (<1%) of dapoxetine was recovered in the urine in an intact form over a period of 3 to 4 days. No dose adjustment is required for patients with mild or moderate renal impairment when taking dapoxetine, but it should be used with caution. The pharmacokinetics of dapoxetine have not been evaluated in patients requiring renal dialysis. Data in patients with severe renal impairment are limited. Patients with severe renal impairment may have poor tolerability or greater variability in exposure; therefore, this product is not recommended for patients with severe renal impairment.
(4) Liver damage
In patients with mild hepatic impairment, the Cmax of free dapoxetine decreased by 28% while the free AUC did not change. The free Cmax and AUC of the active moiety (the total exposure of free dapoxetine and desmethyl dapoxetine) decreased by 30% and 5%, respectively. In patients with moderate hepatic impairment, the Cmax of free dapoxetine did not change substantially (decreased by 3%), while the free AUC increased by 66%. The free Cmax of the active moiety did not change substantially, while the free AUC doubled.
In patients with severe hepatic impairment, the free Cmax of dapoxetine decreased by 42%, but the free AUC increased by approximately 223%. Similar changes were observed in the Cmax and AUC of the active moiety (see Dosage and Administration and Contraindications).
(5) Cytochrome P450 2D6 (CYP2D6)
In a clinical pharmacology trial of a single dose of 60 mg of this product, the plasma concentrations of CYP2D6 poor metabolizers were higher than those of extensive metabolizers (dapoxetine’s Cmax was approximately 31% higher and AUCinf was approximately 36% higher; desmethyl dapoxetine’s Cmax was approximately 98% higher and AUCinf was approximately 161% higher). Therefore, the Cmax of the active portion of this product may increase by approximately 46% and the AUC by approximately 90%. This increase may lead to a higher incidence and severity of dose-related adverse events. The safety of dapoxetine in CYP2D6 poor metabolizers focuses on the concomitant use of other drugs that inhibit the metabolism of dapoxetine, such as neutral and strong inhibitors of CYP3A4. (See Dosage and Administration, Contraindications and Precautions)
Plasma concentrations of dapoxetine and desmethyldapoxetine would be expected to be decreased in rapid CYP2D6 metabolizers.
Storage method
Store at room temperature.
Validity
36 months
Implementation Standards
National Drug Administration standard YBH01162020.
Approval No.
National medicine approval number H20203169.