Date of approval.
Date of revision.
Dapoxetine Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician, this product can only be purchased with a prescription from a urologist or male doctor
Drug Name
Generic name: Dapoxetine Hydrochloride Tablets
English name: Dapoxetine Hydrochloride Tablets
Hanyu Pinyin: Yansuan Daboxiting Pian
Ingredients
The main ingredient of this product is dapoxetine hydrochloride.
Chemical name: (+)-(S)-N,N-dimethyl-(α)-[2-(1-naphthalenyloxy)ethyl]-benzenemethanamine hydrochloride
Chemical structure formula.
Molecular formula: C21H23NO-HCl
Molecular weight: 341.88
Properties
This product is a gray film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is indicated for the treatment of men aged 18 to 64 years with premature ejaculation (PE) who meet all of the following conditions.
-Persistent or repeated ejaculation before, during or shortly after vaginal penetration and before sexual satisfaction due to minimal sexual stimulation alone; and
-Significant personal distress or interpersonal difficulties due to premature ejaculation (PE); and
-Poor ejaculatory control.
【Specifications
According to C21H23NO (1) 30mg (2) 60mg
Dosage
Take orally. The tablets should be swallowed whole. Patients are advised to take the drug with at least one full glass of water. Patients should try to avoid injuries caused by prodromal symptoms such as syncope or dizziness.
Adult males (18 to 64 years of age)
The recommended initial dose for all patients is 30 mg, which needs to be taken approximately 1 to 3 hours prior to sexual intercourse. If the effect of 30mg is not satisfactory and the side effects are still within the acceptable range, the dose can be increased to the maximum recommended dose of 60mg.
This product can be taken before or after meals (see Pharmacokinetics section).
If a physician chooses to use this product for the treatment of premature ejaculation, the risk and patient-reported benefit should be evaluated during the first 4 weeks of treatment with this drug or after 6 therapeutic doses to assess the patient’s risk-benefit balance and decide whether to continue treatment with this product.
Elderly (65 years of age and older)
The safety and efficacy of this product has not been evaluated in patients 65 years of age and older, primarily because of the extremely limited data on its use in this population (see Pharmacokinetics section).
Children and Adolescents
This product is not intended for use in persons under 18 years of age.
Patients with Renal Injury
No dose adjustment is required when taking this product in patients with mild or moderate renal impairment, but it should be taken with caution. This product is not recommended for use in patients with severe kidney injury (see Pharmacokinetics section).
Patients with liver injury
No dose adjustment is required in patients with mild hepatic injury; this product is contraindicated in patients with moderate and severe hepatic injury (Child-Pugh Class C) (see Pharmacokinetics section).
[Adverse Reactions].
Clinical trial data
The safety of this product was evaluated in 6081 subjects with premature ejaculation who participated in five double-blind, placebo-controlled clinical trials. Of these evaluated subjects, 4222 were treated with this product: 1615 received 30 mg of this product as needed and 2607 received 60 mg of this product either as needed or as a once-daily dose.
Syncope (characterized by loss of consciousness) has been reported in clinical trials, and the event was considered drug-related. The majority of cases occurred within 3 hours of administration, after the initial dose, or in conjunction with study-related operations performed in the clinic (e.g., blood draws, upright movements, and blood pressure measurements). Syncope is often preceded by prodromal symptoms.
Upright hypotension has been reported in clinical trials.
The most common (≥5%) adverse drug reactions in clinical trials included headache, dizziness, nausea, diarrhea, insomnia, and fatigue. The most common events leading to discontinuation included nausea (2.2% in subjects in the treatment group) and vertigo (1.2% in subjects in the treatment group). Table 1 lists the adverse drug reactions that occurred in ≥1% of subjects in the treatment group in these trials.
Table 1: Adverse drug reactions with an incidence of ≥1% in subjects in the treatment arm of five double-blind, placebo-controlled clinical trials of this drug
System/Organ Classification
Adverse drug reactions Placebo
(n=1857)
% of this product
30 mg administered on demand
(n=1616)1
% Benadryl
60mg on-demand
(n=2106)1
% Benadryl
60 mg once daily2
(n=502)
%Check
Blood pressure increase3
0.2
0.4
1.1
2.2 Neurological disorders
Vertigo4
Headache
Drowsiness5
Tremors
Inattention
Abnormal sensation
2.2
4.8
0.6
0.2
0.5
0.3
5.8
5.6
3.1
0.5
0.4
0.4
11.0
8.8
4.8
0.9
0.8
0.8
14.9
11.2
4.0
1.6
2.6
1.2 Eye diseases
Blurred vision 6
0.4
0.2
0.6
2.0 Ear and vagus disorders
Tinnitus
0.4
0.2
0.5
1.2 Respiratory, thoracic and mediastinal disorders
Sinus congestion
Yawning
0.3
0
0.7
0.4
1.0
0.9
1.6
1.2 Gastrointestinal disorders
Nausea
Diarrhea7
Abdominal pain8
Dry mouth
Vomiting
Indigestion
Gastrointestinal distention
Constipation
Abdominal bloating
2.2
1.7
1.2
0.7
0.4
0.4
0.1
0.3
0.3
11.0
3.5
2.2
1.2
1.0
0.9
0.4
0.3
0.1
22.2
6.9
2.6
2.6
2.3
1.4
0.9
0.4
0.6
17.1
9.4
4.4
3.4
1.8
0.8
1.4
1.8
1.0 Skin and subcutaneous tissue disorders
Hyperhidrosis
0.2
0.8
1.2
3.0 Vascular disease
Flushing 9
0.3
0.9
1.3
1.4 Systemic diseases and drug administration site conditions
Fatigue
Irritability
1.2
0.8
2.0
0.1
4.1
1.1
9.2
3.6 Reproductive system and breast diseases
Erectile dysfunction
1.6
2.3
2.6
1.2 Psychiatric disorders
Insomnia 10
Anxiety
Hypersensitivity11
Decreased sex drive12
Depression13
Emotional indifference14
Abnormal dreams15
1.6
0.5
0.5
0.4
0.6
0.1
0.3
2.3
1.1
0.6
0.6
0.4
0.4
0.2
4.3
2.0
1.2
0.9
0.9
0.2
0.4
9.0
2.2
3.0
1.4
1.2
1.0
2.01 One patient no longer receiving treatment
2 Duration of treatment was up to 70 days
3 Also included elevated diastolic blood pressure and elevated blood pressure in the standing position
4 Also includes positional vertigo and exertional vertigo
5 Also includes hypersomnia and sudden onset of sleep
6 Also includes visual disturbances
7 Also includes urgency to defecate
8 Also includes epigastric pain, stomach discomfort, abdominal discomfort, and upper abdominal discomfort
9 Also includes hot flashes
10 Also includes intermediate insomnia and early insomnia
11 Also includes agitation and restlessness
12 Also includes lack of sexual desire
13 Also includes depressed affect
14 Also includes apathy
15 Also includes nightmares
Table 2 lists other adverse drug reactions with an incidence of <1% in subjects in the treatment group of this product.
Table 2: Adverse drug reactions with an incidence of <1% in subjects in the treatment arm of five double-blind, placebo-controlled clinical trials of this drug
System/Organ Classification
Adverse drug reactions Cardiac disease
Tachycardia1
Sinus bradycardia
Sinus arrest Neurological disorders
Decreased level of consciousness2
Abnormal taste sensation
Drowsiness
Syncope3
Inability to sit still Eye disorders
Dilated pupils
Eye pain Ear and vagus disorders
Vertigo Skin and subcutaneous tissue disorders
Pruritus
Cold sweat vascular disease
Hypotension
Systolic hypertension systemic disease and administration site conditions
Weakness
Abnormal sensation
Heat sensation
nervousness and anxiety
Sense of intoxication Reproductive and breast disorders
Inability to ejaculate
Male organ disorders4
Male genital sensory abnormalities Mental disorders
Euphoria
Mood changes
State of mental confusion
Sleep disorders
Teeth grinding disorder
Orientation disorder
Hyper-vigilance
Abnormal thinking1 also includes increased heart rate
2 Also includes sedated state
3 Also includes vasovagal syncope
4 Also includes sexual pleasure deficit (also from the systemic organ classification “mental illness”)
The adverse drug reactions reported in the long-term open extension clinical trial were consistent with those observed in the double-blind study, and no other adverse drug reactions were reported.
Contraindications
This product is contraindicated in patients with known hypersensitivity to dapoxetine hydrochloride or any of the excipients.
It is contraindicated in patients with significant cardiac pathology [e.g., heart failure (NYHA class II-IV), conduction abnormalities not treated with a permanent pacemaker (grade 2 or 3 atrioventricular block or sick sinus syndrome), significant myocardial ischemia and valvular disease].
This product should neither be used with monoamine oxidase inhibitors (MAOIs) nor within 14 days after discontinuation of monoamine oxidase inhibitor therapy. Similarly, monoamine oxidase inhibitors should not be used within 7 days after discontinuation of this product (see Drug Interactions section).
This product should not be used either with thioridazine or within 14 days of discontinuation of thioridazine therapy. Similarly, thioridazine should not be administered within 7 days of discontinuation of thioridazine (see Drug Interactions section).
This product should not be used with selective 5-hydroxytryptamine reuptake inhibitors [selective 5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA)] or other drugs/herbs with 5-hydroxytryptamine effects [e.g., L-tryptophan, traprotan, tramadol, linezolid, lithium, and onychomycin extract ( Goldenseal)] are co-administered, nor should they be taken within 14 days of discontinuation of these drugs/herbs. Likewise, these drugs/herbs should not be taken within 7 days of discontinuation of this product (see Drug Interactions section).
This product is contraindicated in patients taking concomitant strong cytochrome P450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nafenavir, and atazanavir.
This product is prohibited for use in patients with moderate and severe liver injury.
Precautions]
General Precautions
This product should be used only in men with premature ejaculation. The safety of this product in men who do not suffer from premature ejaculation is not known, and there are no data on the effect of this product on delaying ejaculation in this population.
Patients are advised not to take this product with “recreational drugs” because of the unknown effects and the potential for serious adverse events. Use of Increational Drugs
Patients are advised not to take this product together with psychoactive controlled substances. Psychotropic controlled substances with 5-hydroxytryptaminergic activity, such as ketamine, methylenedioxymethamphetamine, and lysergic acid diethylamide, may cause serious adverse reactions if taken concurrently with this product. These adverse reactions include, but are not limited to, cardiac arrhythmias, hyperthermia, and 5-hydroxytryptamine syndrome. Drowsiness and dizziness may be exacerbated by concomitant administration of sedative psychoactive controlled substances, such as narcotics and benzodiazepines.
Alcohol
The concomitant use of alcohol with this product may exacerbate alcohol-related neurological recognition effects and may also exacerbate neurocardiovascular adverse effects (e.g., syncope) and therefore increase the risk of unintentional injury; therefore, patients are advised to avoid taking alcohol while taking this product.
Syncope
The use of this product may cause syncope or dizziness.
In the clinical development program for this product, the incidence of syncope (characterized by loss of consciousness) varied with the study population, ranging from 0.06% (30 mg) to 0.23% (60 mg) of subjects in placebo-controlled Phase III clinical trials and 0.64% (including all doses) of subjects in Phase I clinical trials in healthy subjects with non-premature ejaculation ).
Possible prodromal symptoms such as nausea, dizziness and sweating were reported at a higher rate in the product group than in the placebo group. In the Phase 3 study, the incidence of nausea was 11%, dizziness was 5.8%, and sweating was 0.8% in patients receiving 30 mg of this product. In the Phase 3 study, the incidence of nausea was 21.2%, dizziness was 11.7%, and sweating was 1.5% in patients receiving 60 mg of this product. In addition, a higher incidence in the group receiving a higher dose than the recommended maximum daily dose of 60 mg demonstrated that the incidence of syncope and possible prodromal symptoms may be dose dependent.
The cases of syncope (characterized by loss of consciousness) observed in clinical trials were all considered to be vasovagal reflexes in terms of etiology, with the majority of cases occurring within 3 hours of dosing, after the first dose, or in conjunction with study-related operations performed in the clinic (e.g., blood draws, upright movements, and blood pressure measurements). Possible prodromal symptoms such as nausea, dizziness, lightheadedness, palpitations, weakness, confusion, and sweating generally occur within 3 hours of dosing and often precede syncope. Patients must be aware that they may experience syncope (with or without prodromal symptoms) at any time during treatment with this product. Prescribers should inform patients of the importance of maintaining adequate hydration and how to recognize prodromal signs and symptoms to reduce the likelihood of serious injury from a fall due to loss of consciousness. If a patient experiences possible prodromal symptoms, he or she should immediately lie down so that the head is lower than the rest of the body or sit down and place the head between the knees until the symptoms disappear, and should be warned to avoid situations that could cause injury if syncope or other central nervous system (CNS) effects occur, including driving or operating dangerous machinery.
Concomitant administration of alcohol with this product can increase the risk of unintentional injury by increasing the risk of neurocardiovascular adverse events such as syncope. Therefore, patients are advised not to take this product with alcohol.
Patients with cardiovascular risk factors
Subjects with underlying cardiovascular disease are not enrolled in Phase III clinical trials. Patients with underlying organic cardiovascular disease (e.g., with definite outflow tract obstruction, valvular heart disease, carotid stenosis, and coronary artery disease) have an increased risk of adverse cardiovascular reactions resulting from syncope (cardiogenic syncope and other causes of syncope). There are insufficient data to demonstrate whether this increased risk can be interpreted as a risk of vasovagal syncope in patients with underlying cardiovascular disease.
Other forms of sexual dysfunction
Prior to treatment, physicians should carefully examine patients for other forms of sexual dysfunction, including erectile dysfunction. This product should not be used in men with erectile dysfunction (ED) who are using PDE5 inhibitors (see [Drug Interactions]).
Orthostatic hypotension
Prior to initiating treatment, the prescribing physician should perform a careful physical examination of the patient, including a history of uprightness events. An uprightness response test (blood pressure and pulse in the lying and standing positions) should be performed prior to initiating therapy. If a history of uprightness reaction is established or suspected, the product should be avoided.
Upright hypotension has been reported in clinical trials. Prescribers should advise patients in advance that if they experience possible prodromal symptoms (e.g., dizziness shortly after standing up), they should immediately lie down so that their head is lower than the rest of the body or sit down and place their head between their knees until the symptoms disappear. Prescribers should also advise patients that they should not stand up quickly after prolonged lying or sitting down. In addition, caution should be exercised when prescribing this product for patients taking medications with vasodilating effects (e.g., alpha-adrenergic receptor antagonists, nitrates, phosphodiesterase type 5 (PDE5 inhibitors)) because of the potential for decreased standing tolerance.
Moderate cytochrome P450 3A4 inhibitors
Concomitant administration of moderate cytochrome P450 3A4 inhibitors, such as erythromycin, clarithromycin, fluconazole, amiprenavir, furosemivir, aripitant, verapamil, and diltiazem, is limited to a dose of 30 mg and is recommended with caution.
Strong cytochrome P450 2D6 inhibitors
Caution should be exercised when increasing the dose to 60 mg in patients taking concomitant strong cytochrome P450 2D6 inhibitors or known weak metabolizers of cytochrome P450 2D6, as this may result in increased exposure and may ultimately lead to a higher incidence and severity of dose-dependent adverse reactions.
Suicide/suicidal thinking
Short-term studies in children and adolescents with major depression and other psychiatric disorders have found that antidepressants (including selective 5-hydroxytryptamine reuptake inhibitors) can increase the risk of suicidal thinking and suicidal behavior compared to placebo. Short-term studies did not confirm that antidepressants increased the risk of suicidal behavior compared to placebo in adults over 24 years of age. In clinical trials of this product for premature ejaculation, there was no clear suicidal behavior in emergency treatment.
Mania
This product should not be used in patients with a history of mania/hypomania or bipolar disorder, and should be discontinued in any patient presenting with symptoms of these disorders.
Epilepsy
Because selective 5-hydroxytryptamine reuptake inhibitors may lower the threshold for seizures, this product should be discontinued in any patient presenting with seizures and should be avoided in patients with unstable epilepsy. Patients whose epilepsy has been controlled should be closely monitored.
Use in Children and Adolescents Under 18 Years of Age
This product should not be used in people under 18 years of age.
Comorbid depression and psychiatric disorders
Men with signs and symptoms of depression should be evaluated to rule out undiagnosed depressive disorders prior to administration of this product. Concomitant administration of antidepressants, including selective 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors, is prohibited. Interrupting treatment of depression and anxiety to take this product for premature ejaculation is not recommended. It is not indicated for psychiatric disorders and should not be used in men with psychiatric disorders (e.g., schizophrenia) or in patients with psychiatric disorders combined with depression because exacerbation of symptoms associated with depression cannot be ruled out. This may be the result of an underlying psychiatric disorder, or may be the result of medication. The physician should encourage the patient to report any distressing thoughts or feelings at any time and should discontinue the product if signs and symptoms of depression worsen.
Bleeding
Abnormal bleeding has been reported during treatment with selective 5-hydroxytryptamine reuptake inhibitors. Patients should exercise caution when taking this product, especially in patients taking concomitant medications known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet agents) or anticoagulants (e.g., warfarin), and in patients with a history of bleeding or coagulation disorders.
Renal injury
This product is not recommended for use in patients with severe renal impairment and should be used with caution in patients with mild or moderate renal impairment.
Discontinuation Effects
Abrupt discontinuation of long-term selective 5-hydroxytryptamine reuptake inhibitor therapy for chronic depression has been reported to result in the following symptoms: anxious state of mind, irritability, euphoria, dizziness, sensory abnormalities (i.e., sensory confusion, such as electroconvulsive perception), anxiety, confusion, headache, drowsiness, mood swings, insomnia, and light mania.
However, a double-blind clinical trial conducted in subjects with premature ejaculation to evaluate the discontinuation effects of 60 mg once daily or as-needed dosing for 62 days did not find a discontinuation syndrome, and the only evidence of withdrawal symptoms was a mild increase in the incidence of mild or moderate insomnia and dizziness in patients who switched to placebo after once-daily treatment with this drug. Consistent results were also obtained in a second double-blind clinical trial consisting of a 24-week 30- and 60-mg, as-needed dosing treatment period and a subsequent 1-week discontinuation evaluation period.
As with other selective 5-hydroxytryptamine reuptake inhibitors, the use of this product has been associated with a number of ocular reactions, such as pupil dilation and ocular pain. This product should be used with caution in patients with elevated intraocular pressure or at risk for angle-closure glaucoma. Keep out of the reach of children.
For Pregnant and Lactating Women
This product is not suitable for use in women.
Pregnancy
No evidence of teratogenicity, embryotoxicity or fetal toxicity has been found in rats or rabbits receiving up to 100 mg/kg (rats) or 75 mg/kg (rabbits) of this product.
Based on the limited observational data currently available from the clinical trials database, there is no evidence of maternal pregnancy effects associated with dapoxetine administration. A sufficient number of well-controlled studies in pregnant women have not been conducted.
Lactation
It is not known whether dapoxetine or its metabolites can be secreted in human milk.
Pediatric Use]
This product should not be used in people under 18 years of age.
Geriatric Use]
The safety and efficacy of this product has not been evaluated in patients 65 years of age and older, primarily because of the extremely limited data on the use of this product in this population.
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].
Potential for Interaction with Monoamine Oxidase Inhibitors
Serious (sometimes fatal) reactions have been reported in patients taking a selective 5-hydroxytryptamine reuptake inhibitor plus a monoamine oxidase inhibitor (MAOI), including hyperthermia, tonicity, myoclonus, autonomic instability with possible rapid fluctuations in vital signs, and altered mental status, including extreme euphoria that progresses to delirium and coma. These reactions have also been reported in patients who have recently discontinued a selective 5-hydroxytryptamine reuptake inhibitor and started treatment with a monoamine oxidase inhibitor. Some cases exhibit features similar to those of the malignant syndrome of nerve blockers. Data from the combined use of selective 5-hydroxytryptamine reuptake inhibitors and monoamine oxidase inhibitors in animal models suggest that these drugs may have synergistic effects in elevating blood pressure and inducing behavioral arousal. Therefore, this product should not be used in combination with monoamine oxidase inhibitors or within 14 days after discontinuation of monoamine oxidase inhibitor therapy. Similarly, monoamine oxidase inhibitors should not be used within 7 days after discontinuation of this product (see contraindications section).
Potential for Interaction with Thioridazine
Thioridazine alone may prolong the QTc interval, which is associated with severe ventricular arrhythmias. Some drugs that inhibit cytochrome P450 2D6 isoenzymes, such as this product, can inhibit the metabolism of thioridazine, leading to an increase in thioridazine concentration, which increases the prolongation of the QTc interval. This product should not be used in combination with thioridazine or within 14 days of stopping thioridazine therapy. Similarly, thioridazine should not be used within 7 days after discontinuation of thioridazine (see contraindications section).
Drugs/herbs with 5-hydroxytryptamine effects
As with other selective 5-hydroxytryptamine reuptake inhibitors, the combination of this product with drugs/herbs with 5-hydroxytryptamine effects (including monoamine oxidase inhibitors, L-tryptophan, treprostin, tramadol, linezolid, selective 5-hydroxytryptamine reuptake inhibitors, 5-hydroxytryptamine-norepinephrine reuptake inhibitors, lithium, and onychomycin extract (Hypericum perforatum)) may result in the development of 5- serotonin effects. This product should not be used in combination with other selective 5-hydroxytryptamine reuptake inhibitors, monoamine oxidase inhibitors, or other drugs/herbs with 5-hydroxytryptamine-related effects, nor should it be taken within 14 days of discontinuation of these drugs/herbs. Likewise, these drugs/herbs should not be taken within 7 days of discontinuation of the drug (see contraindications section).
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 concomitant use of this product with such drugs is required, patients should be treated with caution.
Effect of Combination Drugs on Dapoxetine Hydrochloride
In vitro studies in human liver, kidney and intestinal microsomes have shown that dapoxetine is metabolized primarily by cytochrome P450 2D6, cytochrome P450 3A4 and flavin-containing monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may reduce the clearance of dapoxetine.
Potent cytochrome P450 3A4 inhibitors
Ketoconazole (200 mg twice daily for 7 days) was able to increase the Cmax and AUCinf of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the effects of unconjugated dapoxetine and desmethyl dapoxetine, the maximum blood concentration of the active fraction (the sum of unconjugated dapoxetine and desmethyl dapoxetine) may be elevated by approximately 25% and the AUC may be doubled if a strong inhibitor of cytochrome P450 3A4 is administered. Such an increase may be significant in certain patients, including primarily those lacking the cytochrome P450 2D6 functional enzyme, i.e., weak metabolizers of cytochrome P450 2D6, or those co-administered with strong inhibitors of cytochrome P450 2D6.
Therefore, this product is contraindicated in patients taking concomitant ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nafenavir, atazanavir, etc.
Grapefruit juice is also a potent CYP3A4 inhibitor and should be avoided for 24 hours prior to taking this product (see [Contraindications]). Moderate cytochrome P450 3A4 inhibitors
Concomitant administration of moderate cytochrome P450 3A4 inhibitors, like erythromycin, clarithromycin, fluconazole, amiprenavir, furosemivir, aripitant, verapamil, and diltiazem, may also significantly increase exposure to dapoxetine and desmethyl dapoxetine, especially in weak metabolizers of cytochrome P450 2D6. Therefore, the maximum dose of this product taken in combination with any of these drugs is limited to 30 mg and is recommended with caution.
Potent inhibitors of cytochrome P450 2D6
When fluoxetine (60 mg/day for 7 days) was combined with dapoxetine (60 mg single dose), the Cmax and AUCinf of the latter were increased by 50% and 88%, respectively. Considering the effects of unconjugated dapoxetine and desmethyl dapoxetine, the maximum blood concentration of the active fraction (the sum of unconjugated dapoxetine and desmethyl dapoxetine) may be increased by approximately 50% and the AUC may be doubled if a strong inhibitor of cytochrome P450 2D6 is administered. This elevation in the maximum blood concentration and AUC of the active fraction is similar to that expected in weak metabolizers of cytochrome P450 2D6 and may increase the incidence and severity of dose-dependent adverse events. Therefore, careful consideration should be given to increasing the dose to 60 mg in patients taking potent inhibitors of cytochrome P450 2D6 and known weak metabolizers of cytochrome P450 2D6.
Type 5 phosphodiesterase inhibitors
This product should not be used in patients using type 5 phosphodiesterase inhibitors due to the potential for decreased stand-up tolerance. A single-dose crossover study evaluated the pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg). Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil can mildly alter the pharmacokinetics of dapoxetine (22% increase in AUCinf and 4% increase in Cmax), but this effect is not clinically significant.
Concomitant use of this product with a type 5 phosphodiesterase inhibitor may result in upright hypotension. The efficacy and safety of this product in patients with premature ejaculation and erectile dysfunction co-morbidities in combination with a type 5 phosphodiesterase inhibitor has not been established.
Effects of dapoxetine hydrochloride on co-administered drugs
Tamsulosin
Concomitant (single or multiple) doses of 30 mg or 60 mg of this product in patients receiving daily tamsulosin therapy do not alter the pharmacokinetics of tamsulosin. The addition of tamsulosin to tamsulosin does not result in a change in standing tolerance, and the standing effect of tamsulosin in combination with tamsulosin 30 mg or 60 mg is not different from that of tamsulosin alone; however, due to the potential for decreased standing tolerance, this product should be used with caution in patients receiving alpha-adrenergic receptor antagonist therapy.
Drugs metabolized by cytochrome P450 2D6
A single dose of 50 mg of dexipramine followed by multiple doses of this product (60 mg/day for 6 days) can increase the mean Cmax and AUCinf of dexipramine by approximately 11% and 19%, respectively, compared to dexipramine alone. Dapoxetine was also able to increase plasma concentrations of the drug metabolized by cytochrome P450 2D6 to a similar extent. This increase was of less clinical significance.
Drugs metabolized by cytochrome P450 3A4
Multiple doses of this drug (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 enhanced cytochrome P450 3A4 activity may be clinically relevant in patients who are also taking drugs that are dependent on cytochrome P450 3A4 metabolism and have a narrow therapeutic window.
Drugs metabolized by cytochrome P450 2C19
Multiple dosing of this product (60 mg/day for 6 days) does not affect the pharmacokinetics of omeprazole (40 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other cytochrome P450 2C19 substrates.
Drugs metabolized by cytochrome P450 2C9
Multiple administration of this product (60 mg/day for 6 days) does not affect the pharmacokinetics or pharmacodynamics of glibenclamide (5 mg single dose). Dapoxetine is unlikely to affect the pharmacokinetics of other cytochrome P450 2C9 substrates.
Type 5 phosphodiesterase inhibitors
In a single-dose crossover study, dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) or sildenafil (100 mg).
Warfarin
No data are available to evaluate the effect of this product on long-term warfarin administration; therefore, it should be used with caution in patients on long-term warfarin (see 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).
Alcohol
Single concomitant consumption of 0.5 g/kg of alcohol did not affect the pharmacokinetics of dapoxetine (60 mg single dose) and alcohol; however, the combination of this product with alcohol increased the incidence of drowsiness and significantly decreased self-rated alertness. Pharmacodynamic measures of cognitive impairment (numerical alertness speed, numerical symbol substitution test) also showed no significant difference between alcohol or this product alone compared to placebo, but a statistically significant difference between this product and alcohol in combination with alcohol compared to alcohol alone. The combination of alcohol and this product may increase the incidence or severity of the following adverse reactions: dizziness, drowsiness, slow response or altered judgment. The combination of alcohol with this product may also increase the risk of unintentional injury by increasing neurocardiovascular adverse reactions such as syncope; therefore, patients should be advised to avoid alcohol while taking this product.
[Drug Overdose].
No overdose has been reported during clinical trials.
In clinical pharmacology studies in which this product was administered at a maximum of 240 mg daily (two doses of 120 mg with a 3-hour interval), there were no unintended adverse events. In general, symptoms of selective 5-hydroxytryptamine reuptake inhibitor overdose include 5-hydroxytryptamine-mediated adverse reactions such as drowsiness, gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremors, euphoria, and vertigo.
In the case of overdose, standard supportive measures should be taken as needed. Intensive diuresis, dialysis, hemoperfusion and blood exchange therapy are unlikely to be effective due to the high protein binding and large volume of distribution of dapoxetine hydrochloride. There is no specific antidote for this product.
Pharmacology and Toxicology
Pharmacological effects
Dapoxetine is a potent selective 5-hydroxytryptamine reuptake inhibitor (SSRI) with an IC50 of 1.12nM and its major metabolites are equipotent (e.g. desmethyl dapoxetine (IC50 <1.0nM) and dimethyl dapoxetine (IC50=2.0nM)) or weak (e.g. methotrexate dapoxetine, IC50=282nM) to the original drug.
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, which is initially influenced by many brain nuclei (medial preoptic nucleus and inferior paraventricular nucleus).
The mechanism of action of dapoxetine in the treatment of premature ejaculation may be related to its inhibition of neuronal reuptake of 5-hydroxytryptamine, thereby enhancing the action of neurotransmitters at presynaptic and postsynaptic receptors.
In rats, dapoxetine inhibits the ejaculatory drive reflex by acting at the supraspinal level, where the lateral paracellular giant nucleus (LPGi) is an essential brain structure. Postganglionic sympathetic fibers that innervate the seminal vesicles, vas deferens, prostate, urethral bulb muscles, and bladder neck synergistically contract these organs to achieve ejaculation. Dapoxetine can modulate the ejaculatory reflex in rats.
Toxicological studies
Genotoxicity: Dapoxetine was negative in the Ames test, the in vitro mouse lymphoma tk test, the in vitro chromosome aberration test in Chinese hamster ovary cells, and the in vitro mouse micronucleus test.
Reproductive toxicity: Dapoxetine had no significant effect on fertility, reproductive function or morphology of reproductive organs in male and female rats, and no embryonic or fetal toxicity was observed in rats or rabbits.
Carcinogenicity: Dapoxetine given by gavage to rats at 225 mg/kg/day for 2 years (exposure approximately twice the maximum clinically indicated dose of 60 mg in males) was not shown to be carcinogenic. 200 mg/kg for 4 months did not lead to tumorigenesis.
Pharmacokinetics]
Absorption
After oral administration, dapoxetine is rapidly absorbed and reaches maximum plasma concentration (Cmax) in about 1-2 hours. The absolute bioavailability is 42% (range 15-76%). After a single oral dose of 30 mg and 60 mg of dapoxetine in the fasted state, peak plasma concentrations were reached after 1.01 and 1.27 hours, respectively (297 ng/ml and 498 ng/ml, respectively).
Intake of a high-fat diet modestly decreased the Cmax (10%) and modestly increased the AUC (12%) of dapoxetine, and also mildly delayed the time to peak dapoxetine concentration; however, intake of a high-fat diet did not affect the extent of absorption. None of these changes are clinically significant. This product may or may not be taken with or without a meal.
Distribution
In vitro, more than 99% of dapoxetine is bound to human serum proteins. The active metabolite, desmethyl dapoxetine, has a protein binding rate of 98.5%. Dapoxetine is rapidly distributed with a mean steady-state volume of distribution of 162 L. The estimated mean early, intermediate, and terminal half-lives of dapoxetine in humans following intravenous administration are 0.10, 2.19, and 19.3 hours, respectively.
Metabolism
In vitro studies have shown that dapoxetine is cleared by multiple enzyme systems in the liver and kidney, primarily cytochrome P450 2D6, cytochrome P450 3A4, and flavin-containing monooxygenase 1 (FMO1). In a clinical study looking at the metabolism of 14C-dapoxetine, dapoxetine was extensively metabolized after oral administration to a variety of metabolites, mainly through the following biotransformation pathways: N-terminal oxidation, N-terminal demethylation, naphthyl hydroxylation, glucosylation, and sulfation. There is evidence of first-pass metabolism prior to absorption into the bloodstream after oral administration.
Intact dapoxetine and dapoxetine-N-oxide are the major circulating forms in the plasma. Other metabolites include desmethyl dapoxetine, which has an activity equal to that of dapoxetine, and bis-desmethyl dapoxetine, which is approximately 50% as active as dapoxetine. Considering the activity and plasma unbound concentrations, only desmethyl dapoxetine increases the activity of dapoxetine in vivo.
Excretion
The metabolites of dapoxetine are mainly cleared by urine in the form of conjugates. No protoactive material was detected in the urine. Dapoxetine is rapidly cleared, as evidenced by low blood concentrations (less than 5% of peak concentration) 24 hours after administration. Drug accumulation with daily dapoxetine administration is minimal. The terminal half-life of orally administered dapoxetine is approximately 19 hours. The half-life of desmethyl dapoxetine is similar to that of dapoxetine.
Pharmacokinetics in Special Populations
Race
An 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 concentration) of dapoxetine were 10% to 20% higher in Japanese subjects than in white subjects due to the former’s lower body weight. This mild increase in exposure is not expected to be clinically significant.
Older adults (65 years and older)
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.
Renal impairment
In a single-dose clinical pharmacology study with 60 mg dapoxetine, no association was observed between creatinine clearance and dapoxetine Cmax or AUCinf were associated with each other. In all subjects, only a small percentage (<1%) of dapoxetine was able to be recovered from the urine in its complete form over a 3-4 day period. Patients with mild or moderate renal impairment do not require dose adjustment 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 be less well tolerated or have greater variability in exposure; therefore, it is not recommended for patients with severe renal impairment.
Hepatic Impairment
In patients with mild hepatic impairment, the Cmax of unconjugated dapoxetine was reduced by 28% while the AUC of unconjugated dapoxetine was unchanged. The Cmax and AUC of the unconjugated active fraction (defined as the total exposure of unconjugated dapoxetine and desmethyl dapoxetine) were reduced by 30% and 5%, respectively. In patients with moderate liver injury, there was no essential change in Cmax for unbound dapoxetine (3% decrease) and a 66% increase in AUC for unbound dapoxetine. There was no essential change in Cmax for the non-conjugated active fraction and a doubling of AUC for the non-conjugated active fraction.
In patients with severe liver injury, the Cmax of unconjugated dapoxetine was reduced by 42%, but the AUC of unconjugated dapoxetine was elevated by approximately 223%. Similar changes in Cmax and AUC were observed for the active fraction. (See Dosage and Contraindications)
Cytochrome P450 2D6 (CYP2D6)
In a clinical pharmacology trial with a single dose of 60 mg of this product, plasma concentrations were higher in CYP2D6 weak metabolizers than in pan-metabolizers (approximately 31% higher Cmax and 36% higher AUCinf for dapoxetine; approximately 98% higher Cmax and 161% higher AUCinf for desmethyl dapoxetine). Thus, the Cmax of the active portion of the drug may be approximately 46% higher and the AUC approximately 90% higher. This elevation may result in a higher incidence and severity of dose-related adverse events. The safety of dapoxetine in weak CYP2D6 metabolizers focuses on the concomitant administration of other drugs that would inhibit dapoxetine metabolism, like neutralizing strong inhibitors of CYP3A4. (See Dosage, Contraindications and Precautions)
Plasma concentrations of dapoxetine and desmethyl dapoxetine are expected to decrease in CYP2D6 fast metabolizers.
Storage】Store at room temperature.
Package】Aluminum-plastic blister package: 3 tablets/plate, 2 plates/box.
Expiration date】24 months
【Execution standard
Approval number】
[Drug Marketing Authorization Holder
Holder Name: Shenzhen Xinlitai Pharmaceutical Co.
Registered address: 37th Floor, Main Building, Chegongmiao Greenview Plaza, No. 6009 Shennan Avenue, Futian District, Shenzhen
Telephone number: (0755) 83867888
Fax number: (0755) 83867338
Website: www.salubris.com
Manufacturer
Company name: Shenzhen Xinlitai Pharmaceutical Co.
Address: No. 1, Planning Road 5, Longtian Street Industrial Zone, Pingshan District, Shenzhen
Postal code: 518118
Telephone number: (0755) 83867888
Fax number: (0755) 83867338
Website: www.salubris.com