Agent for premature ejaculation shows no interactions with PDE-5 inhibitors

What is the satisfaction rate with dapoxetine?
How do I take Priligy, and how often?
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Volume 2, Issue 4
Possible Side Effects
Key Uses of Sildenafil and Dapoxetine Tablet
Why is Priligy priced so high?

What is the satisfaction rate with dapoxetine?

5HT1A receptors Stimulation of postsynaptic 5HT2C receptor by its agonist delays ejaculation Stimulation of somatodendritic 5HT1A receptors decreases ejaculation latency The Male SexualResponse Sexual Ejaculation Interest/ Orgasm Accompanied by Stimulation Orgasm Penile Penile Penetration tumescence Detumesence Plateau Resolution High arousal/ Erection Excitement Time Premature Ejaculation (PE)[ICD-10 F52.4] WHO 2nd International consultation on sexual health:- “Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it, over which the sufferer has little or no voluntary control, which causes the sufferer and/or his partner bother or distress” (Leu et al 2004) International Society for Sexual Medicine(ISSM) :- “ Male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within approximately 1 minute of vaginal penetration; the inability to delay ejaculation on all or nearly all vaginal penetration; and negative personal consequences such as distress, bother, frustration and/or the avoidance of sexual intimacy” Recent normative data suggest that men with an :- Intravaginal Ejaculatory Latency Time (IELT) less than 1 min have “definite PE” IELT between 1 and 1.5 min have “probable PE” (Waldiner, Zwinderman 2005) DSM IV TRDiagnostic criteria for PE A.

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Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it.

How do I take Priligy, and how often?

present in plasma after 24 hrs Dose dependant pharmacokinetics Metabolized by liver via glucuronidation, N- demethylation, N- oxidation & sulphation Enzymes CYT P 450 3A4, CYP2D6 are involved Metabolites excreted in urine Pharmacokinetics of singledose of dapoxetine and effect of food Dapoxetine 30 mg Dapoxetine 60 mg Cmax (ng/ml) 297 349 Tmax (h) 1.01 1.27 Initial T half 1.31 1.42 Terminal T half 18.7 21.0 Effect of high fat meal Cmax (fasted) - 443 Cmax (high fat meal) - 398 Tmax (h) (fasted) - 1.30 Tmax (h) buy cheap dapoxetine (high fat meal) - 1.83 Mechanism of action Dapoxetine ↑ 5HT Activation of neurotransmission 5HT2C Elevates ejaculatory threshold "set" point Delays Ejaculation Indian J Urol 2007;23:97-108 Pharmacodynamic profile Inhibit neuronal reuptake of serotonin Potentiation of neurotransmitter’s action at pre & post synaptic receptors Modulate ejaculatory expulsion reflex by elevating latency & reducing amplitude of pudendal motor neuron reflex discharge (Giuliano et al 2006) Not associated with clinically significant ECG changes Blood pressure, heart rate not affected Moderate to severe (Child Pugh class B & C) Drug interactions Co-administration of moderate or potent CYP3A4 inhibitor as erythromycin, fluconazole, verapamil, ketoconazole resulted in elevation in dapoxetin Cmax & AUC Concomitant potent CYP2D6 inhibitors results in higher incidence & severity of adverse events Concurrent fluoxetin, desipramine therapy also increases Cmax & AUC by 50% & 88% No clinically significant alteration of pharmacokinetics of dapoxetin with co administration of sildenafil/tadalafil. (caution-hypotension) Alcohol increased somnolence & reduced alertness Concomitant MAOI & SSRI/SNRI may result in serotonin related A/E Human clinical trials Phase 2 trials:- Two phase 2 randomized, placebo controlled, double blind, cross over designed studies Heterosexual men with PE diagnosed according to DSM IV criteria and a baseline IELT less than 2 mins. Study drug was administered 2 hrs prior to planned intercourse Primary efficacy measure was IELT measured by partner operated switch Result of dapoxetinephase 2 study (Hellstrom et al 2004) Age range (yrs)- 18-60 Inclusion IELT- less than 2 mins estimated Treatment period- 4 weeks/treatment Dapoxetine Dose 20 mg 40 mg Placebo (n=145) (n=141) (n=142) Mean baseline IELT 1.34 1.34 1.34 Mean treatment IELT 2.72 3.31 2.22 IELT fold increase 2 2.5 1.7 Discontinuation due to adverse 0 2 0 effect Result of dapoxetinephase 2 study (Hellstrom et al 2005) Age range (yrs)- 18-65 Inclusion IELT- less than 2 mins by stopwatch Treatment period- 2 weeks/treatment Dapoxetine Dose 60 mg 100 mg Placebo (n=144) (n=155) (n=145) Mean baseline IELT 1.01 1.01 1.01 Mean treatment IELT 2.86 3.24 2.07 IELT fold increase 2.9 3.2 2.0 Discontinuation due to 0 9 1 adverse effect Analysis Magnitude of effect of 20 mg dapoxetine on IELT was small Adverse events were dose dependant Most common AE were nausea, diarrhea headache, dizziness Overall 60 mg dose was better tolerated Most common reason of study withdrawal at dose 100 mg was nausea Based on these results 30, 60 mg dose were chosen for phase 3 study Phase 3 studies:- To present safety & efficacy data five randomized, double blinded, placebo controlled studies conducted in over 25 countries All studies enrolled heterosexual men & their partners who were more than 18 yrs age, in monogamous relationship and met DSMIV TR criteria for PE Study Description Treatmen Randomiz Inclusion criteria t duration ed subjects U.S.

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The clinician must take into account factors that affect duration of excitement phase, such as age, novelty of sexual partner or situation, and recent frequency of sexual activity.B.

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The disturbance causes dapoxetine sildenafil online marked distress or interpersonal difficulty.

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Possible Side Effects

A sense of general relaxation, wellbeing & Post coital dysphoria; post Resolution muscle relaxation coital headache PHYSIOLOGY OF EJACULATION Normal ante grade ejaculation:- 3 basic mechanism (Lipshultz 1981) (1) Emission:- Result of a sympathetic spinal cord reflex Initiated by genital/cerebral erotic stimuli Involves sequential contraction of accessory sexual organs (2) Ejection:- Involve bladder neck closure Rhythmic contraction of bulbocavernosus, bulbospongiosus and other pelvic floor muscles Relaxation of external urethral sphincter (Yeates 1987) (3) Orgasm:- Result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in posterior urethra, contraction of urethral bulb & accessory sexual Neurology of ejaculation Seminal emission & ejection are integrated by medial preoptic area(MPOA) and nucleus paragigantocellularis (nPGI) Descending serotonergic pathway from nPGI to lumbosacral motor nuclei tonically inhibit ejaculation (Yells 1992) Disinhibition of nPGI by MPOA facilitates ejaculation Lumbar spinothalamic neurons send projection to autonomic nuclei & motor neurons involved in emission and ejection, while they receive sensory projection from pelvis Neurobiology of ejaculation(Ahlenius 1981) Ejaculatory reflex is controlled by central serotonergic & dopaminegric neurons with secondary involvement of cholinergic, adrenergic, nitregic, oxytocinergic neurons Speed of ejaculation appears to be determined by 5HT2C & 5HT1A receptors Stimulation of postsynaptic 5HT2C receptor by its agonist delays ejaculation Stimulation of somatodendritic 5HT1A receptors decreases ejaculation latency The Male SexualResponse Sexual Ejaculation Interest/ Orgasm Accompanied by Stimulation Orgasm Penile Penile Penetration tumescence Detumesence Plateau Resolution High arousal/ Erection Excitement Time Premature Ejaculation (PE)[ICD-10 F52.4] WHO 2nd International consultation on sexual health:- “Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it, over which the sufferer has little or no voluntary control, which causes the sufferer and/or his partner bother or distress” (Leu et al 2004) International Society for Sexual Medicine(ISSM) :- “ Male sexual dysfunction characterized by ejaculation which always or nearly always occurs before or within approximately 1 minute of vaginal penetration; the inability to delay ejaculation on all or nearly all vaginal penetration; and negative personal consequences such as distress, bother, frustration and/or the avoidance of sexual intimacy” Recent normative data suggest that men with an :- Intravaginal Ejaculatory Latency Time (IELT) less than 1 min have “definite PE” IELT between 1 and 1.5 min have “probable PE” (Waldiner, Zwinderman 2005) DSM IV TRDiagnostic criteria for PE A. Persistent or recurrent ejaculation with minimal stimulation before, on, or shortly after penetration, and before the person wishes it. The clinician must take into account factors that affect duration of excitement phase, such as age, novelty of sexual partner or situation, and recent frequency of sexual activity.B. The disturbance causes dapoxetine sildenafil online marked distress or interpersonal difficulty. C.

CAS registry number (Chemical Abstracts Service)

The premature ejaculation is not due to exclusively to the direct effect of the substance (e.g., withdrawal from opioids) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response. Most cases are due to performance anxiety Etiology:- Combination of Psychogenic and Organic factor is presumed, with role of endocrinopathy, Peyronie disease & Prostatitis PE is a psychosomatic disturbance & due to over Biological anxious personality Young Genes age Cultural Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe most prevalent male sexual dysfunction (4-39% of men in general community) Distribution of IELT values in a random cohort of 491 men demonstrated median IELT of 5.4 min. (range 1-45 min) Median IELT decreased with age Median IELT varied between countries (Waldinger, Quinn 2005) In a study dapoxetine order online of 1326 men with PE:- lifelong PE was present in 74.4% men acquired PE was found in 25.6% men (McMohan 2002) Men with PE appear younger than those without. (Fasolo, Mirone 2005) No association found with HTN, Cardiac disease, Peripheral or central neuropathy MANAGEMENT OF PE Detailed medical & sexual history should be taken Physical examination Appropriate investigation Identify obvious biological causes as genital & urinary tract infection Treatment encompasses:- Behavioral aspect Pharmacological aspect Psychological aspect TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) Treatment PE cont’d Sensate focus: Tailor to clients, work on intimacy Sexual script change: Extend foreplay, modify rigid sex patterns, “partner first” Treatment aim: Restore IELT, address relationship issues, restore confidence Pharmacological management SSRIs has been used as off the label drugs for the treatment of PE for past 15 to 20 years utilizing its side effect delayed ejaculation as therapeutic effect Paroxetin, Fluoxetin, Sertraline, Cetalopram, Fluvoxamine and Clomipramine has revolutionized the approach to treat PE Yet daily dosing, long half life, accumulation of drug, gradual receptor desensitization and other side effects of long acting SSRIs were the drawbacks However lack of approved drug & total reliance on off Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol Dapoxetine, an SSRI is first oral pharmacological agent indicated for treatment of men aged 18- 64 years with PE Has been approved in various European countries, South America & Asia Pacific It is novel potent SSRI structurally similar to Fluoxetin Pharmacokinetics Oral formulation Rapidly absorbed Absolute bioavailability 42% Tmax of 1.4-2 hrs Cmax of 1.01-1.27 hrs Initial half life 1.3-1.5 hrs Terminal half life 15-19 hrs Steady state plasma conc. reaches in 4 days Rapid, biphasic elimination Less than 4% peak conc. The premature ejaculation is not due to exclusively to the direct effect of the substance (e.g., withdrawal from opioids) PE sub classification:- (Schapiro1943) Lifelong(Primary) PE :- Commences with onset of sexual activity Acquired(secondary) PE :- Develops following a period of normal ejaculatory response.

Drug Name	Class	Mechanism of Action	Common Uses
Dapoxetin	Selective Serotonin Reuptake Inhibitor (SSRI)	Increases serotonin levels in the brain	Premature ejaculation treatment
Sildenafil	Phosphodiesterase type 5 (PDE5) inhibitor	Enhances blood flow by relaxing smooth muscles	Erectile dysfunction
Tadalafil	PDE5 inhibitor	Longer duration of action compared to sildenafil	Erectile dysfunction, BPH
Dapoxetin	SSRI - Short-acting	Rapid onset for premature ejaculation	Premature ejaculation
Vardenafil	PDE5 inhibitor	Similar to sildenafil, rapid onset	Erectile dysfunction
Sildenafil	PDE5 inhibitor	Vasodilation effect on penile blood vessels	Erectile dysfunction

Most cases are due to performance anxiety Etiology:- Combination of Psychogenic and Organic factor is presumed, with role of endocrinopathy, Peyronie disease & Prostatitis PE is a psychosomatic disturbance & due to over Biological anxious personality Young Genes age Cultural Etiology of PrematureEjaculation Low 5HT Hyposensitivity of neurotransmission 5HT2C Ejaculatory threshold genetically "set" at a lower point Ejaculate quickly and with minimal stimulation Epidemiology:- PE isthe most prevalent male sexual dysfunction (4-39% of men in general community) Distribution of IELT values in a random cohort of 491 men demonstrated median IELT of 5.4 min.

Medication	Typical Dosage	Administration Time	Frequency
Dapoxetin	30 mg per dose	1-3 hours before sexual activity	Once daily or as needed
Sildenafil	50 mg, 100 mg, or 25 mg	30-60 minutes before activity	As needed, up to once daily
Tadalafil	10 mg, 20 mg, or 2.5 mg	30 minutes before activity	Once daily or as needed
Vardenafil	10 mg	25-60 minutes before activity	As needed
Dapoxetin	30 mg as a starting dose	1-3 hours before sexual activity	As needed

(range 1-45 min) Median IELT decreased with age Median IELT varied between countries (Waldinger, Quinn 2005) In a study dapoxetine order online of 1326 men with PE:- lifelong PE was present in 74.4% men acquired PE was found in 25.6% men (McMohan 2002) Men with PE appear younger than those without.

Documented case reports of adverse events exist in medical literature.
These often involve inappropriate use, overdose, or interaction with other drugs.
The medical community remains cautious about widely recommending this combo.
It is considered a second or third-line option after other treatments have failed.
Lifestyle modifications are always recommended as a first-line intervention.
Psychological therapies like CBT are effective for both PE and ED.
The placebo effect can play a significant role in the treatment of sexual dysfunction.
Clinical trials are always conducted with a placebo control group to account for this.
The subjective nature of the endpoints makes designing robust trials challenging.
Future research may provide clearer guidelines on the safe use of this combination.
For now, it remains a valuable but carefully considered tool for specialists.

(Fasolo, Mirone 2005) No association found with HTN, Cardiac disease, Peripheral or central neuropathy MANAGEMENT OF PE Detailed medical & sexual history should be taken Physical examination Appropriate investigation Identify obvious biological causes as genital & urinary tract infection Treatment encompasses:- Behavioral aspect Pharmacological aspect Psychological aspect TREATMENT OF PREMATURE EJACUALTION Incorporate into sexual practice Behavioural techniques - stop/start, squeeze Oral medication - SSRI, clomipramine, PDE5i Intra-cavernosal injections Anaesthetic cream Pelvic floor exercises Surgery to dorsal nerve (Brazil) Treatment PE cont’d Sensate focus: Tailor to clients, work on intimacy Sexual script change: Extend foreplay, modify rigid sex patterns, “partner first” Treatment aim: Restore IELT, address relationship issues, restore confidence Pharmacological management SSRIs has been used as off the label drugs for the treatment of PE for past 15 to 20 years utilizing its side

Key Uses of Sildenafil and Dapoxetine Tablet

Quá liều

effect delayed ejaculation as therapeutic effect Paroxetin, Fluoxetin, Sertraline, Cetalopram, Fluvoxamine and Clomipramine has revolutionized the approach to treat PE Yet daily dosing, long half life, accumulation of drug, gradual receptor desensitization and other side effects of long acting SSRIs were the drawbacks However lack of approved drug & total reliance on off Ejaculo-Selective Serotonin TransportInhibitor (ESSTIs) Drugs under investigation are Dapoxetine UK-390 UK-957 Tramadol Dapoxetine, an SSRI is first oral pharmacological agent indicated for treatment of men aged 18- 64 years with PE Has been approved in various European countries, South America & Asia Pacific It is novel potent SSRI structurally similar to Fluoxetin Pharmacokinetics Oral formulation Rapidly absorbed Absolute bioavailability 42% Tmax of 1.4-2 hrs Cmax of 1.01-1.27 hrs Initial half life 1.3-1.5 hrs Terminal half life 15-19 hrs Steady state plasma conc. reaches in 4 days Rapid, biphasic elimination Less than 4% peak conc.

Why is Priligy priced so high?

The volume of distribution and protein binding differ between the two drugs.
These pharmacokinetic parameters influence how the drugs are distributed in the body.
They do not significantly affect the practical on-demand dosing schedule for patients.
Patient information leaflets for each drug must be read and understood.
The leaflets contain crucial information about contraindications and warnings.
Patients should not hesitate to ask their doctor or pharmacist any questions.
Keeping a diary to note doses, timing, effects, and side effects can be helpful.
This diary can provide valuable information for the doctor at follow-up visits.
The treatment is not intended to be lifelong for every patient.
Periodic reassessment can determine if the treatment is still needed or effective.
Some men may find that confidence gained allows them to stop medication.

(caution-hypotension) Alcohol increased somnolence & reduced alertness Concomitant MAOI & SSRI/SNRI may result in serotonin related A/E Human clinical trials Phase 2 trials:- Two phase 2 randomized, placebo controlled, double blind, cross over designed studies Heterosexual men with PE diagnosed according to DSM IV criteria and a baseline IELT less than 2 mins.

The demographic most commonly prescribed this combination is middle-aged men.
However, it can be considered for adult men of any age after proper diagnosis.
Efficacy and safety in elderly patients (>65) have not been extensively studied.
Dosing for older patients usually starts at the lowest possible amounts.
Age-related decline in liver and kidney function affects drug metabolism.
Comorbid conditions are more common in older adults, increasing interaction risks.
The combination is not studied or used in men with spinal cord injuries.
It is also not indicated for men with anatomical deformities of the penis.
Penile implants or other surgical interventions are alternative options.
The field of sexual medicine is evolving, with new treatments constantly emerging.
This combination represents a pragmatic approach to a complex clinical problem.

Study drug was administered 2 hrs prior to planned intercourse Primary efficacy measure was IELT measured by partner operated switch Result of dapoxetinephase 2 study (Hellstrom et al 2004) Age range (yrs)- 18-60 Inclusion IELT- less than 2 mins estimated Treatment period- 4 weeks/treatment Dapoxetine Dose 20 mg 40 mg Placebo (n=145) (n=141) (n=142) Mean baseline IELT 1.34 1.34 1.34 Mean treatment IELT 2.72 3.31 2.22 IELT fold increase 2 2.5 1.7 Discontinuation due to adverse 0 2 0 effect Result of dapoxetinephase 2 study (Hellstrom et al 2005) Age range (yrs)- 18-65 Inclusion IELT- less than 2 mins by stopwatch Treatment period- 2 weeks/treatment Dapoxetine Dose 60 mg 100 mg Placebo (n=144) (n=155) (n=145) Mean baseline IELT 1.01 1.01 1.01 Mean treatment IELT 2.86 3.24 2.07 IELT fold increase 2.9 3.2 2.0 Discontinuation due to 0 9 1 adverse effect Analysis Magnitude of effect of 20 mg dapoxetine on IELT was small Adverse events were dose dependant Most common AE were nausea, diarrhea headache, dizziness Overall 60 mg dose was better tolerated Most common reason of study withdrawal at dose 100 mg was nausea Based on these results 30, 60 mg dose were chosen for phase 3 study Phase 3 studies:- To present safety & efficacy data five randomized, double blinded, placebo controlled studies conducted in over 25 countries All studies enrolled heterosexual men & their partners who were more than 18 yrs age, in monogamous relationship and met DSMIV TR criteria for PE Study Description Treatmen Randomiz Inclusion criteria t duration ed subjects U.S.

Condition	Dapoxetin	Sildenafil
Cardiovascular disease	Use cautiously	Contraindicated with nitrates
Use with MAO inhibitors	Avoid	Avoid
Liver impairment	Dose adjustment required	Use with caution
Eye Disorders (e.g., retinitis pigmentosa)	No specific caution	Caution due to rare visual disturbances
Medication interactions	Serotonergic drugs may increase risk of serotonin syndrome	Other vasodilators or antihypertensives