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Cardiovascular safety profile of dapoxetine during the premarketing evaluation.

Kowey PR, Mudumbi RV, Aquilina JW, DiBattiste PM - Drugs R D (2011)

Bottom Line: Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses.Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage.No other associated significant cardiovascular adverse events were identified.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Disease, Lankenau Hospital and Institute of Medical Research, Wynnewood, Pennsylvania 19096, USA. KoweyP@MLHS.ORG

ABSTRACT
The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses. Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30 mg and 60 mg as required). Events of syncope were reported during the clinical development program, with the majority occurring during study visits (on site) on day 1 following administration of the first dose when various procedures (e.g. orthostatic maneuvers, venipunctures) were performed, suggesting that the procedures contributed to the incidence of syncope. This was consistent with previous reports showing that these and similar factors contribute to or trigger vasovagal syncope. Findings of the dapoxetine development program demonstrate that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified.

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Incidence of orthostatic hypotension (JNC-7 criteriaa), shifts from baseline, and outliers at the time of first dose in three phase III studies
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Tab3: Incidence of orthostatic hypotension (JNC-7 criteriaa), shifts from baseline, and outliers at the time of first dose in three phase III studies

Mentions: The number and percentage of subjects with orthostatic hypotension, shifts from baseline, and outliers at the time of first dose are summarized in table III. There were small differences with orthostatic hypotension and orthostatic systolic BP after dosing on the first day, but these were not statistically different across the groups. Shift analysis for orthostatic hypotension and BP comparing pre- and post-dose incidence after dosing on the first day showed no notable or consistent differences between the placebo and dapoxetine groups. Additionally, evaluation of orthostatic BP changes after dosing by category/limits of change showed that the majority of subjects in all treatment groups had diastolic BP changes ≤10 mmHg and systolic BP changes of ≤20 mmHg, with no significant differences between the placebo and dapoxetine groups. These results indicated no evidence of an effect of dapoxetine on orthostatic blood pressure.


Cardiovascular safety profile of dapoxetine during the premarketing evaluation.

Kowey PR, Mudumbi RV, Aquilina JW, DiBattiste PM - Drugs R D (2011)

Incidence of orthostatic hypotension (JNC-7 criteriaa), shifts from baseline, and outliers at the time of first dose in three phase III studies
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585760&req=5

Tab3: Incidence of orthostatic hypotension (JNC-7 criteriaa), shifts from baseline, and outliers at the time of first dose in three phase III studies
Mentions: The number and percentage of subjects with orthostatic hypotension, shifts from baseline, and outliers at the time of first dose are summarized in table III. There were small differences with orthostatic hypotension and orthostatic systolic BP after dosing on the first day, but these were not statistically different across the groups. Shift analysis for orthostatic hypotension and BP comparing pre- and post-dose incidence after dosing on the first day showed no notable or consistent differences between the placebo and dapoxetine groups. Additionally, evaluation of orthostatic BP changes after dosing by category/limits of change showed that the majority of subjects in all treatment groups had diastolic BP changes ≤10 mmHg and systolic BP changes of ≤20 mmHg, with no significant differences between the placebo and dapoxetine groups. These results indicated no evidence of an effect of dapoxetine on orthostatic blood pressure.

Bottom Line: Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses.Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage.No other associated significant cardiovascular adverse events were identified.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Disease, Lankenau Hospital and Institute of Medical Research, Wynnewood, Pennsylvania 19096, USA. KoweyP@MLHS.ORG

ABSTRACT
The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses. Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30 mg and 60 mg as required). Events of syncope were reported during the clinical development program, with the majority occurring during study visits (on site) on day 1 following administration of the first dose when various procedures (e.g. orthostatic maneuvers, venipunctures) were performed, suggesting that the procedures contributed to the incidence of syncope. This was consistent with previous reports showing that these and similar factors contribute to or trigger vasovagal syncope. Findings of the dapoxetine development program demonstrate that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified.

Show MeSH
Related in: MedlinePlus