Pharmacodynamic Interactions: Potential for Interaction with Monoamine Oxidase Inhibitors: In patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on a MAOI. Some cases 7 presented with features resembling neuroleptic malignant syndrome. Animal data on the effects of combined use of an SSRI and MAOIs suggest that these medicinal products may act synergistically to elevate blood pressure and evoke behavioural excitation. Therefore, Priligy should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI. Similarly, a MAOI should not be administered within 7 days after Priligy has been discontinued (see Contraindications).
Potential for Interaction with Thioridazine: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias. Medicinal products such as Priligy that inhibit the CYP2D6 isoenzyme appear to inhibit the metabolism of thioridazine and the resulting elevated levels of thioridazine are expected to augment the prolongation of the QTc interval. Priligy should not be used in combination with thioridazine or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after Priligy has been discontinued (see Contraindications).
Medicinal/Herbal Products with Serotonergic Effects: As with other SSRIs, co-administration with serotonergic medicinal/herbal products [including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium and St. John's Wort (Hypericum perforatum) preparations] may lead to an incidence of serotonin associated effects. Priligy should not be used in combination with other SSRIs, MAOIs or other serotonergic medicinal/herbal products or within 14 days of discontinuing treatment with these medicinal/herbal products. Similarly, these medicinal/herbal products should not be administered within 7 days after Priligy has been discontinued (see Contraindications).
CNS Active Medicinal Products: The use of Priligy in combination with CNS active medicinal products (e.g., antiepileptics, antidepressants, antipsychotics, anxiolytics, sedative hypnotics) has not been systematically evaluated in patients with premature ejaculation. Consequently, caution is advised if the concomitant administration of Priligy and such medicinal products is required.
Pharmacokinetic Interactions: Effects of Co-Administered Medicinal Products on the Pharmacokinetics of Dapoxetine: In vitro studies in human liver, kidney, and intestinal microsomes indicate dapoxetine is metabolized primarily by CYP2D6, CYP3A4 and flavin monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may reduce dapoxetine clearance.
CYP3A4 Inhibitors: Potent CYP3A4 inhibitors. Administration of ketoconazole (200 mg twice daily for 7 days) increased the Cmax and AUCinf of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 25% and the AUC of the active fraction may be doubled if taken with potent CYP3A4 inhibitors.
The increases in the Cmax and AUC of the active fraction may be markedly increased in a part of the population which lack a functional CYP2D6 enzyme, i.e., CYP2D6 poor metabolizers, or in combination with potent inhibitors of CYP2D6.
Therefore, concomitant use of Priligy and potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir, is contraindicated (see Contraindications).
Moderate CYP3A4 inhibitors. Concomitant treatment with moderate CYP3A4 inhibitors (e.g., erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also give rise to significantly increased exposure of dapoxetine and desmethyldapoxetine, especially in CYP2D6 poor metabolizers. The maximum dose of dapoxetine should be 30 mg if dapoxetine is combined with any of these drugs (see Dosage & Administration, Precautions and text as follows).
These two measures apply to all patients unless the patient has been verified to be a CYP2D6 extensive metabolizer by geno- or phenotyping. In patients verified to be CYP2D6 extensive metabolizers, a maximum dose of 30 mg is advised if dapoxetine is combined with a potent CYP3A4 inhibitor and caution is advised if dapoxetine in 60 mg doses is taken concomitantly with a moderate CYP3A4 inhibitor.
Potent CYP2D6 Inhibitors: The Cmax and AUCinf of dapoxetine (60 mg single dose) increased by 50% and 88%, respectively, in the presence of fluoxetine (60 mg/day for 7 days). Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 50% and the AUC of the active fraction may be doubled if taken with potent CYP2D6 inhibitors. These increases in the Cmax and AUC of the active fraction are similar to those expected for CYP2D6 poor metabolizers and may result in a higher incidence and severity of dose dependent adverse events (see Precautions).
PDE5 Inhibitors: Priligy should not be used in patients using PDE5 inhibitors due to possible reduced orthostatic tolerance (see Precautions). The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were evaluated in a single dose crossover study. Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused slight changes in dapoxetine pharmacokinetics (22% increase in AUCinf and 4% increase in Cmax), which are not expected to be clinically significant.
Concomitant use of Priligy with PDE5 inhibitors may result in orthostatic hypotension (see Precautions). The efficacy and safety of Priligy in patients with both premature ejaculation and erectile dysfunction concomitantly treated with Priligy and PDE5 inhibitors has not been established.
Effects of Dapoxetine on the Pharmacokinetics of Co-Administered Medicinal Products: Tamsulosin: Concomitant administration of single or multiple doses of 30 mg or 60 mg dapoxetine to patients receiving daily doses of tamsulosin did not result in changes in the pharmacokinetics of tamsulosin. The addition of dapoxetine to tamsulosin did not result in a change in the orthostatic profile and there were no differences in orthostatic effects between tamsulosin combined with either 30 or 60 mg dapoxetine and tamsulosin alone; however, Priligy should be prescribed with caution in patients who use alpha adrenergic receptor antagonists due to possible reduced orthostatic tolerance (see Precautions).
Medicinal products metabolized by CYP2D6: Multiple doses of dapoxetine (60 mg/day for 6 days) followed by a single 50 mg dose of desipramine increased the mean Cmax and AUCinf of desipramine by approximately 11% and 19%, respectively, compared to desipramine administered alone. Dapoxetine may give rise to a similar increase in the plasma concentrations of other drugs metabolized by CYP2D6. The clinical relevance is likely to be small.
Medicinal Products Metabolized by CYP3A4: Multiple dosing of dapoxetine (60 mg/day for 6 days) decreased the AUCinf of midazolam (8 mg single dose) by approximately 20% (range -60 to +18%). The clinical relevance of the effect on midazolam is likely to be small in most patients. The increase in CYP3A activity may be of clinical relevance in some individuals concomitantly treated with a medicinal product mainly metabolized by CYP3A and with a narrow therapeutic window.
Medicinal Products Metabolized by CYP2C19: Multiple dosing of dapoxetine (60 mg/day for 6 days) did not inhibit the metabolism of a single 40 mg dose of omeprazole. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.
Medicinal Products Metabolized by CYP2C9: Multiple dosing of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of a single 5 mg dose of glyburide. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.
Warfarin and Medicinal Products that Are Known to Affect Coagulation and/or Platelet Function: There are no data evaluating the effect of chronic use of warfarin with dapoxetine; therefore, caution is advised when dapoxetine is used in patients taking warfarin chronically (see Precautions). In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics (PT or INR) of warfarin following a single 25 mg dose. There have been reports of bleeding abnormalities with SSRIs (see Precautions).
Ethanol: Coadministration of a single dose of ethanol, 0.5 g/kg (approximately 2 drinks), did not affect the pharmacokinetics of dapoxetine (60 mg single dose); however, dapoxetine in combination with ethanol increased somnolence and significantly decreased self-rated alertness. Pharmacodynamic measures of cognitive impairment (Digit Vigilance Speed, Digit Symbol Substitution Test) also showed an additive effect when dapoxetine was coadministered with ethanol. Concomitant use of alcohol and dapoxetine increases the chance or severity of adverse reactions such as dizziness, drowsiness, slow reflexes, or altered judgment. Combining alcohol with dapoxetine may increase these alcohol-related effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking Priligy (see Precautions).