Zileuton
Sildenafil (Viagra) Interactions
NOTE: Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors.
Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates. Deaths have been reported in men who were using sildenafil while taking nitrate or nitrite therapy for angina. Sildenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.
Coadministration of sildenafil, tadalafil or vardenafil and other organic nitrates has been shown to potentiate the hypotensive effects of nitrates; concomitant administration of these drugs for erectile dysfunction with nitrates is contraindicated. Many methscopolamine-containing products list methscopolamine nitrate as the ingredient. Therefore, the concomitant use of sildenafil, tadalafil or vardenafil and products which contain methscopolamine nitrate is not recommended.
Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Cimetidine is a known inhibitor of hepatic CYP enzymes and reduces the metabolism of sildenafil. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population data from patients in clinical trials also indicate a reduction in sildenafil clearance when it was coadministered with cimetidine. If possible, cimetidine use should be avoided in patients who take sildenafil.
Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Anti-retroviral agents, such as anti-retroviral protease inhibitors, delavirdine, or efavirenz may reduce sildenafil clearance and result in an increase in sildenafil-induced adverse effects, including hypotension, visual changes, and priapism. In a study performed in healthy male volunteers, coadministration of saquinavir resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. In a small pharmacokinetic study, the coadministration of sildenafil and indinavir resulted in markedly increased AUC values for sildenafil (340% increase) as compared to historical controls. Particular caution should also be used when coadministering sildenafil and ritonavir; coadministration of ritonavir with sildenafil is expected to substantially increase sildenafil concentrations (up to an 11-fold increase in AUC). The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors (see Dosage). The dose of sildenafil should not exceed 25 mg in a 48-hour period when given concurrently with any of these agents.
Sildenafil is metabolized principally by the hepatic cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) isoenzymes. Inhibitors of these isoenzymes may reduce sildenafil clearance. Increased systemic exposure to sildenafil may result in an increase in sildenafil-induced adverse effects. The manufacturer recommends dosage reduction in patients receiving potent cytochrome CYP3A4 inhibitors such as erythromycin, ritonavir, ketoconazole, itraconazole, and saquinavir (see Dosage). When a single 100 mg dose of sildenafil is administered with erythromycin (500 mg bid for 5 days), a specific CYP3A4 inhibitor, at steady state, there is a 182% increase in sildenafil systemic exposure (AUC). More potent CYP3A4 inhibitors such as itraconazole, ketoconazole, or mibefradil would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors. Other inhibitors of CYP3A4 may reduce the clearance of sildenafil, however, no interaction studies have been performed. Other CYP3A4 inhibitors include: aprepitant, conivaptan, diltiazem, imatinib, STI-571, fluconazole, fluoxetine, fluvoxamine, nefazodone, other macrolide antibiotics (clarithromycin and troleandomycin ), quinidine, ranolazine, sparfloxacin, verapamil, voriconazole, zafirlukast, and zileuton. This list is not inclusive of all medications that may inhibit CYP3A4. In vivo studies of healthy male volunteers show no clinically significant effect of azithromycin (500 mg PO daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.
Sildenafil is metabolized principally by cytochrome P450 (CYP) 3A4 (major route) and 2C9 (minor route) enzymes. In healthy subjects, coadministration of multiple doses of 125 mg twice daily bosentan with 80 mg three times daily sildenafil has resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. Dosage adjustment for this interaction is not needed for bosentan or sildenafil (including when used to treat pulmonary arterial hypertension or erectile dysfunction). It can be expected that concomitant administration of sildenafil with other CYP3A4 enzyme inducers will decrease plasma concentrations of sildenafil. CYP3A4 inducers may include, but are not limited to: barbiturates, carbamazepine, dexamethasone, phenytoin, fosphenytoin, nevirapine, rifabutin, rifampin, and troglitazone.
Sildenafil is metabolized through CYP3A4 and may cause adverse effects if its metabolism is altered by other agents that are substrates for CYP3A4, like cisapride. Sildenafil is also a weak inhibitor of CYP3A4 and thus, could increase serum cisapride concentrations. Avoid concurrent sildenafil and cisapride use, as QT prolongation and other cardiac arrhythmias could occur.
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µ M). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes. No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Sildenafil 50 mg did not potentiate the increase in bleeding time caused by aspirin, ASA 150 mg. In vitro studies with human platelets indicate, however, that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).
Sildenafil 50 mg did not potentiate the hypotensive effect of ethanol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
No interaction was seen when sildenafil 100 mg was coadministered with amlodipine in hypertensive patients. The mean additional reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when sildenafil was administered alone to healthy volunteers. Additionally, the manufacturer of Viagra® reports no difference in the adverse reaction profile in patients taking sildenafil with and without antihypertensive agents. Sildenafil pharmacokinetics were not affected by CYP2C9 inhibitors, CYP2D6 inhibitors, thiazide and related diuretics, ACE inhibitors, or calcium channel blockers during clinical trials. The AUC of sildenafil’s active metabolite, N-desmethyl sildenafil, however, was increased 62% by loop diuretics and potassium-sparing diuretics and 102% by non-specific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.
Concurrent dosing with sildenafil and alpha-blockers may lead to symptomatic hypotension in some patients. When sildenafil (25 mg) was simultaneously administered with doxazosin (4 mg) to patients with BPH, mean additional reductions in supine blood pressure of 7 mmHg systolic and 7 mmHg diastolic were observed. When higher doses of sildenafil were administered with doxazosin (4 mg), symptomatic postural hypotension within 1 to 4 hours was reported in some patients. Sildenafil doses greater than 25 mg should not be taken within 4 hours of taking alpha-blockers.
Sildenafil is metabolized via the cytochrome CYP 3A4 isozyme. Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7 - dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract. Sildenafil levels may increase; it is possible that sildenafil-induced side effects could also be increased in some individuals. One study has confirmed a potential interaction; sildenafil’s AUC increased 23% with coadministration of grapefruit juice.
Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels drugs metabolized via CYP3A4, such as sildenafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Sildenafil is metabolized principally by the hepatic CYP3A4 (major route) and 2C9 (minor route) isoenzymes. The coadministration of tacrolimus with sildenafil has been associated with an increase in the AUC, Cmax, and half-life of sildenafil in one report; the interaction may have resulted from inhibition of CYP3A4 metabolism by tacrolimus. Decreases in blood pressure were also observed. Until further data are available, it may be prudent to reduce the initial dosage of sildenafil in patients who are concurrently taking tacrolimus.
Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. In both cases, patients reported erections subsided immediately after orgasm when taking sildenafil alone. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
[ Last revised: 2/28/2006 10:18:00 PM ]
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