Interaction with other drugs
Effect of other medicinal products
funds for the metabolism of sildenafil Metabolism of sildenafil occurs mainly in the liver under the action of cytochrome P 450 isoenzymes CYP3A4 (main path) and CYP2C9 (secondary pathway).
When combined sildenafil and inhibitors CYP3A4 (such as ketoconazole, erythromycin, cimetidine) there was an increase concentration of sildenafil in blood plasma.
Cimetidine (800 mg) at simultaneous reception from sildenafil (50 mg) causes an increase in the concentration sildenafil in plasma by 56%.
Erythromycin (500 mg twice a day for 5 days) with a single dose of sildenafil in a dose of 100 mg causes an increase AUC sildenafil by 182%.
Despite the lack of an increase in the frequency of IH, treatment with sildenafil in this group of patients should begin with a dose of 25 mg.
With the simultaneous use of sildenafil (once in a dose of 100 mg) and inhibitor B of the IF protease saquinavir (inhibitor CYP3A4, when taking saquinavir 3 times / day at a dose of 1200 mg) Cpsh sildenafil in the inhibitor of HIV protease, and inhibitor CYP3A4 (with the administration of saquinavir 3 times / day.in a dose of 1200 mg), against the background of achieving a constant level of saquinavir in the blood, Cmax sildenafil in the blood increased by 140%, a AUC increased by 210%.
Sildenafil does not affect the pharmacokinetic parameters of saquinavir.
Other potent inhibitors of isoenzyme CYP3A4, such as ketoconazole or itraconazole, can cause pronounced changes in the pharmacokinetics of sildenafil. Simultaneous application sildenafil (once in a dose of 100 mg) and ritonavir, which is an inhibitor of HIV protease and a potent inhibitor of cytochrome P450 isoenzymes (when ritonavir is taken 500 mg twice a day), Cmax sildenafil increased by 300% (4 times), a AUC on 1000% (in 11 times). After 24 hours, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml (with a single application of one sildenafil - 5 ng / ml). For this reason, the combined use of sildenafil and ritonavir is contraindicated. Sildenafil did not affect the metabolism of ritonavir.
Grapefruit juice, a weak inhibitor CYP3A4, can moderately increase plasma concentrations of sildenafil.
Single intake of antacids (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil Inhibitors СУР2С9 (such as tolbutamide, warfarin, phenytoin), CYP2D6 (such as selective serotonin reuptake inhibitors, tricyclic antidepressants, thiazides and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, "slow" calcium channel blockers and beta-blockers), inducers CYP450 (rifampicin, barbiturates) do not affect the pharmacokinetic parameters of sildenafil.
Simultaneous reception azithromycin (500 mg / day for 3 days) has no effect on AUC, Cmax, Tmax, the elimination rate constant and T1 / 2 sildenafil or its main circulating mof the metabolite.
Nicorandil has properties Nitrates and potassium activator channels. Due to the availability of nitrate component, this drug is characterized by a high probability of significant interaction with sildenafil. Bosentan (endothelin antagonist, moderate inductor CYP3A4, CYP2C9 and, perhaps, CYP2C19) when administered in doses of 125 mg twice daily (achieving equilibrium concentration) with concomitant administration sildenafil (80 mg three times a day, achieving equilibrium concentration) lead to a decrease AUC sildenafil by 62.6% and Cmax sildenafil by 55.4%.
Effect of sildenafil on other drugs Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19 cytoplasmic isofermites, 2D6, 2E1 and 4A (IR5about> 150 μM). Given that the maximum concentration of sildenafil in the blood plasma after taking recommended dis 1 μmol / L, it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.
Data on the interaction of sildenafil with by specific inhibitors of PDE, such as theophylline or dipyridamole, are absent.
In accordance with the known effect on the nitric oxide signal pathway / cGMP, sildenafil increases hypotensive effect nitrates, as with long-term use, and when applied for acute indications. In this regard, the use of sildenafil in combination with nitrates or other donators of nitric oxide it is contraindicated.
When sharing alpha-adrenobacter of doxazosipa (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, an average additional reduction systolic / diastolic blood pressure in the supine position on the back was 7/7 mm pg. st., 9/5 mm Hg. Art. and 8/4 mm Hg. st., respectively, and in the standing position - 6/6 mm Hg. st., 1 1/4 mm Hg. Art. and 4/5 mm Hg. Art. respectively. It is reported that there are rare cases of postural hypotension in such patients, manifested in the form dizziness (without fainting). Individual sensitive patients receiving alpha-blockers, simultaneous use of sildenafil can lead to clinically pronounced hypotension.
Signs of significant interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized CYP2C9, not found.
Sildenafil (50 mg) does not cause an additional increase bleeding time on admission acetylsalicylic acid (150 mg). Sildenafil (50 mg) does not increase the hypotensive effect ethanol in healthy volunteers the maximum level of ethanol in the blood is on average 80 mg / dL.
In patients with arterial hypertension symptoms interaction of sildenafil (100 mg) with amlodipine was not revealed. The average additional decrease in blood pressure in the prone position is: systolic - by 8 mm Hg. st, diastolic - by 7 mm pg.st. The use of sildenafil in combination with antihypergene agents does not lead to additional side effects.