Studies of the interaction of sildenafil with other drugs were performed on healthy volunteers, except for the cases indicated separately. These results are valid for other groups of patients and methods of administration.
The effect of other drugs on the pharmacokinetics of sildenafil
Research in vitro
The metabolism of sildenafil occurs mainly under the action of cytochrome P450 isoenzymes: isoenzyme CYP3A4 (main path) and isoenzyme CYP2C9 (minor way), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors - to increase its clearance.
Research in vivo
In a study on healthy male volunteers, the use of the bosentan endothelin antagonist, which is a moderate inducer of isoenzymes CYP3A4, CYP2C9 and, perhaps, CYP2C19, in an equilibrium state (125 mg twice a day) resulted in a decrease AUC and CmOh sildenafil in the equilibrium state (80 mg 3 times a day) by 62.6% and 55.4%, respectively. Although co-administration of two drugs was not accompanied by clinically significant changes in blood pressure in the "lying" and "standing" position and was well tolerated by healthy volunteers, sildenafil together with bosentan should be used with caution. The use of ritonavir (500 mg twice daily), an HIV protease inhibitor and a potent inhibitor of the isoenzyme CYP3A4, in combination with sildenafil (100 mg once) led to an increase in CmOh sildenafil by 300% (4 times) and AUC on 1000% (in 11 times). After 24 hours, the concentration of sildenafil in blood plasma was about 200 ng / ml versus 5 ng / ml for sildenafil alone, consistent with information on the pronounced effect of ritonavir on the pharmacokinetics of various substrates of cytochrome P450. The simultaneous use of the drug Sildenafil-SZ with ritonavir is contraindicated.
Joint application of saquinavir (1200 mg 3 times daily), HIV protease inhibitor and isoenzyme CYP3A4, with sildenafil (100 mg once) leads to an increase in CmOh sildenafil by 140% and AUC by 210%, respectively. Sildenafil did not influence the pharmacokinetics of saquinavir (see the section "Dosing and Administration").
The most potent inhibitors of isoenzyme CYP3A4, such as ketoconazole and itraconazole, may have an effect similar to that of ritonavir. With a single admission of sildenafil in a dose of 100 mg against the background of therapy with erythromycin, which is a moderate inhibitor of the isoenzyme CYP3A4, in an equilibrium state (500 mg twice a day for 5 days), an increase AUC sildenafil by 182% (see section "Method of administration and dose").
Such inhibitors of isoenzyme CYP3A4, as clarithromycin, telithromycin and nefazodone may presumably have an effect similar to that of ritonavir. Such inhibitors of isoenzyme CYP3A4, as saquinavir or erythromycin can increase AUC in 7 times. In this regard, with simultaneous application with sildenafil should adjust the dose of inhibitors of isoenzyme CYP3A4 (see section "Method of administration and dose").
In healthy male volunteers azithromycin (500 mg / day for 3 days) had no effect on AUC, FROMmOh, TSmOh, the elimination rate constant or T1 / 2 of sildenafil and its main circulating metabolite.
Cimetidine (800 mg), a cytochrome P450 inhibitor and a nonspecific isoenzyme inhibitor CYP3A4, caused an increase in the concentrations of sildenafil (50 mg) in the blood plasma of healthy volunteers by 56%. A single intake of antacids (magnesium hydroxide and aluminum hydroxide) had no effect on the bioavailability of sildenafil.
The combined use of oral contraceptives (ethinylestradiol 30 μg and levonorgestrel 150 μg) had no effect on the pharmacokinetics of sildenafil.
Inhibitor inhibitors CYP3A4 and β-adrenobiocators
It was found that in patients with PAH, the clearance of sildenafil is reduced by approximately 30% when used simultaneously with weak or medium inhibitors of the isoenzyme CYP3A4 and by 34% when applied simultaneously with βadrenoblockers. AUC sildenafil at its application in a dose of 80 mg three times a day was 5 times higher than when the drug was prescribed in a dose of 20 mg 3 times a day. In studies of interaction with inhibitors of isoenzyme CYP3A4, such as saquinavir and erythromycin (excluding the most potent inhibitors of isoenzyme CYP3A4, such as ketoconazole, itraconazole, ritonavir) AUC sildenafil in this concentration range increased.
Inductors of isoenzyme CYP3A4
The clearance of sildenafil increases approximately three times with simultaneous application with weak isoenzyme inducers CYP3A4, which corresponds to the effect of bosentan on the clearance of sildenafil in healthy volunteers. It is expected that the simultaneous use of sildenafil with powerful isoenzyme inducers CYP3A4 will lead to a significant decrease in the concentration of sildenafil in the blood plasma.
With the simultaneous use of sildenafil (20 mg three times a day) in adult patients with PAH and bosentan at a stable dose (62.5 - 125 mg twice daily), the same decrease in sildenafil exposure was observed as in the case of healthy volunteers .
Simultaneous use of sildenafil and epoprostenol leads to a decrease in mean pressure in the pulmonary artery, (see the section "Pharmacodynamics").
Simultaneous use of sildenafil with iloprost, for the treatment of pulmonary hypertension was not carried out, so therapy with Sildenafil Cardio should be carried out with caution, it may be necessary to correct the dose of sildenafil.
With the simultaneous use of sildenafil with ambrisent, a slight increase in the maximum concentration of sildenafil in blood plasma was observed, which is not considered clinically significant.
Simultaneous use of sildenafil with other PDE5 inhibitorspatients with pulmonary arterial hypertension have not been studied, so the use of such a combination is not recommended.
Simultaneous use of sildenafil with powerful inducers CYP3A4 (carbamazepine, phenytoin, phenobarbital, preparations of St. John's wort, rifampicin) can lead to a significant decrease in the concentration of sildenafil in blood plasma.
Grapefruit juice, a weak inhibitor CYP3A4, can moderately increase plasma concentrations of sildenafil.
Simultaneous use of sildenafil with nicorandil is contraindicated, because can lead to a sharp drop in blood pressure.
Effect of sildenafil on the pharmacokinetics of other drugs
Research in vitro
Sildenafil is a weak inhibitor of isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 cytochrome P450 (IFROM50 > 150 μM). It is not expected that sildenafil will have an effect on compounds that are substrates of these isoenzymes in clinically significant concentrations.
Research in vivo
Sildenafil has an effect on the system NO/ cGMP and enhances the hypotensive effect of nitrates. Its combined use with donators of nitric oxide or nitrates in any form is contraindicated.
With simultaneous administration of α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia, the additional reduction in systolic / diastolic blood pressure in prone position was 7/7, 9/5 and 8/4 mm Hg, and in the standing position - 6/6, 11/4 and 4/5 mm Hg, respectively. When prescribing sildenafil to patients receiving doxazosin, rare cases of development of orthostatic hypotension, accompanied by dizziness, but not fainting, were noted.
The use of sildenafil in patients taking α-adrenoblockers can lead to clinically significant arterial hypotension in patients with AD lability.
When studying the interaction of sildenafil (100 mg) with amlodipine in patients with arterial hypertension, there was an additional decrease in systolic and diastolic blood pressure in the prone position by 8 mm Hg. and 7 mm Hg, respectively. A similar decrease in blood pressure was noted with the use of one sildenafil in healthy volunteers.
Signs of interaction of sildenafil (50 mg) with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by isoenzyme CYP2C9, not found.
Sildenafil (50 mg) did not cause an additional increase in bleeding time caused by acetylsalicylic acid (ASA) as the antiplatelet agents (150 mg).
Sildenafil (50 mg) did not increase the hypotensive effect of ethanol in healthy volunteers at a maximum ethanol concentration of 80 mg / dL.
In healthy volunteers sildenafil in an equilibrium state (80 mg 3 times a day) caused an increase AUC and CmOh bosentan (125 mg twice daily) by 49.8% and 42%, respectively.
With the simultaneous administration of bosentan at an initial dose of 62.5 mg to 125 mg twice daily in adult patients with PAH and sildenafil at a dose of 20 mg three times a day, a smaller increase AUC bosentan compared to healthy volunteers receiving sildenafil in a dose of 80 mg three times a day.
Sildenafil in a single dose of 100 mg did not affect the equilibrium pharmacokinetics of HIV protease inhibitors saquinavir and ritonavir, which are substrates of the isoenzyme CYP3A4.
Sildenafil had no clinically significant effect on the concentration of oral contraceptives in blood plasma (ethinylestradiol 30 μg and levonorgestrel 150 μg).
Simultaneous reception of riotsiguata with PDE-5 inhibitors, including sildenafil, is contraindicated, tk. riotsiguat enhances the hypotensive effect of PDE-5 inhibitors.
Simultaneous reception sildenafila and nonspecific inhibitors of PDE (theophylline and dipyridamole) is contraindicated.
Simultaneous administration with acenocoumarol can lead to an increased risk of bleeding.
The combination of atorvastatin and sildenafil for the treatment of pulmonary hypertension has significant therapeutic advantages. Simultaneous administration with atorvastatin reduces hypoxic-induced pulmonary hypertension. The effect on vascular remodeling and hypertrophy of the right ventricle increases with the combined use of medications, rather than with monotherapy.