The effect of other drugs on the pharmacokinetics of sildenafil
The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (the main pathway) and CYP2C9, so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil with simultaneous application of inhibitors of the cytochrome isoenzyme CYP3A4 (
ketoconazole,
erythromycin,
cimetidine).
Cimetidine (800 mg), a non-specific inhibitor of the cytochrome isoenzyme CYP3A4, when co-administered with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%. A single dose of 100 mg of sildenafil together with erythromycin (500 mg / day twice a day for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, with the achievement of a constant concentration of erythromycin in the blood, increases the sildenafil AUC by 182%.
When co-administered sildenafil (single dose 100 mg) and saquinavir (1200 mg / day, 3 times a day), an inhibitor of HIV protease and isoenzyme cytochrome CYP3A4, against the backdrop of constant saquinavir blood concentration Cmax of sildenafil increased by 140%, a AUC was increased by 210
%.
Sildenafil does not affect
pharmacokinetics of saquinavir.
More potent cytochrome CYP3A4 isoenzyme inhibitors, such as
ketoconazole and
itraconazole, can cause and stronger changes in the pharmacokinetics of sildenafil.
The simultaneous use of sildenafil (single dose 100 mg) and RTV (500 mg, 2 times a day), HIV protease inhibitor and a potent inhibitor of cytochrome R45o, against the backdrop of a constant concentration in the blood of ritonavir increases the Cmax of sildenafil in 300% (4 times ), a AUC 1000% (11 times).After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single application of one sildenafil - 5 ng / ml), which is consistent with information on the pronounced effect of ritonavir on the pharmacokinetics of various substrates of cytochrome P450.
Sildenafil does not affect the pharmacokinetics of ritonavir. Combined use of sildenafil with ritonavir is not recommended.
If
sildenafil take in recommended doses of patients receiving simultaneously strong inhibitors of the cytochrome isoenzyme CYP3A4, then Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.
A single dose of antacid (hydroxide / magnesium hydroxide, aluminum) did not affect the bioavailability of sildenafil.
Inhibitors of the cytochrome isoenzyme CYP2C9 (tolbutamide,
warfarin), cytochrome isoenzyme CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors, and calcium antagonists have no effect on the pharmacokinetics of sildenafil.
Azithromycin (500 mg / day for 3 days) does not affect AUC, Cmax Tmax, rate of elimination rate and T1 / 2 sildenafil or its main circulating metabolite.
Effect of sildenafil on other drugs
Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2D6, 2E1 and ZA4 isoenzymes (IC50> 150 μmol). When taking sildenafil in recommended doses, its Stach is about 1 μmol, so it is unlikely that
sildenafil can affect the clearance of the substrates of these isoenzymes.
Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter, and when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or donators of nitric oxide is contraindicated.
With simultaneous administration of a-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic / diastolic blood pressure in the supine position was 7 / 7 mm Hg. st., 9/5 mm Hg. and 8/4 mm Hg, respectively, and in the standing position - 6/6 mm Hg, 11/4 mm Hg. and 4/5 mm Hg, respectively. We report rare cases of development in these patients of symptomatic postural hypotension, manifested as dizziness (without syncope). In individual sensitive patients receiving a-adrenergic blockers, simultaneous use of sildenafil can lead to symptomatic hypotension.
Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the isoenzyme of cytochrome CYP2C9, have not been identified.
Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease, saquinavir and ritonavir inhibitors, which are substrates of the cytochrome CYP3A4 isoenzyme, at their constant level in the blood.
Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).
Sildenafil (50 mg) does not increase the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of 0.08% (80 mg / dl)
In patients with arterial hypertension, there was no evidence of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the prone position is 8 mm Hg. (systolic) and 7 mm Hg. (diastolic).
The use of sildenafil in combination with antihypertensive agents does not lead to the occurrence of additional side effects by these or other factors.
Hypotension
Viagra has systemic vasodilatory effect resulting in a transient decrease in blood pressure that is not clinically significant phenomenon and does not lead to any consequences in most patients.However, prior to the prescription of the drug
Sildenafil the doctor should carefully
assess the risk of possible unwanted manifestations
vasodilating effect in patients with the corresponding diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with a rare syndrome of multiple systemic atrophy, manifested severe violation of the regulation of blood pressure from the autonomic nervous system.
Since the joint use of sildenafil and a-adrenoblockers can lead to symptomatic hypotension in selected sensitive patients, the drug
Sildenafil should be administered with caution to patients taking a-adrenoblockers (see section "Interaction with other drugs"). To minimize the risk of postural hypotension in patients taking a-adrenoblockers, taking the drug
Sildenafil It should be started only after achieving stabilization of hemodynamic parameters in these patients.It should also consider the desirability of reducing the initial dose of the drug
Sildenafil (see section "Method of administration and dose"). The doctor should inform patients about what actions should be taken in case of symptoms of postural hypotension.
Visual disorders
Rare cases of development of anterior non-artery ischemic neuropathy of the optic nerve were noted as a cause of impairment or loss of vision against the background of the use of all PDE5 inhibitors, including
sildenafil. Most of these patients had risk factors, such as optic disc excavation, age over 50, diabetes, hypertension, ischemic heart disease, hyperlipidemia and smoking. The causal relationship between the intake of PDE5 inhibitors and the development of anterior non-artery ischemic neuropathy of the optic nerve was not revealed. The physician should inform the patient about the increased risk of developing anterior non-artery ischemic neuropathy of the optic nerve if this condition has already been noted. In the event of a sudden loss of vision, patients should immediately provide the necessary medical care.A small number of patients with hereditary pigment retinitis have genetically determined impairments of the functions of the retina phosphodiesterase. Information on the safety of the drug
Sildenafil in patients with retinitis pigmentosa absent, therefore
sildenafil should be used with caution (see "With caution").
Hearing Impairment
Some post-marketing and clinical studies report cases of sudden deterioration or hearing loss associated with the use of all PDE5 inhibitors, including
sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. The causal relationship between the use of PDE5 inhibitors and sudden deterioration of hearing or loss of hearing is not established. In the event of a sudden deterioration in hearing or hearing loss, taking sildenafil should immediately consult a doctor.
Bleeding
Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a donator of nitric oxide, on human platelets in vitro. Data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of gastric ulcer and12 duodenal ulcers are absent, therefore the drug
Sildenafil these patients should be used with caution (see "With caution"). The frequency of nasal bleeding in patients with PH associated with diffuse connective tissue diseases was higher (
sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (
sildenafil 3.0%, placebo 2.4%). In patients who received
sildenafil in combination with a vitamin K antagonist, the incidence of nasal bleeding was higher (8.8%) than in patients who did not take a vitamin K antagonist
(1,7%).
Application in conjunction with other treatments for erectile dysfunction. Safety and efficacy of the drug
Sildenafil together with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see the section "Contraindications").