Sildenafil-SZ (Tablets, Granules) Instructions for Use

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of erectile dysfunction

Pharmacological Action

Mechanism of Action

Sildenafil is intended for the oral therapy of erectile dysfunction. Under natural conditions, i.e., in the presence of sexual stimulation, it restores impaired erectile dysfunction by enhancing blood flow to the penis. The physiological mechanism underlying penile erection involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. The resulting nitric oxide activates the enzyme guanylate cyclase, leading to an increase in cGMP levels, which causes relaxation of smooth muscles in the corpus cavernosum and increased blood flow.

Sildenafil is a potent and selective inhibitor of cGMP-specific PDE5, which is responsible for the degradation of cGMP in the corpus cavernosum. Sildenafil has a peripheral effect on erection. Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum but actively enhances the relaxing effect of NO on this tissue. When the NO/cGMP cascade is activated, which is observed during sexual stimulation, inhibition of PDE5 by sildenafil leads to increased cGMP levels in the corpus cavernosum. Thus, sexual stimulation is necessary for the desired pharmacological effect of sildenafil to develop.

Pharmacodynamic Effects

In vitro studies have demonstrated that Sildenafil is selective for PDE5, which is involved in the process of erection development. Its activity against PDE5 exceeds its activity against other known phosphodiesterases. It is 10 times less active against PDE6, which is involved in the phototransduction process in the retina. At the maximum recommended doses, Sildenafil is 80 times less selective for PDE1 and 700 times less selective for PDE2, 3, 4, 7, 8, 9, 10, and 11. Furthermore, the selectivity of sildenafil for PDE5 is approximately 4000 times greater than its selectivity for PDE3, a cAMP-specific phosphodiesterase involved in the regulation of heart contractions.

Clinical Efficacy and Safety

Two clinical studies were designed to assess the time after drug administration during which Sildenafil leads to an erection in response to sexual stimulation. In a clinical study involving patients who used Sildenafil on an empty stomach, during penile plethysmography (using the RigiScan device), the median time to the onset of erection in patients who achieved an erection with penile rigidity of 60% (sufficient for sexual intercourse) was 25 minutes (range 12-37 minutes). In a separate study using the RigiScan device, Sildenafil was still able to induce an erection in response to sexual stimulation 4-5 hours after administration.

Sildenafil causes a mild and transient decrease in blood pressure, which in most cases has no clinical manifestations. The mean maximum decrease in systolic blood pressure, measured in the supine position, after oral administration of sildenafil at a dose of 100 mg was 8.4 mmHg. The corresponding change in diastolic blood pressure was 5.5 mmHg. These blood pressure reductions are consistent with the vasodilatory effect of sildenafil, likely due to increased cGMP levels in vascular smooth muscles. A single oral administration of sildenafil at doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers.

In a study of the hemodynamic effects of a single oral dose of sildenafil 100 mg in 14 patients with severe coronary artery disease (with at least one coronary artery stenosis greater than 70%), the mean resting systolic and diastolic blood pressure decreased by 7% and 6% from baseline, respectively. Mean systolic pulmonary artery pressure decreased by 9%. Sildenafil did not affect cardiac output and did not impair blood flow in stenosed coronary arteries.

In a double-blind, placebo-controlled clinical study using an exercise test involving 144 patients with erectile dysfunction and chronic stable angina who were continuously taking antianginal drugs (other than nitrates), no clinically significant differences in the time to limiting angina with sildenafil compared to placebo were demonstrated.

Mild and transient impairments in the ability to distinguish color shades (blue/green) were detected in some patients using the 100-hue Farnsworth-Munsell test 1 hour after administration of sildenafil 100 mg. These changes completely disappeared 2 hours after drug administration. The possible mechanism of this change in color recognition is related to the inhibition of PDE6, which is involved in the phototransduction cascade in the retina. Sildenafil does not affect visual acuity or contrast sensitivity. In a small placebo-controlled clinical study involving patients with documented age-related macular degeneration (n=9), the use of sildenafil (single dose of 100 mg) did not cause significant changes in the results of vision tests (visual acuity, Amsler grid, traffic light color recognition simulation, Humphrey perimetry, and photostress test).

A single oral dose of sildenafil 100 mg in healthy volunteers did not affect sperm motility or morphology.

Additional Clinical Trial Data

In clinical trials, Sildenafil was used in more than 8000 patients aged 19 to 87 years. The studies included the following patient groups: elderly individuals (19.9%), patients with arterial hypertension (30.9%), patients with diabetes mellitus (20.3%), coronary artery disease (5.8%), hyperlipidemia (19.8%), spinal cord injuries (0.6%), depression (5.2%), transurethral resection of the prostate (3.7%), and radical prostatectomy (3.3%). The following patient groups were not sufficiently represented or were excluded from clinical trials: patients after pelvic surgery, patients after radiation therapy, patients with severe renal or hepatic insufficiency, and patients with certain cardiovascular diseases (see section “Contraindications”).

In fixed-dose studies, the proportion of patients who reported improvement in erectile function with the drug was 62% (25 mg), 74% (50 mg), and 82% (100 mg) compared to 25% in the placebo group. In controlled clinical trials, the number of sildenafil discontinuations was small and comparable to the placebo group. The number of patients reporting improvement with sildenafil in all these studies was as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly patients (67%), diabetes mellitus (59%), coronary artery disease (69%), arterial hypertension (68%), transurethral resection of the prostate (61%), radical prostatectomy (43%), spinal cord injuries (83%), depression (75%). The safety and efficacy of sildenafil are confirmed by long-term study data.

Pharmacokinetics

Absorption

After oral administration, Sildenafil is rapidly absorbed. The maximum observed plasma concentrations after oral administration of sildenafil on an empty stomach are reached within 30-120 minutes (median 60 minutes). The absolute bioavailability averages about 41% (25-63%). After oral administration of the drug in the recommended dose range (25-100 mg), the AUC and C_max of sildenafil increase proportionally to the dose.

When sildenafil is taken with food, the rate of its absorption decreases, with T_max increasing by an average of 60 minutes, and C_max decreasing by an average of 29%.

Distribution

The V_d of sildenafil at steady state averages 105 L, indicating its distribution into tissues. The maximum total plasma concentration of sildenafil after a single oral dose of 100 mg averages about 440 ng/mL (coefficient of variation – 40%). Since the binding of sildenafil (and its main circulating N-desmethyl metabolite) to plasma proteins reaches 96%, the mean C_max of the free fraction of sildenafil in plasma is 18 ng/mL (38 nM). Binding to plasma proteins is independent of the total drug concentration. In healthy volunteers, less than 0.0002% of the administered dose (average – 188 ng) was detected in the ejaculate 90 minutes after a single dose of sildenafil 100 mg.

Metabolism

Sildenafil is biotransformed mainly in the liver by the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite, formed as a result of N-demethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil.

The plasma concentration of the metabolite in healthy volunteers was about 40% of the sildenafil concentration. The N-desmethyl metabolite undergoes further biotransformation; T_1/2 is about 4 hours.

Excretion

The total clearance of sildenafil is 41 L/h, and the terminal T_1/2 is 3-5 hours. After oral administration, as well as after intravenous administration, Sildenafil is excreted as metabolites, mainly via the intestine (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

The pharmacokinetics of sildenafil in the recommended dose range are linear.

Pharmacokinetics in Special Patient Groups

Renal impairment. In volunteers with mild and moderate renal impairment (creatinine clearance 30-80 mL/min), the pharmacokinetic parameters of sildenafil after a single oral dose (50 mg) did not change. The mean AUC and C_max values of the N-desmethyl metabolite increased by 126% and 73%, respectively, compared to volunteers of the same age without renal impairment. However, due to significant interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), the clearance of sildenafil decreased, leading to an average increase in AUC and C_max of 100% and 88%, respectively, compared to these parameters in patients of the same age group with normal renal function. Furthermore, the AUC and C_max values of the N-desmethyl metabolite increased by 200% and 79%, respectively.

Hepatic impairment. In volunteers with mild and moderate cirrhosis (Child-Pugh class A and B), the clearance of sildenafil decreased, leading to an increase in AUC (84%) and C_max (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Elderly individuals. In healthy elderly volunteers (65 years and older), the clearance of sildenafil is reduced, and the plasma concentration of sildenafil and the active N-desmethyl metabolite is approximately 90% higher than its level in healthy young volunteers (18-45 years). Due to age-related differences in drug binding to plasma proteins, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Indications

• Erectile dysfunction in adult men, characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

The drug Sildenafil-SZ is effective only with sexual stimulation.

ICD codes

Dosage Regimen

Granules

Orally, if necessary, with a small amount of water.

The recommended dose is 50 mg, taken as needed, approximately 1 hour before anticipated sexual activity. Depending on efficacy and tolerability, the dose of Sildenafil-SZ can be increased to 100 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of drug use is once daily.

Special Patient Groups

In elderly patients, no dose adjustment of Sildenafil-SZ is required.

In mild to moderate renal impairment (creatinine clearance 30-80 mL/min), no dose adjustment is required; in severe renal impairment (creatinine clearance less than 30 mL/min), the dose of Sildenafil-SZ should be reduced to 25 mg. Depending on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

Since the elimination of sildenafil is impaired in patients with impaired liver function (e.g., cirrhosis), the drug dose should be reduced to 25 mg. Depending on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

Concomitant use with other drugs

Concomitant use with ritonavir is contraindicated.

When used concomitantly with inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, erythromycin, cimetidine, except for ritonavir), the initial dose of Sildenafil-SZ should not exceed 25 mg.

To reduce the likelihood of orthostatic hypotension, stable hemodynamic conditions should be achieved during therapy with alpha-blockers before starting sildenafil. The initial dose of Sildenafil-SZ should be reduced to 25 mg.

Tablets

The drug is taken orally.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose can be increased to 100 mg or decreased to 25 mg.

The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily. The time to onset of activity of the drug Sildenafil-SZ may be increased when taken with food compared to taking on an empty stomach (see section “Pharmacokinetics”).

Special Patient Groups

Elderly patients (over 65 years)

No dose adjustment of Sildenafil-SZ is required (see section “Pharmacokinetics”).

Patients with impaired renal function

In mild to moderate renal impairment (creatinine clearance 30-80 mL/min), no dose adjustment is required. In severe renal impairment (creatinine clearance <30 mL/min), the dose of sildenafil should be reduced to 25 mg. Based on the efficacy and tolerability of the drug, if necessary, the dose can be gradually increased to 50 mg and to 100 mg.

Patients with impaired liver function

Since the elimination of sildenafil is impaired in patients with impaired liver function (in particular, cirrhosis), the dose of Sildenafil-SZ should be reduced to 25 mg. Based on the efficacy and tolerability of the drug, if necessary, the dose can be gradually increased to 50 mg and to 100 mg.

Use in patients taking other medicines

Except for ritonavir, which is not recommended to be taken concomitantly with sildenafil (see section “Special Instructions”), in patients taking concomitant CYP3A4 inhibitors, the possibility of using the drug at an initial dose of 25 mg should be considered (see section “Drug Interactions”).

To minimize the risk of orthostatic hypotension in patients taking alpha-blockers, sildenafil should be initiated only after hemodynamic stabilization has been achieved in these patients. Furthermore, in such cases, it is recommended to start sildenafil at a dose of 25 mg (see sections “Special Instructions” and “Drug Interactions”).

Children

Sildenafil-SZ is contraindicated for use in children and adolescents aged 0 to 18 years.

Adverse Reactions

Summary of the safety profile

The most frequent adverse effects were headache and flushing.

Usually, the adverse effects of Sildenafil-SZ are mild or moderate and transient.

Fixed-dose studies have shown that the incidence of some adverse events increases with increasing dose.

Tabulated summary of adverse reactions

Adverse reactions are distributed by system organ class in order of decreasing severity with an indication of their frequency of occurrence according to WHO recommendations: very common (≥1/10%), common (from ≥1% to <10%), uncommon (from ≥0.1% to <1%), rare (from ≥0.01% to <0.1%), very rare (<0.01%), frequency not known (cannot be estimated from the available data).

* Reported only during post-marketing surveillance.

** Color vision deficiency: chloropsia, chromatopsia, cyanopsia, erythropsia, and xanthopsia.

*** Lacrimal disorders: dry eye, lacrimation deficiency, and increased lacrimation.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are recommended to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to sildenafil or any other component of the drug;
• Use in patients receiving nitric oxide donors (such as amyl nitrite) or nitrates in any form, since Sildenafil enhances the hypotensive effect of nitrates by affecting nitric oxide/(cGMP) metabolism (see section "Pharmacological action");
• Concomitant use of phosphodiesterase type 5 (PDE5) inhibitors, including Sildenafil, with guanylate cyclase stimulators, such as riociguat, as it may potentially lead to symptomatic arterial hypotension (see section "Drug interactions");
• Use in patients for whom sexual activity is not recommended (e.g., patients with severe cardiovascular pathology, such as unstable angina, severe heart failure);
• Patients with vision loss in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this pathology is associated with previous use of PDE5 inhibitors or not (see section "Special precautions");
• Severe hepatic impairment;
• Arterial hypotension (BP <90/50 mmHg);
• Recent stroke or myocardial infarction;
• Patients with known hereditary degenerative retinal diseases, such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal phosphodiesterase);
• Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption;
• In children and adolescents aged 0 to 18 years.

With caution

• Anatomical deformation of the penis (angulation, cavernous fibrosis, or Peyronie’s disease);
• Conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia);
• Conditions accompanied by bleeding;
• Gastric and duodenal ulcer in the acute stage;
• Mild to moderate hepatic impairment;
• Severe renal failure (CrCl <30 ml/min);
• Patients with a history of an episode of NAION;
• Concomitant use of alpha-adrenergic receptor blockers.

Use in Pregnancy and Lactation

The drug Sildenafil-SZ is not intended for use in women.

Use in Hepatic Impairment

Since the elimination of sildenafil is impaired in patients with liver damage (particularly cirrhosis), the dose of Sildenafil-SZ should be reduced.

Use in Renal Impairment

In mild to moderate renal impairment (CrCl 30-80 ml/min), dose adjustment is not required; in severe renal impairment (CrCl <30 ml/min), the sildenafil dose should be reduced.

Pediatric Use

The drug Sildenafil-SZ is not intended for use in children and adolescents under 18 years of age.

Geriatric Use

Dose adjustment of Sildenafil-SZ in elderly patients is not required.

Special Precautions

To diagnose erectile dysfunction, determine its possible causes, and select adequate treatment, it is necessary to take a complete medical history and perform a thorough physical examination.

Cardiovascular risk factors

Sexual activity carries a certain risk in the presence of heart disease, so before initiating any therapy for erectile dysfunction, the physician should refer the patient for assessment of cardiovascular status.

Sildenafil has a vasodilatory effect, leading to a small transient decrease in BP (see section "Pharmacological action"). Before prescribing sildenafil, the physician should carefully assess the risk of possible adverse reactions of the vasodilatory effect in patients with relevant conditions, especially during sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of left ventricular outflow (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe autonomic nervous system dysregulation of BP. The drug Sildenafil-SZ enhances the hypotensive effect of nitrates (see section "Contraindications").

During post-marketing surveillance, cases of serious cardiovascular complications (including myocardial infarction, unstable angina, sudden coronary death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack (TIA), arterial hypertension and hypotension) have been reported, which had a temporal relationship with the use of sildenafil. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse reactions were observed shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct causal relationship between these reactions and the mentioned or other factors.

Priapism

Drugs for the treatment of erectile dysfunction, including Sildenafil, should be used with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernous fibrosis, or Peyronie’s disease) or in patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

During post-registration use of sildenafil, reports of prolonged erection and priapism have been received. If an erection lasts more than 4 hours, the patient should seek immediate medical attention. If priapism is not treated urgently, penile tissue damage and irreversible loss of potency may occur.

Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction

The safety and efficacy of sildenafil when used in combination with other PDE5 inhibitors or other drugs for pulmonary arterial hypertension containing Sildenafil (e.g., Revatio), as well as other treatments for erectile dysfunction, have not been studied, so the use of such combinations is not recommended.

Effect on vision

Spontaneous reports of visual disturbances have been received with the use of sildenafil and other PDE5 inhibitors. Spontaneous reports and an observational study have noted cases of the rare disease non-arteritic ischemic optic neuropathy, which were associated with the use of sildenafil and other PDE5 inhibitors (see section "Adverse reactions"). Patients should be warned that in case of sudden visual impairment, they should discontinue Sildenafil-SZ and immediately consult a doctor (see section "Contraindications").

Concomitant use with ritonavir

Concomitant use of sildenafil and ritonavir is not recommended (see section "Drug interactions").

Concomitant use with alpha-blockers

Since concomitant use of sildenafil and alpha-blockers may lead to symptomatic hypotension in some sensitive patients, Sildenafil should be prescribed with caution to patients taking alpha-blockers (see section "Drug interactions"). The development of this condition is most likely to be observed within 4 hours after taking a dose of sildenafil. To minimize the risk of orthostatic hypotension, sildenafil therapy can only be started in hemodynamically stable patients using alpha-adrenergic receptor blockers. Consideration should also be given to using sildenafil at an initial dose of 25 mg (see section "Dosage and administration"). The physician should inform patients about what actions to take in case of symptoms of orthostatic hypotension.

Effect on blood coagulation

In vitro studies on human platelets have shown that Sildenafil potentiates the antiplatelet effect of sodium nitroprusside. There is no information on the safety of sildenafil use in patients with bleeding disorders or acute peptic ulcer, so the use of sildenafil in these patients should only be considered after careful assessment of the benefit/risk ratio.

Women

The drug Sildenafil-SZ is not intended for use in women.

Excipients

The drug Sildenafil-SZ contains lactose monohydrate, patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive and operate machinery

The drug Sildenafil-SZ has an insignificant effect on the ability to drive vehicles or operate machinery.

Since sildenafil may cause decreased BP, chromatopsia, blurred vision, and other adverse reactions, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Individual response to the drug in these situations should also be carefully considered, especially at the start of treatment and when changing the dosage regimen.

Overdose

Symptoms the use of sildenafil at a dose of 200 mg did not lead to an increase in the drug’s efficacy, but the frequency of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual impairment) increased. With a single dose of Sildenafil-SZ up to 800 mg, adverse events were comparable to those at lower doses but occurred more frequently.

Treatment symptomatic therapy should be administered. Hemodialysis does not accelerate the clearance of sildenafil, as the latter is actively bound to plasma proteins and is not excreted by the kidneys.

Drug Interactions

Effect of other drugs on the pharmacokinetics of sildenafil

In vitro studies

The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers, respectively, may increase the clearance of sildenafil.

In vivo studies

Population pharmacokinetic analysis of clinical trial data demonstrated a decrease in sildenafil clearance with concomitant use of CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine ). Although no increase in the frequency of adverse reactions was observed with the concomitant use of sildenafil and CYP3A4 inhibitors, consideration should be given to using the drug at an initial dose of 25 mg.

Concomitant use of sildenafil (single dose 100 mg) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, at steady-state ritonavir concentrations leads to an increase in sildenafil C_max by 300% (4-fold), and AUC by 1000% (11-fold). After 24 hours, the plasma concentration of sildenafil is about 200 ng/ml (after a single dose of sildenafil alone – 5 ng/ml), which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on the results of pharmacokinetic studies, concomitant use of sildenafil and ritonavir is not recommended (see section "Special precautions") and under no circumstances should the maximum dose of sildenafil exceed 25 mg within 48 hours.

With concomitant use of sildenafil (single dose 100 mg) and saquinavir (1200 mg three times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme inhibitor, at steady-state saquinavir concentrations, sildenafil C_max increased by 140%, and AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole , may cause more pronounced changes.

A single dose of sildenafil 100 mg co-administered with erythromycin (500 mg twice daily for 5 days), a moderate CYP3A4 isoenzyme inhibitor, at steady-state erythromycin concentrations led to an increase in sildenafil AUC by 182%.

Administration of azithromycin (500 mg/day for 3 days) to healthy male volunteers did not affect the AUC, C_max, T_max, elimination rate constant, and T_1/2 of sildenafil or its main circulating metabolite.

Cimetidine (at a dose of 800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, when co-administered with sildenafil (at a dose of 50 mg), led to an increase in sildenafil plasma concentration in healthy volunteers by 56%.

Grapefruit juice is a weak inhibitor of CYP3A4 biotransformation in the intestinal wall and may cause a moderate increase in sildenafil plasma levels.

A single dose of an antacid ( magnesium hydroxide/aluminum hydroxide ) does not affect the bioavailability of sildenafil.

Although specific interaction studies of sildenafil with all drugs have not been conducted, according to population pharmacokinetic analysis, the pharmacokinetics of sildenafil did not change when used concomitantly with drugs belonging to the CYP2C9 inhibitor group (such as tolbutamide, warfarin, phenytoin ), the CYP2D6 inhibitor group (such as SSRIs, tricyclic antidepressants ), the group of thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, calcium channel blockers, beta-adrenergic receptor antagonists, or inducers of CYP450 biotransformation (such as rifampicin, barbiturates ). In a study with healthy male volunteers, concomitant use of the endothelin antagonist bosentan (which is an inducer of CYP3A4 (moderate), CYP2C9 and possibly CYP2C19 isoenzymes) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) led to a decrease in sildenafil AUC and C_max by 62.6 and 55.4%, respectively. Concomitant use of strong CYP3A4 inducers, such as rifampicin , is expected to cause a more pronounced decrease in sildenafil plasma concentration.

Nicorandil has properties of a potassium channel activator and nitrate-like action. Due to the nitrate component, this drug has the potential for clinically significant interaction with sildenafil.

Effect of sildenafil on other drugs

In vitro studies

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀>150 µmol). When sildenafil is taken at recommended doses, its C_max is about 1 µmol, so it is unlikely that Sildenafil can affect the clearance of substrates of these isoenzymes.

Information on the interaction of sildenafil with non-specific phosphodiesterase inhibitors, such as theophylline and dipyridamole, is not available.

In vivo studies

Consistent with the known effect on the NO/cGMP signaling cascade (see section "Pharmacological action"), Sildenafil has been shown to potentiate the hypotensive effect of nitrates, therefore the use of nitric oxide donors or nitrates in any form concomitantly with sildenafil is contraindicated (see section "Contraindications").

Preclinical studies have shown an additional effect of reducing systemic BP with simultaneous use of PDE5 inhibitors and riociguat . In clinical trials, riociguat showed an enhancement of the hypotensive effect of PDE5 inhibitors. There are no data on a favorable clinical effect of this combination in population studies. Concomitant use of riociguat and PDE5 inhibitors, including Sildenafil, is contraindicated (see section "Contraindications").

Concomitant use of sildenafil and alpha-blockers may lead to symptomatic hypotension in some predisposed patients. The development of this condition is most likely to be observed within 4 hours after taking a dose of sildenafil (see sections "Dosage and administration" and "Special precautions"). In three specific drug interaction studies, patients with benign prostatic hyperplasia (BPH) in a stable condition while taking doxazosin were co-administered the alpha-blocker doxazosin (at doses of 4 and 8 mg) and Sildenafil (at doses of 25, 50, and 100 mg). In patients included in these studies, a mean additional decrease in supine BP of 7/7, 9/5, and 8/4 mmHg, and a mean decrease in standing BP of 6/6, 11/4, and 4/5 mmHg, respectively, were noted. With concomitant use of sildenafil and doxazosin in patients stable on doxazosin, reports of symptomatic orthostatic hypotension were infrequent. These reports included cases of dizziness and lightheadedness without syncope.

No signs of significant interaction between sildenafil (at a dose of 50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9, were identified.

Sildenafil (at a dose of 50 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (at a dose of 150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of ethanol in healthy volunteers at a maximum blood ethanol concentration averaging 80 mg/dL.

In patients using sildenafil, no differences in the safety profile compared to placebo were noted with the concomitant use of such classes of antihypertensive medications as diuretics, beta-adrenergic receptor blockers, ACE inhibitors, angiotensin II receptor antagonists, antihypertensive drugs (vasodilators and centrally acting agents), adrenergic receptor blockers, calcium channel blockers, and alpha-adrenergic receptor blockers.

In a special clinical study aimed at investigating drug interactions, with the combined use of sildenafil (at a dose of 100 mg) and amlodipine in patients with arterial hypertension, an additional reduction in supine systolic blood pressure of 8 mmHg was noted. The corresponding reduction in diastolic blood pressure was 7 mmHg. In magnitude, these additional reductions in blood pressure were comparable to those observed in the group of healthy volunteers using sildenafil alone (see the “Pharmacological Action” section).

Sildenafil (at a dose of 100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme, at steady state.

Sildenafil at steady state (80 mg 3 times/day) caused an increase in the AUC of bosentan (125 mg 2 times/day) by 49.8% and C_max by 42% in healthy male volunteers.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.