Dynamico, 100 mg

AtCode: G04BE03

Pharmacological properties

Pharmacodynamics.

The erectile dysfunction drug restores impaired erectile function under sexual stimulation by increasing blood flow in the penis.

The physiological mechanism of erection involves the release of nitric oxide (NO) in the cavernous body due to sexual arousal. NO activates the enzyme guanylate cyclase, which increases the concentration of cyclic guanosine monophosphate (cGMP). In turn, cGMP causes the smooth muscles of blood vessels to relax and, consequently, the flow of blood into the cavernous body of the penis.

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which causes the breakdown of cGMP in the cavernous body of the penis. It does not have a direct relaxing effect on the smooth muscles of the cavernous body, but increases the relaxing effect of nitric oxide on this tissue and increases blood flow in the

C penis. During activation of the NO – cGMP chain observed during sexual stimulation, inhibition of FDE5 leads to an increase of cGMP in the cavernous body. The pharmacological effect is achieved only in the presence of sexual stimulation.

The activity of sildenafil in relation to FDE5 is superior to other known phosphodiesterase isoenzymes: FDE6 – 10 times, FDE1 – more than 80 times; FDE2 – FDE4, FDE7-FDE11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE5 compared with FDE3, which is important because FDE3 is one of the key enzymes regulating myocardial contractility.

Sildenafil has a mild and short-lived hypotensive effect, in most cases with no clinical manifestation when taken at recommended doses. The hypotensive effect is due to the vasodilatory effect of sildenafil due to an increase in cGMP in the vascular smooth muscle membrane.

Clinical data

Cardiology studies

The use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after sildenafil administration at a dose of 100 mg was 8.3 mm Hg, and in diastolic blood pressure, 5.3 mm Hg. A more pronounced, but also transient effect on blood pressure (BP) was noted in patients taking nitrates (see “Contraindications” and “Interaction with other medications”).

In a study of the hemodynamic effects of sildenafil at a single dose of 100 mg in 14 patients with severe coronary heart disease (CHD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic BP decreased by 7% and 6%, respectively, and pulmonary systolic BP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenosed coronary arteries, and it also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until the severity of angina symptoms decreased. Exercise duration was significantly longer (19.9 seconds; 0.9 to 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of a variable dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and arterial hypertension taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in those taking more than three antihypergenic drugs.

Studies on visual impairment

In some patients, a mild and transient impairment in the ability to distinguish shades of color (blue/green) was detected 1 hour after taking sildenafil at a dose of 100 mg using the Farnsworth-Munsel 100 test. These changes were absent 2 hours after taking the drug. The color vision impairment is thought to be caused by inhibition of FDE6, which is involved in the transmission of light in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

In a placebo-controlled, crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil at a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision as assessed by specific visual tests (visual acuity, Amsler grid, color perception, color passage simulation, Humphrey perimeter, and photostress).

The efficacy and safety of sildenafil were evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic, or mixed). Efficacy of the drug was evaluated globally using an erection diary, the International Erectile Function Index (a validated sexual function questionnaire), and a partner survey.

The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies conducted and has been confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients reporting that therapy improved their erections was 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose), compared with 25% in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improved erections, sildenafil treatment also improved the quality of orgasm, allowed to achieve satisfaction of intercourse and overall satisfaction.

The pooled data showed that 59% of patients who reported improved erections with sildenafil treatment were diabetic patients, 43% of patients who had undergone radical prostatectomy, and 83% of patients with spinal cord injuries (versus 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics

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

Absorption. After oral administration, it is rapidly absorbed. Maximum plasma concentration (C_max) when taken on an empty stomach is reached within 0.5-2 hours, bioavailability is on average 41% (25-63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. When taken in combination with fatty foods the absorption rate is reduced: C_max is reduced by an average of 29% and the time to reach maximum concentration (T_max) is increased by 60 minutes, but the degree of absorption is not significantly changed (the area under the pharmacokinetic curve of concentration-time (AUC) is reduced by 11%).

Distribution. The apparent volume of distribution in the equilibrium state is 105 liters. The binding of sildenafil and its main active metabolite to plasma proteins is 96% of the administered dose and is not dose-dependent. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 min after drug administration.

Metabolism. Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (additional pathway). The main circulating active metabolite is N-desmethylmetabolite (N-desmethyl metabolite), whose activity against phosphodiesterase is 50% of sildenafil activity and its plasma concentration reaches 40% of sildenafil concentration. N-desmethylmetabolite undergoes further metabolism with a half-life of 4 hours.

Elimation. Total clearance of sildenafil is 41 l/h. The half-life (T_½) of sildenafil is 3-5 hours. Inactive metabolites are excreted through the intestine (80%) and the kidneys (13%).

Pharmacokinetics in special groups of patients.

In healthy patients over 65 years of age, the C_max of sildenafil and its active metabolite is increased by approximately 90% compared to younger patients (18-45 years) due to decreased sildenafil clearance. Plasma concentrations of free sildenafil are approximately 40% higher in older patients than in younger patients.

Age has no clinically significant effect on the incidence of side effects.

In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil are not altered by taking 50 mg, and C_max and area under the concentration-time curve (AUC) for N-desmethylmetabolite are increased by 73% and 126%, respectively. In patients with severe renal impairment (creatinine clearance less than 30 mL/min), C_max and AUC are increased by 88% and 100%, respectively, C_max and AUC of N-desmethylmetabolite are increased by 79% and 200%, respectively.

In patients with cirrhosis (Child-Pugh grades A and B), C_max and AUC are increased by 47% and 84%, respectively.

The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain penile erection sufficient for satisfactory sexual intercourse.
Effective only with sexual stimulation.

Pharmacological effect

Pharmacotherapeutic group: treatment of erectile dysfunction – PDE5 inhibitor.

ATX code: G04BE03

Pharmacological properties

Pharmacodynamics

A drug for the treatment of erectile dysfunction, it restores impaired erectile function under conditions of sexual stimulation by increasing blood flow in the penis.

The physiological mechanism of erection involves the release of nitric oxide (NO) in the corpus cavernosum due to sexual arousal. NO activates the enzyme guanylate cyclase, which leads to increased concentrations of cyclic guanosine monophosphate (cGMP). In turn, cGMP causes relaxation of the smooth muscles of the blood vessels and, accordingly, blood flow into the cavernous body of the penis.

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which causes the breakdown of cGMP in the corpus cavernosum of the penis. It does not have a direct relaxing effect on the smooth muscle of the corpus cavernosum, but it enhances the relaxing effect of nitric oxide on this tissue and increases blood flow in the penis. When the NO – cGMP chain is activated, observed during sexual stimulation, inhibition of PDE5 leads to an increase in cGMP in the corpus cavernosum. The pharmacological effect is achieved only in the presence of sexual stimulation.

The activity of sildenafil against PDE5 exceeds the activity against other known phosphodiesterase isoenzymes: PDE6 – 10 times, PDE1 – more than 80 times; PDE2 – PDE4, PDE7-PDE11 – more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of great importance since PDE3 is one of the key enzymes in the regulation of myocardial contractility.

Sildenafil has a mild and short-term hypotensive effect, in most cases without clinical manifestations when taken in recommended doses. The hypotensive effect is associated with the vasodilating effect of sildenafil due to an increase in the content of cGMP in the smooth muscle of the blood vessels.

Clinical data

Cardiac research

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mm Hg. Art., and diastolic pressure – 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure (BP) was observed in patients taking nitrates (see sections “Contraindications” and “Interaction with other drugs”).

In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (CAD) (more than 70% of patients had stenosis of at least one coronary artery), resting systolic and diastolic blood pressure decreased by 7% and 6%, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 seconds; 0.9 – 38.9 seconds) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of a variable dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.

Visual impairment studies

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n = 9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grating, color perception, color transmission simulation, Humphrey perimeter, and photostress).

Efficiency

The efficacy and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and was confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportions of patients who reported that the therapy improved their erections were: 62% (sildenafil 25 mg dose), 74% (sildenafil 50 mg dose), and 82% (sildenafil 100 mg dose), compared with 25% in the placebo group. Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, among patients who reported improved erections with sildenafil treatment, 59% of patients with diabetes, 43% of patients undergoing radical prostatectomy, and 83% of patients with spinal cord injury (versus 16%, 15% and 12% in the placebo group, respectively) were included.

Pharmacokinetics

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

Suction. After oral administration, it is quickly absorbed. The maximum concentration in blood plasma (Cmax) when taken on an empty stomach is achieved within 0.5-2 hours, bioavailability averages 41% (25-63%). In vitro, sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human PDE5 activity by 50%. When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).

Distribution. The apparent volume of distribution at steady state is 105 l. The binding of sildenafil and its main active metabolite to plasma proteins is 96% of the administered dose and is not dose-dependent. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after dosing.

Metabolism. Sildenafil is metabolized mainly by the CYP3A4 (main pathway) and CYP2C9 (additional pathway) liver microsomal isoenzymes. The main circulating active metabolite is N-desmethyl metabolite, whose activity against phosphodiesterase is 50% of the activity of sildenafil, and its plasma concentration reaches 40% of the concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism with a half-life of 4 hours.

Excretion. The total clearance of sildenafil is 41 l/h. The half-life (T½) of sildenafil is 3-5 hours. Inactive metabolites are excreted through the intestines (80%) and kidneys (13%).

Pharmacokinetics in special groups of patients.

In healthy patients over 65 years of age, the Cmax of sildenafil and its active metabolite is increased by approximately 90% compared to young patients (18-45 years of age) due to reduced clearance of sildenafil. The plasma concentration of free sildenafil in elderly patients is approximately 40% higher than in young patients.

Age does not have a clinically significant effect on the incidence of side effects.

In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil do not change when taking 50 mg, and Cmax and the area under the concentration-time curve (AUC) for the N-desmethyl metabolite are increased by 73% and 126%, respectively. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), Cmax and AUC are increased by 88% and 100%, respectively, Cmax and AUC of N-desmethyl metabolite are increased by 79% and 200%, respectively.

In patients with liver cirrhosis (Child-Pugh classes A and B), Cmax and AUC were increased by 47% and 84%, respectively.

The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) has not been studied.

Special instructions

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination. Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, you should immediately seek medical help. If treatment for priapism is not carried out immediately, it can lead to damage to the tissue of the penis and irreversible loss of potency.

Medicines intended to treat erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the condition of the cardiovascular system. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg). Taking sildenafil in such patients is contraindicated (see section "Contraindications"). Clinical studies showed no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular death (0.3 per 100 people per year) in patients receiving sildenafil compared with patients receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) were reported, which were temporarily associated with the use of sildenafil. Most of these patients (but not all of them) had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing the drug, the physician must carefully assess the risk of possible undesirable manifestations of the vasodilating effect in patients with relevant 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 the rare syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the combined use of sildenafil and α-blockers can lead to symptomatic hypotension in some sensitive patients, the drug should be prescribed with caution to patients taking α-blockers (see section “Interaction with other drugs”). To minimize the risk of postural hypotension in patients taking α-blockers, sildenafil should be started only after hemodynamic stability has been achieved in these patients. You should also consider the advisability of reducing the initial dose of sildenafil (see section “Dosage and Administration”). The physician should inform patients about what actions to take if symptoms of postural hypotension occur.

Visual impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy (NAION), a rare disease and cause of vision loss or reduction, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. Results indicate an approximately 2-fold increase in the risk of NPINSID within 5 half-lives of PDE5 inhibitor use. According to the published literature, the annual incidence of NPINSID is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPINSID are at increased risk of recurrent NPINSID. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk. In patients with episodes of NPINS development with loss of vision in one eye, sildenafil is contraindicated (see section “Contraindications”).

A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of the drug in patients with retinitis pigmentosa, therefore sildenafil should not be used in such patients (see section “Contraindications”).

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. If there is a sudden deterioration in hearing or hearing loss while taking sildenafil, you should consult your doctor immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so the drug should be used with caution in these patients (see section “With caution”). The incidence of epistaxis in patients with pulmonary hypertension associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary arterial hypertension (sildenafil 3.0%, placebo 2.4%). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction

The safety and effectiveness of sildenafil in combination with other PDE5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil, or other drugs for the treatment of erectile dysfunction, therefore the use of such combinations is not recommended (see section “Contraindications”).

Impact on the ability to drive vehicles and machinery

While taking sildenafil, no negative effects on the ability to drive a car or use other technical equipment were observed.

However, since when taking sildenafil, dizziness, decreased blood pressure, development of chromatopsia, blurred vision, etc. are possible. side effects, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. You should also be careful about the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Active ingredient

Sildenafil

Composition

1 tablet contains:

active ingredient sildenafil citrate 35.12 mg, 70.24 mg or 140.48 mg (in terms of sildenafil 25.00 mg, 50.00 mg or 100.00 mg);

excipients: microcrystalline cellulose (PH 101) 102.88 mg, 205.76 mg or 411.52 mg; croscarmellose sodium 5.25 mg, 10.50 mg or 21.00 mg; hyprolose (hydroxypropylcellulose) 4.50 mg, 9.00 mg or 18.00 mg; colloidal silicon dioxide (anhydrous colloidal silicon dioxide) 0.75 mg, 1.50 mg or 3.00 mg; magnesium stearate 1.50 mg, 3.00 mg or 6.00 mg; film coating: Opadry II 31F58914 white (hypromellose (E 464), lactose monohydrate, titanium dioxide (E 171), macrogol-4000, sodium citrate dihydrate (E 331)) 5.955 mg, 11.91 mg or 23.82 mg, indigo carmine (E 132) 0.045 mg, 0.09 mg or 0.18 mg.

Pregnancy

According to its registered indication, the drug is not intended for use in women.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug; simultaneous intake of nitric oxide donors or organic nitrates or nitrates in any dosage forms; simultaneous use of ritonavir; patients for whom sexual activity is undesirable, including those with severe cardiovascular diseases, such as: unstable angina, severe heart failure, life-threatening arrhythmias; co-administration with guanylate cyclase stimulants such as riociguat, as this may lead to symptomatic hypotension; arterial hypotension (blood pressure (BP) less than 90/50 mm Hg), arterial hypertension (BP more than 170/100 mm Hg): recent cerebrovascular accident or myocardial infarction; patients with loss of vision in one eye due to anterior ischemic optic neuropathy of non-arteritic origin (regardless of whether this occurred due to taking a PDE5 inhibitor or not); hereditary degenerative diseases of the retina, including retinitis pigmentosa (a minority of these patients have a genetic disease of retinal PDE); severe liver failure; female gender; age up to 18 years.

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

The safety and effectiveness of sildenafil when used in combination with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section “Special Instructions”).

With caution

Anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease) (see section “Special instructions”).

Diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section “Special instructions”).

Diseases accompanied by bleeding.

Peptic ulcer of the stomach and duodenum in the acute stage.

Liver dysfunction.

Severe renal failure (creatinine clearance less than 30 ml/min).

Patients with a history of an episode of anterior non-arteritic ischemic optic neuropathy (see section “Special Instructions”).

Concomitant use of alpha-adrenergic blockers.

Side Effects

The most common side effects were headache and flushing.

Typically, the side effects of sildenafil are mild or moderate and transient.

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

The frequency of adverse reactions is presented according to the following classification:

Very often

≥10%

Often

≥1% and <10%

Uncommon

≥0.1% and <1%

Rarely

≥0.01% and <0.1%

Very rarely

<0.01%

Frequency unknown

cannot be determined based on available data

From the immune system: rarely – hypersensitivity reactions (including skin rash), allergic reactions.

From the organ of vision: often – blurred vision, blurred vision, cyanopsia; uncommon – eye pain, photophobia, photopsia, chromatopsia, redness of the eyes/scleral injections, changes in the brightness of light perception, mydriasis, conjunctivitis, hemorrhage in the eye tissue, cataracts, disruption of the lacrimal apparatus; rarely – swelling of the eyelids and adjacent tissues, a feeling of dryness in the eyes, the presence of rainbow circles in the field of view around the light source, increased eye fatigue, seeing objects in yellow (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, irritation of the mucous membrane of the eyes, discomfort in the eyes; frequency unknown – non-arteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect, diplopia*, temporary loss of vision or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreal traction.

From the organ of hearing: uncommon – sudden decrease or loss of hearing, noise, ringing in the ears, pain in the ears.

From the cardiovascular system: often – “hot flashes”; uncommon – tachycardia, palpitations, decreased blood pressure, increased blood pressure, increased heart rate, unstable angina, atrioventricular block, myocardial infarction, cerebral thrombosis, cardiac arrest, heart failure, abnormalities in electrocardiogram readings, cardiomyopathy; rarely – atrial fibrillation, sudden cardiac death*, ventricular arrhythmia*.

From the blood and lymphatic system: infrequently – anemia, leukopenia.

From the side of metabolism and nutrition: infrequently – a feeling of thirst, edema, gout, uncompensated diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

From the respiratory system: often – nasal congestion; uncommon – nosebleeds, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased volume of sputum, increased cough; rarely – a feeling of tightness in the throat, dryness of the nasal mucosa, swelling of the nasal mucosa.

From the gastrointestinal tract: often – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, abdominal pain, dry oral mucosa, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding; rarely – hypoesthesia of the oral mucosa.

From the musculoskeletal system: often – back pain; uncommon – myalgia, pain in the limbs, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.

From the genitourinary system: infrequently – cystitis, nocturia, breast enlargement, urinary incontinence, hematuria, ejaculation disorders, genital swelling, anorgasmia, hematospermia, damage to penile tissue; rarely – prolonged erection and/or priapism, bleeding from the penis.

From the central and peripheral nervous system: very often – headache; often – dizziness; uncommon – drowsiness, migraine, ataxia, hypertonicity, neuralgia, neuropathy, paresthesia, tremor, vertigo, symptoms of depression, insomnia, unusual dreams, increased reflexes, hypoesthesia; rarely – convulsions*, repeated convulsions*, fainting, cerebrovascular accident, transient ischemic attack.

From the skin and subcutaneous tissues: uncommon – skin rash, urticaria, herpes simplex, itching, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis.

Other: infrequently – feeling of heat, swelling of the face, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various localizations, chills, accidental falls, pain in the chest, accidental injuries; rarely – irritability.

* Side effects identified during post-marketing studies.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) were reported, which were temporarily associated with the use of sildenafil. Most of these patients (but not all of them) had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Visual impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy (NAION), a rare disease and cause of vision loss or reduction, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. Results indicate an approximately 2-fold increase in the risk of NPINSID within 5 half-lives of PDE5 inhibitor use. According to the published literature, the annual incidence of NPINSID is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPINSID are at increased risk of recurrent NPINSID. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk.

When sildenafil was used in doses higher than recommended, adverse events were similar to those noted above, but usually occurred more frequently.

Interaction

The influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the influence of the cytochrome isoenzymes CYP3A4 (the main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, accordingly, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in plasma sildenafil concentrations by 56%.

A single dose of 100 mg of sildenafil together with erythromycin (500 mg/day 2 times a day for 5 days), a moderate inhibitor of the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When co-administered with sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times a day), an inhibitor of HIV protease and the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more severe changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong inhibitor of cytochrome P450, while achieving a constant concentration of ritonavir in the blood leads to an increase in Cmax of sildenafil by 300% (4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng/ml (after a single use of sildenafil alone – 5 ng/ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these data, simultaneous use of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil should under no circumstances exceed 25 mg in 48 hours.

If sildenafil is taken in recommended doses by patients simultaneously receiving strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the Cmax of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

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

In studies involving healthy volunteers, with simultaneous use of the endothelin receptor antagonist, bosentan (an inducer of the isoenzyme CYP3A4 (moderate), CYP2C9 and possibly CYP2C19) at equilibrium concentration (125 mg twice daily) and sildenafil at equilibrium concentration (80 mg three times daily), a decrease in AUC and Cmax of sildenafil by 62.6% and 52.4% was observed. respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It is assumed that the simultaneous use of sildenafil with potent inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater decrease in the concentration of sildenafil in the blood plasma.

Inhibitors of the cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), the cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil. Azithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T1/2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other drugs

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

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated. When taking the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) simultaneously in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic/diastolic blood pressure in the supine position was 7/7 mm Hg. Art., 9/5 mm Hg. Art. and 8/4 mm Hg. Art., respectively, and in a standing position – 6/6 mm Hg. Art., 11/4 mm Hg. Art. and 4/5 mm Hg. Art., respectively. Rare cases of symptomatic postural hypotension, manifested in the form of dizziness (without fainting), have been reported in such patients. In selected sensitive patients receiving α-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There were no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme.

Sildenafil (100 mg) does not affect the pharmacokinetics of the HIV protease inhibitor, saquinavir, which is a substrate of the cytochrome CYP3A4 isoenzyme, at constant blood levels.

Co-administration of sildenafil at steady state (80 mg three times daily) increased the AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) does not enhance the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with hypertension, there were no signs of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the supine position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic). The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.

Overdose

Symptoms: with a single dose of the drug up to 800 mg, adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, blurred vision) were more pronounced and occurred more often than when taking regular doses; Doses up to 200 mg increase the frequency, but not the severity, of adverse reactions.
Treatment: symptomatic therapy. Hemodialysis is ineffective.

Storage conditions

Store at a temperature not exceeding 25 C.
Keep out of the reach of children!

Shelf life

3 years.
Do not use after expiration date.

Manufacturer

Pliva Hrvatska d.o.o., Croatia