Gent, 12.5mg/dose 5 ml

Pharmacotherapeutic group: Erectile dysfunction treatment – FDE5 inhibitor.

ATX code: G04BE03

Pharmacological properties

Pharmacodynamics

Sildenafil is a selective inhibitor of cycloguanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (FDE5).

The mechanism of action

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This in turn leads to an increase in cGMP levels, a subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and an increase in blood flow.

Sildenafil has no direct relaxant effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against FDE5 in vitro, its activity against 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 to FDEZ, which is of great importance because FDEZ is one of the key enzymes regulating myocardial contractility.
Sexual stimulation is necessary condition for effectiveness of sildenafil.

Pharmacokinetics

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

Intake

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (25% to 63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. After a single sildenafil dose of 100 mg, the average maximum plasma concentration (Cmax) of free sildenafil in men is about 18 ng/ml (38 nM). Cmax when sildenafil is taken orally on an empty stomach is reached on average within 60 min (30 to 120 min). When taken in combination with fatty food the absorption rate decreases: Cmax is decreased by 29 % on average, and time to maximum concentration (Tmax) is increased by 60 min, but absorption degree does not change significantly (area under the pharmacokinetic curve of concentration-time (AUC) is decreased by 11 %).

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 liters. The binding of sildenafil and its main circulating N-demethyl metabolite to plasma proteins is about 96% and is independent of the total drug concentration. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 min after taking the drug.

Metabolism

Sildenafil is metabolized primarily 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. Selectivity of this metabolite against FDE in vitro is about 50% of sildenafil activity. The concentration of the metabolite in plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite is further metabolized; its half-life (T1/2) is about 4 hours.

The total clearance of sildenafil is 41 l/hour and the final T1/2 is 3-5 hours. After oral administration as well as after intravenous administration sildenafil is excreted as metabolites mainly by the intestine (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

Pharmacokinetics in special patient groups

Elderly patients

In healthy elderly patients (over 65 years), sildenafil clearance is reduced and free sildenafil plasma concentrations are about 40% higher than in younger patients (18-45 years). Age has no clinically significant effect on the incidence of side effects.

Renal dysfunction

In mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal impairment (creatinine clearance < 30 ml/min) sildenafil clearance is decreased, resulting in approximately twofold increase of area under pharmacokinetic curve of concentration-time (AUC by 100%) and Cmax (88%) compared to those in normal renal function patients of the same age group.

Hepatic disorders

In patients with cirrhosis (Child-Pugh stages A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) and Cmax (47%) compared to normal hepatic function in patients in the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway), therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance. There is a decrease in sildenafil clearance when concomitant use of inhibitors of cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine).

Cimetidine (800 mg), a non-specific inhibitor of cytochrome CYP3A4 isoenzyme, when combined with sildenafil (50 mg) causes an increase in plasma concentration of sildenafil by 56 %. Simultaneous use of sildenafil 100 mg together with erythromycin (500 mg/day 2 times a day for 5 days), a moderate inhibitor of cytochrome CYP3A4 isoenzyme, against the background of achieving a constant concentration of erythromycin in blood, leads to an increase in sildenafil AUC by 182%. When taking sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times a day), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, together against achieving a steady concentration of saquinavir in blood Cmax of sildenafil was increased by 140 %, and AUC was increased by 210 %. Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of CYP3A4 cytochrome isoenzyme, such as ketoconazole and itraconazole, may also cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P450 inhibitor, on reaching a steady blood concentration of ritonavir results in a 300% (4-fold) increase in Cmax of sildenafil and a 1000% (11-fold) increase in AUC. After 24 hours, plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil has no effect on the pharmacokinetics of ritonavir. Given these data, concomitant administration of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil should never exceed 25 mg for 48 hours.

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

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

. In studies involving healthy volunteers, concomitant use of the endothelin receptor antagonist, bosentan (an inducer of the CYP3A4 (moderate), CYP2C9 and possibly CYP2C19 isoenzymes) at equilibrium concentration (125 mg 2 times daily) and sildenafil at equilibrium concentration (80 mg 3 times daily) resulted in a 62.6 % and 52.4 % decrease in AUC and Cmax of sildenafil, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively. It is suggested that concomitant use of sildenafil with potent inducers of CYP3A4 isoenzyme, such as rifampicin, may lead to a greater reduction in plasma concentration of sildenafil.

. CYP2C9 isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not influence sildenafil pharmacokinetics.

Asithromycin (500 mg/day for 3 days) has no effect on AUC, Cmax, Tmax, elimination rate constant and T1/2 of sildenafil or its main circulating metabolite.

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and WA4 (inhibitory molar concentration of IC50 >150 μmol). When sildenafil is taken at the recommended doses, its Cmax is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes. Sildenafil enhances the hypotensive effect of nitrates both during long-term use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When the alpha-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were administered simultaneously in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic BP/diastolic BP in the supine position was 7/7 mm Hg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension, manifested as dizziness (without fainting), have been reported in these patients. In some sensitive patients receiving alpha-adrenoblockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There are no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9. Sildenafil (100 mg) has no effect on the pharmacokinetics of the HIV protease inhibitor, saquinavir, which is a substrate of the cytochrome CYP3A4 isoenzyme, at constant blood levels.

Concomitant use of sildenafil at equilibrium (80 mg 3 times daily) increases the AUC and Cmax of bosentan (125 mg 2 times daily) by 49.8% and 42%, respectively. Sildenafil (50 mg) does not cause an additional increase in bleeding time with acetylsalicylic acid (150 mg).

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

In patients with arterial hypertension, there is no evidence of interaction between sildenafil (100 mg) and amlodipine. The mean additional reduction of BP in the supine position is 8 mmHg (systolic) and 7 mmHg (diastolic).

The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.

Special Instructions

To diagnose erectile dysfunction, determine its possible causes, and choose an adequate treatment, a complete medical history and a thorough physical examination must be taken. Erectile dysfunction treatments should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

In the post-marketing period, the development of prolonged erections and priapism has been reported. If an erection persists for more than 4 hours, immediate medical attention should be sought. If priapism therapy is not carried out in time, it may lead to damage of penile tissues and permanent loss of potency.

The drugs intended to treat erectile dysfunction should not be used in men for whom sexual activity is undesirable.

Sexual activity poses a risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any therapy for erectile dysfunction. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg). Sildenafil is contraindicated in these patients (see section “Contraindications”). There is no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality rate (0.3 per 100 people per year) in patients who received sildenafil compared to patients who received placebo.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (includingincluding myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after sildenafil administration without subsequent sexual activity. There is no direct correlation between the adverse events noted and these or other factors.

Hypotension

Sildenafil has a systemic vasodilator effect resulting in a transient decrease in BP, which is not clinically significant and does not result in any consequences in most patients. Nevertheless, before prescribing sildenafil, the physician should assess the risk of possible adverse effects of vasodilatation in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), and with the rare syndrome of multiple systemic atrophy manifested by severe BP regulation disorder of the autonomic nervous system.

Caution should be exercised when using sildenafil concomitantly with alpha-adrenoblockers due to the risk of symptomatic hypotension in some sensitive patients (see section “Interaction with other medicinal products”). To minimize the risk of postural hypotension in patients taking alpha-adrenoblockers, sildenafil should be started only after hemodynamic stabilization is achieved. It should also be considered whether it is reasonable to reduce the initial dose of Gent® (see section “Dosage and administration”). The physician should inform the patient about what actions should be taken if symptoms of postural hypotension occur.

Visual disturbances

In the postmarketing period, rare cases of NSAIDs, a rare condition and cause of decreased or lost vision when using FDE5 inhibitors, including sildenafil, have been reported. Most of these patients had risk factors, such as decreased ratio of excavation and optic disc diameters (“stagnant disc”), age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease, hyperlipidemia, and smoking. The observational study evaluated the association of recent use of drugs in the class of FDE5 inhibitors with the acute onset of NSAIDs. Results indicated an approximately 2-fold increased risk of NPINDN within 5 half-lives of use of an FDE5 inhibitor. According to published literature, the annual incidence of NSAIDs is 2.5 to 11.8 cases per 100,000 men aged ≥50 years in the general population. Patients should be advised to discontinue sildenafil therapy in case of sudden vision loss and immediately consult a physician. Individuals who have already had a history of NSAIDs have an increased risk of recurrence of NSAIDs. Therefore, the physician should discuss this risk with such patients and also discuss with them the potential for adverse effects of FDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in these patients and only in situations where the expected benefits outweigh the risks.

A small number of patients with hereditary retinitis pigmentosa have genetically determined retinal phosphodiesterase dysfunction. There is no information on the safety of sildenafil use in patients with retinitis pigmentosa, so these patients should not use sildenafil (see section “Contraindications”).

Hearing impairment

There have been reports of sudden hearing impairment or loss associated with use of FDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden hearing impairment or loss. A causal relationship between the use of FDE5 inhibitors and sudden hearing impairment or hearing loss has not been established. In case of sudden hearing impairment or hearing loss while taking sildenafil, consult a physician immediately.

Bleeding

Sildenafil enhances the antiaggregant effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil administration in patients with a tendency to bleeding or exacerbation of peptic ulcer disease, so sildenafil should be used with caution in these patients (see section “Caution”). The incidence of nasal bleeding in patients with pulmonary hypertension associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). Patients who received sildenafil in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).

The concomitant use of Gent® with other erectile dysfunction therapy is not recommended with other FDE5 inhibitors, other sildenafil-containing pulmonary arterial hypertension drugs, or other treatments for erectile dysfunction, becausebecause the efficacy and safety of co-administration has not been studied (see Contraindications).

No adverse effects on the ability to operate vehicles and other mechanisms have been observed during sildenafil use. However, since taking sildenafil may cause dizziness, decreased blood pressure, chromatopsia, blurred vision and other side effects, caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require high concentration and rapid psychomotor reactions. Care should also be taken with regard to the individual action of the drug in the above situations, especially at the beginning of treatment and when changing the dosing regimen.

Contraindications

Side effects

Overdose

Pregnancy use

Similarities