GENT spray internal

Instructions for use

GENT spray internal 12.5 mg / dose vial-doses 32 doses

Composition

Composition for 1 dose

Active ingredient: sildenafil citrate 17.559 mg (in terms of sildenafil 12.5 mg).

Excipients: propylene glycol 92.625 mg, alcohol 96% 23.400 mg,

macrogol-400 (polyethylene glycol 400) 9.360 mg, purified water 7.513 mg, concentrated hydrochloric acid 2.773 mg, lemon oil 1.310 mg, sucralose 1.200 mg, saccharin 0.187 mg, racemic menthol 0.047 mg, sodium cyclamate 0.016 mg.

Dosage form

dosed oral spray

Description

Transparent liquid of yellowish or greenish-yellow color with a characteristic odor.

Action

For erectile dysfunction, the treatment is a PDE5 inhibitor.

Pharmacodynamics

Sildenafil is a selective inhibitor of cycloguanosine monophosphate (cGMP), a specific phosphodiesterase type 5 (PDE5).

Mechanism of action

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

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is superior to that 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.

Sexual stimulation is a prerequisite for the effectiveness of sildenafil.

Pharmacokinetics

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

Suction

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) inhibits human PDE5 activity by 50%. After a single dose of 100 mg of sildenafil, the average maximum plasma concentration of free sildenafil (C max) in men is about 18 ng / ml (38 nM). C max when taking sildenafil inside on an empty stomach is achieved on average within 60 minutes (from 30 minutes to 120 minutes). When taken in combination with fatty foods, the absorption rate decreases: C max decreases by an average of 29%, and the time to reach the maximum concentration (T max) increases by 60 minutes, but the degree of absorption does not change significantly (area under the concentration-time pharmacokinetic curve (AUC ) decreases by 11%).

Distribution

The volume of distribution of sildenafil at steady state averages 105 liters. The connection of sildenafil and its main circulating N-demethyl metabolite with blood plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in semen 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized mainly in the liver under the action of the cytochrome CYP3A4 isoenzyme (main pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite resulting from N-demethylation of sildenafil is further metabolized. The selectivity of this metabolite in relation to PDE in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; its half-life (T?) is about 4 hours.

Withdrawal

The total clearance of sildenafil is 41 l / h, and the final T? - 3-5 hours. After oral administration, as well as after intravenous administration, sildenafil is excreted as metabolites, mainly by the intestines (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 old), the clearance of sildenafil is reduced, and the concentration of free sildenafil in the blood plasma is about 40% higher than in young people (18-45 years old). Age does not have a clinically significant effect on the incidence of side effects.

Renal dysfunction

With mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-49 ml / min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance <30 ml / min), sildenafil clearance decreases, which leads to an approximately two-fold increase in the area under the concentration-time pharmacokinetic curve (AUC by 100%) and C max (88%) compared with that and indicators for normal renal function in patients of the same age group.

Liver dysfunction

In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil decreases, which leads to an increase in the AUC (84%) and C max (47%) values ​​compared with those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severely impaired liver function (class C according to the Child-Pugh classification) has not been studied.

Indications for use

Treatment of erectile dysfunction, characterized by an inability to achieve or maintain an erection of the penis sufficient for satisfactory intercourse.

Sildenafil is only effective for sexual stimulation.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug.

Use in patients receiving continuous or intermittent nitric oxide donors, organic nitrates or nitrites in any form, since sildenafil enhances the hypotensive effect of nitrates.

Concomitant use with guanylate cyclase stimulants, such as riociguat, as this can lead to symptomatic hypotension.

Concomitant use with other drugs for the treatment of erectile dysfunction has not been studied, so the use of such combinations is not recommended.

Severe hepatic impairment (Child-Pugh class C). Concomitant use of ritonavir.

Severe cardiovascular diseases (severe heart failure, unstable angina pectoris, stroke or myocardial infarction within the last six months, life-threatening arrhythmias, hypertension (BP> 170/100 mm Hg) or arterial hypotension (BP <90/50 mm Hg)).

Patients with episodes of non-arteritis anterior ischemic neuropathy of the optic nerve with loss of vision in one eye.

Hereditary retinitis pigmentosa.

Female.

Age up to 18 years (efficacy and safety have not been established).

Application during pregnancy and lactation

The drug is not intended for use in women.

Application in children

The drug is not intended for use in children.

Side effects

The most common side effects were headache and hot flashes.

Usually, the side effects of the drug are mild to moderate and transient.

When using a fixed dose, the frequency of some adverse events increases with increasing dose.

To assess the incidence of adverse events, the following criteria were used (according to the classification of the World Health Organization): very often (? 10%); often (? 1% and <10%); infrequently (? 0.1% and <1%); rarely (? 0.01% and <0.1%); very rare (<0.01%); the frequency is unknown (there is not enough data to estimate the frequency of development).

From the immune system: infrequently - hypersensitivity reactions (including skin rash), allergic reactions.

From the side of the organ of vision: often - blurred vision, blurred vision, cyanopsia; infrequently - eye pain, photophobia, chromatopsia, redness of the eyes / sclera 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 vision around the light source, increased eye fatigue, seeing objects in yellow color (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, irritation of the mucous membranes membranes of the eyes, discomfort in the eyes; frequency unknown - non-arteritis 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 / vitreous traction.

From the side of the organ of hearing and labyrinth disorders: infrequently - sudden hearing loss or loss, tinnitus, ear pain.

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

On the part of 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, chest and mediastinal organs: often - nasal congestion; infrequently - epistaxis, rhinitis, asthma, dyspnoea, laryngin, pharyngitis, sinusitis, bronchitis, increased sputum volume, increased cough; rarely - a feeling of tightness in the throat, dryness of the nasal mucosa, edema of the nasal mucosa.

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

Musculoskeletal and connective tissue disorders: often - back pain; infrequently - myalgia, limb pain, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.

From the side of the kidneys and urinary tract: infrequently - cystitis, nocturia, urinary incontinence, hematuria.

On the part of the genitals and mammary gland: infrequently - an increase in the mammary glands (men), impaired ejaculation, edema of the genitals, anorgasmia, hematospermia, damage to the tissues of the penis; rarely, prolonged erection and / or priapism.

From the nervous system: very often - headache; often - dizziness; infrequently - drowsiness, migraine, ataxia, hypertonicity, neuralgia, neuropathy, paresthesia, tremor, vertigo, symptoms of depression, insomnia, unusual dreams, increased reflexes, hypesthesia; rarely - convulsions, repeated convulsions, fainting.

On the part of the skin and subcutaneous tissues: infrequently - skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis.

Others: infrequently - a feeling of heat, swelling of the face, photosensitivity reaction, shock, asthenia, fatigue, pain of various localization, chills, accidental falls, chest pain, accidental trauma; rarely - irritability.

Cardiovascular complications

During the post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina pectoris, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension), which had a temporary connection 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 were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish the presence of a direct connection between the observed undesirable phenomena and the indicated or other factors.

Visual impairment

In rare cases, during the post-registration use of all PDE5 inhibitors, including sildenafil, non-arteritis anterior ischemic neuropathy of the optic nerve (NPINZN), a rare disease and the cause of a decrease or loss of vision, has been reported. Most of these patients had risk factors, in particular a decreased ratio of the diameters of the excavation and the optic nerve head ("stagnant disc"), age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking. An observational study assessed the association of recent use of drugs of the PDE5 inhibitor class with acute onset of NPINZN. The results indicate an approximately 2-fold increased risk of NPINZN within 5 elimination half-lives after PDE5 inhibitor administration. According to published literature data, the annual incidence of NPINZN is 2.5-11.8 cases per 100,000 men of the age? 50 years in the general population. In case of sudden loss of vision, patients should be advised to discontinue sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPINZN have an increased risk of recurrence of NPINZN. Therefore, the physician should discuss this risk with such patients, and also discuss with them the potential risk of adverse effects of PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in these patients and only in situations where the expected benefit outweighs the risk.

When using sildenafil in doses higher than recommended, adverse events were similar to those noted above, but usually more common.

If any of the side effects indicated in the instructions are aggravated, or you notice any other side effects not listed in the instructions, inform your doctor.

Interaction

The effect of other drugs on the pharmacokinetics of sildenafil

Sildenfil metabolism occurs mainly under the influence of cytochrome isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil was noted with the simultaneous use of inhibitors of the isoenzyme of cytochrome CYP3A4 (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 concentration of sildenafil 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, against the background of reaching a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%. With the combined administration of sildenafil (100 mg once) and saquinavir (1200 mg / day 3 times a day), an inhibitor of HIV protease and cytochrome CYP3A4 isoenzyme, against the background of reaching a constant concentration of saquinavir in the blood, the C max 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, can also cause stronger changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg 2 times a day), an inhibitor of HIV protease and a strong inhibitor of cytochrome P 450, against the background of reaching a constant concentration of ritonavir in the blood leads to an increase in Cmax of sildenafil by 300% (in 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 one sildenafil - 5 ng / ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P 450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these data, concomitant 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 receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the C max 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 with the participation of healthy volunteers with the simultaneous use of an endothelin receptor antagonist, bosentan (inducer of the isoenzyme CYP3A4 (moderate), CYP2C9 and possibly CYP2C19) at an equilibrium concentration (125 mg 2 times a day) and sildenafil at an equilibrium concentration (80 mg 3 times a day) there was a decrease in AUC and Cmax of sildenafil by 62.6% and 52.4%, 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 powerful inducers of the isoenzyme CYP3A4, such as rifampicin, may lead to a greater decrease in the concentration of sildenafil in blood plasma.

Inhibitors of cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACP inhibitors and calcium antagonists have no effect on calcium pharmacokinetics. Azithromycin (500 mg / day for 3 days) has no effect on AUC, C max, T max, elimination rate constant and T 1/2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other medicines

Sildenafil is a weak inhibitor of cytochrome P 450 isoenzymes - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (inhibiting molar concentration of IC 50> 150 μmol). When sildenafil is taken in recommended doses, its C max is about 1 μmol, therefore it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes. Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter and with their appointment for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

With the simultaneous administration of the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic blood pressure / 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. Reported rare cases of the development of symptomatic postural hypotension in such patients, manifested in the form of dizziness (without fainting). In some sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil can lead to symptomatic hypotension.

Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme, have not been identified. 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 a constant level in the blood.

The simultaneous use of sildenafil in an equilibrium state (80 mg 3 times a day) leads to an increase in AUC and C max of bosentan (125 mg 2 times a day) 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 an average of 0.08% (80 mg / dL).

In paients with arterial 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.

Method of administration and dosage

Inside.

When using for the first time or during a break in the use of the drug, you should sharply press the sprayer several times, directing the spray into the air until a uniform spray cloud is formed.

When using, the bottle should be held vertically, with the spray up. Bring the bottle close to the mouth and, pressing with a short sharp movement on the nebulizer, inject the solution (one dose contains 12.5 mg of sildenafil). Repeat the injection procedure until the recommended dose is reached and drink water. The solution should not be inhaled.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Taking into account the effectiveness and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once a day.

Renal dysfunction

In case of mild to moderate renal failure (creatinine clearance 30-80 ml / min), dose adjustment is not required; in severe renal failure (creatinine clearance <30 ml / min), the dose of sildenafil should be reduced to 25 mg.

Storage conditions

At a temperature not higher than 30 ° C.

Keep out of the reach of children.

Shelf life

2 years.