Buy Sildenafil Verte film-coated tablets 50mg N1

Sildenafil Verte film-coated pills 50mg N1

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Active ingredients

Sildenafil

Release form

Pills

Composition

One capsule with a prolonged release contains: Tamsulosin hydrochloride substance-pellets 0.2% - 200.0 mg [active substance: tamsulosin hydrochloride - 0.4 mg; excipients: sugar spheres (sucrose  99%, hypromellose 1%) - 190.0 mg, methacrylic acid copolymer - 4.8 mg, ethyl cellulose - 4.0 mg, polyethylene glycol - 0.8 mg]. Hard gelatin capsules: titanium dioxide - 1.0%, iron yellow oxide (iron oxide) - 0.27%, blue patented dye - 0.015%, gelatin - up to 100%.

Pharmacological effect

Sildenafil is a potent selective cycloguanosine monophosphate (cGMP) inhibitor of type 5 phosphodiesterase (PDE5). Restores impaired erectile function due to increased blood flow to the penis. The implementation 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 the level of cGMP, subsequent relaxation of the smooth muscle tissue of the cavernous body and an increase in blood flow. Sildenafil does not have a direct relaxing effect on the isolated cavernous body of a person, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP. When activating the NO / cGMP bond, which occurs under the influence of sexual stimuli, suppression of FDE5 by sildenafil leads to an increase in cGMP in the cavernous body. Thus, sexual stimulation is necessary for the development of the desired pharmacological action of sildenafil. Sildenafil is selective for in vitro PDE5, its activity against PDE5 exceeds that for other known phosphodiesterase isoenzymes: PDE6 - 10 times; PDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4,000 times more selective with respect to PDE5 compared with PDE3, which is of paramount importance, since PDE3 is one of the key enzymes in the regulation of myocardial contractility. Sildenafil causes a slight and transient decrease in blood pressure (BP), which in most cases has no clinical manifestations. The average maximum decrease in systolic blood pressure in the supine position, after taking sildenafil orally at a dose of 100 mg is 8.3 mm Hg. st.The corresponding change in diastolic blood pressure is 5.3 mmHg. st. A single dose of sildenafil in a dose of 100 mg was not accompanied by clinically significant changes on the electrocardiogram (ECG) in healthy volunteers. Sildenafil has no effect on cardiac output and does not alter the blood flow through stenotic arteries. A more pronounced, but also transient effect on blood pressure was noted in patients taking nitrates. Some patients 1 hour after taking sildenafil at a dose of 100 mg using the Farnsworth-Munsel 100 test revealed a slight and transient violation of the ability to distinguish between shades of color (blue / green). 2 hours after taking the drug, these changes were absent. It is believed that the violation of color vision is caused by inhibition of PDE6, which is involved in the process of transmitting light in the retina. Sildenafil has no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

Pharmacokinetics

The pharmacokinetics of sildenafil in the recommended dose range is linear. Sildenafil absorption is rapidly absorbed after oral administration. 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 sildenafil in a dose of 100 mg, the average maximum concentration of free sildenafil in the blood plasma (Cmax) of men is about 18 ng / ml (38 nM). Cmax 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: Cmax decreases by an average of 29%, and the time to reach the maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the pharmacokinetic concentration-time curve (AUC) decreases by 11%). Distribution The volume of distribution of sildenafil in the equilibrium state is on average 105 l. The relationship of sildenafil and its main circulating N-demethyl metabolite with plasma proteins is about 96% and does not depend on the total concentration of the drug. Less than 0.0002% of a dose of sildenafil (an average of 188 ng) was detected in semen 90 minutes after taking the drug.Metabolism Sildenafil is metabolized mainly in the liver by the action of the cytochrome CYP3A4 isoenzyme (primary pathway) and the cytochrome CYP2C9 isoenzyme (additional pathway). The main circulating active metabolite resulting from N-demethylation of sildenafil is further metabolized. The selectivity of this metabolite in relation to PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The metabolite concentration 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 (T1 / 2) is about 4 hours. Withdrawal The total clearance of sildenafil is 41 l / h, and the final T1 / 2 - 3-5 hours. After ingestion, sildenafil is excreted as metabolites, mainly by the intestines (about 80% of the dose) and to a lesser extent by the kidneys (about 13% of the dose). Pharmacokinetics in special groups of patients Elderly patients In healthy elderly patients (over 65 years old), the clearance of sildenafil is reduced, and the concentration of free sildenafil in blood plasma is about 40% higher than in young people (18-45 years). Age does not have a clinically significant effect on the incidence of side effects. Patients with impaired renal function With mild (creatinine clearance (CK) 50-80 ml / min) and moderate (CK 30-49 ml / min) degree of renal failure, the pharmacokinetics of sildenafil after a single dose of 50 mg does not change. With severe renal failure (CK ≤ 30 ml / min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with those in normal renal function in patients of the same age group. Patients with impaired liver function Patients with liver cirrhosis (stages A and B according to Child-Pugh classification) decrease the clearance of sildenafil, which leads to an increase in the AUC value (84%) and Cmax (47%) compared to those in normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh stage C) has not been studied.

Indications

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

Contraindications

hypersensitivity to sildenafil or to any other component of the drug; use in patients who constantly or intermittently donate nitric oxide, organic nitrates or nitrites in any form, since sildenafil enhances the hypotensive effect of nitrates (see the section "Interaction with other drugs"); use in patients for whom sexual activity is undesirable (for example, with severe cardiovascular diseases such as severe heart failure, unstable angina); arterial hypotension (blood pressure less than 90/50 mm Hg. Art.); a cerebral circulation disorder or myocardial infarction suffered in the last six months; hereditary degenerative diseases of the retina, including retinitis pigmentosa (a smaller proportion of these patients have a genetic disorder of retinal phosphodiesterase); lactose intolerance, lactase deficiency, glucose-galactose malabsorption; severe liver failure; simultaneous administration of ritonavir; simultaneous use of other medicines for the treatment of erectile dysfunction; age up to 18 years; use of the drug in women.

Precautionary measures

arterial hypertension (arterial pressure> 170/100 mmHg); life-threatening arrhythmias; obstructive diseases of the left ventricular excretory part of the heart (aortic stenosis, hypertrophic obstructive cardiomyopathy); with episodes of the development of anterior non-arteritis ischemic neuropathy of the optic nerve in history; diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombus tsitemiya), diseases accompanied by bleeding, peptic disease in the acute phase, Simultaneous reception alpha blockers.

Use during pregnancy and lactation

According to the registered indication of the drug is not intended for use in women.
Dosage and administration
Inside The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Given the efficacy and tolerability, the dose may 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. With mild and moderately severe renal failure (CK 30-80 ml / min), dose adjustment is not required, with severe renal failure (CK <30 ml / min), the dose of sildenafil should be reduced to 25 mg. Since the elimination of sildenafil is impaired in patients with liver damage (in particular, with cirrhosis), the dose of sildenafil should be reduced to 25 mg. Dose adjustment of sildenafil in elderly patients is not required. When combined with cytochrome CYP3A4 isoenzyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of sildenafil should be 25 mg (see section "Interaction with other drugs"). To minimize the risk of postural hypotension in patients taking alpha blockers, sildenafil should be started only after stabilization of hemodynamics is achieved in these patients. Initial dose of sildenafil - 25 mg

Side effects

Classification of the incidence of side effects (WHO): very often> 1/10; often from> 1/100 to <1/10; infrequently from> 1/1000 to <1/100; rarely from> 1/10000 to <1/1000; very rarely <1/10000, including individual messages; frequency unknown: according to the available data, it is not possible to establish the frequency of occurrence. From the nervous system: very often - a headache; often - dizziness; infrequently - drowsiness, hypesthesia; rarely - cerebrovascular events, syncope; frequency unknown - transient ischemic attack, convulsions, incl. recurrent. On the part of the organ of vision: often - visual disturbances, transient disorders of color perception (chromatopsia); infrequently - the defeat of the conjunctiva, a violation of tears; unknown frequency - anterior ischemic optic neuropathy of non-arterial origin, retinal vascular occlusion, visual field defects. On the part of the organ of hearing: infrequently - dizziness, tinnitus; rarely - deafness. Since the cardiovascular system: often - flushing to the skin of the face; infrequently - palpitations, tachycardia; rarely - increase or decrease in blood pressure, myocardial infarction, atrial fibrillation; frequency is unknown - ventricular arrhythmia, unstable angina, sudden cardiac arrest. On the part of the respiratory system: often - nasal congestion; rarely - nosebleeds.From the gastrointestinal tract: often - dyspepsia; infrequently - vomiting, nausea, dryness of the oral mucosa. Allergic reactions: rarely - skin rash; frequency is unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis (Layel syndrome). On the part of the musculoskeletal system: infrequently - myalgia. On the part of the genital organs: infrequently - hematospermia, bleeding from the penis; frequency unknown - priapism, prolonged erection. Other: Infrequent - chest pain, fatigue.

Overdose

Symptoms: headache, "flushes" of blood to the skin of the face, dizziness, dyspepsia, nasal congestion, blurred vision. With a single dose of sildenafil at a dose of up to 800 mg, adverse events were comparable to those with a lower dose of the drug, but were more common. Treatment: symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, since the latter is actively associated with plasma proteins and is not excreted by the kidneys.

Interaction with other drugs

The influence of other drugs on the pharmacokinetics of sildenafil Sildenafil metabolism occurs mainly in the liver under the action of cytochrome CYP3A4 (main pathway) and CYP2C9 isoenzymes, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil with simultaneous use of cytochrome CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine) was noted. Cimetidine (800 mg), a non-specific 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 specific inhibitor of the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of erythromycin in the blood, leads to an increase in AUC of sildenafil by 182%. When coadministration of sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 times a day), HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, Cmax of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil has no effect on the pharmacokinetics of saquinavir.More potent inhibitors of cytochrome CYP3A4 isoenzyme, such as ketoconazole and itraconazole, can also cause stronger changes in the pharmacokinetics of sildenafil. The simultaneous use of sildenafil (once 100 mg) 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 one sildenafil - 5 ng / ml). Grapefruit juice, a weak CYP3A4 inhibitor, can moderately increase plasma concentrations of sildenafil. If sildenafil is taken in recommended doses by patients receiving simultaneously strong inhibitors of the cytochrome CYP3A4 isoenzyme, then C max of free sildenafil does not exceed 200 nM, and the drug is well tolerated. A single antacid (magnesium hydroxide / aluminum hydroxide) does not affect the bioavailability of sildenafil. Inhibitors of the cytochrome CYP2C9 (such as tolbutamide, warfarin), the isoenzyme of the cytochrome, CYP2D6 Azithromycin (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. Nicorandil is a hybrid of nitrate and an activator of potassium channels. Due to the presence of the nitrate component, it can enter into serious interactions with sildenafil. 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 at recommended doses, its Cmax is about 1 micromol, so it is unlikely that sildenafil can affect the substrate clearance 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.While taking alpha-adrenergic 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 / diastolic blood pressure in the supine position was 7/7 mm Hg. Art., 9/5 mm Hg. st. and 8/4 mm Hg. st. accordingly, and in the standing position - 6/6 mm Hg. Art., 11/4 mm Hg. st. and 4/5 mm Hg. st. respectively. Rare cases of the development of symptomatic postural hypotension, manifested in the form of dizziness (without fainting), have been reported in these patients. In individual sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil can lead to symptomatic hypotension. Signs of significant interaction of sildenafil (50 mg) 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 HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, at their constant level in the blood. Sildenafil (50 mg) does not cause an additional increase in bleeding time when taking acetylsalicylic acid (150 mg). Sildenafil (50 mg) does not enhance the hypotensive effect of ethanol in healthy volunteers with an average concentration of ethanol in the blood of an average of 0.08% (80 mg / dL). In patients with arterial hypertension, there were no signs of interaction of sildenafil (100 mg) with amlodipine. The average additional decrease in blood pressure in the prone position is 8 mm Hg. st. (systolic) and 7 mm Hg. st. (diastolic). The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.

special instructions

For the diagnosis of erectile dysfunction, the determination of their possible causes and the choice of adequate treatment, it is necessary to gather a full medical history and conduct a thorough physical examination. Erectile dysfunction medications should be used with caution in patients with anatomical deformation of the penis (penile angulation, cavernous fibrosis, Peyronie's disease) or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).Drugs intended for the treatment of erectile dysfunction should not be given 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 to an examination of the cardiovascular system. The use of sildenafil is contraindicated in patients with heart failure, unstable angina, suffered a myocardial infarction or stroke in the past six months, hypotension (BP <90/50 mm Hg). Clinical studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 people per year) or the mortality rate from cardiovascular diseases (0.3 per 100 people per year) in patients who received sildenafil, compared with patients receiving placebo.

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