Sildenafil-SZ granules for oral use 50mg packets, 4pcs

Composition

1 package contains: Active ingredient: sildenafil citrate-70.2 mg (based on sildenafil-50 mg); excipients: sucralose – 24.0 mg; pharmaspers® 416-499.8 mg; mint flavor-6.0 mg

Pharmacological action

A treatment for erectile dysfunction is a PDE-5 inhibitor. Sildenafil is a potent selective inhibitor of cyclo-guanosine monophosphate (cGMP) – specific phosphodiesterase type 5 (PDE-5). Restores impaired erectile function under conditions of sexual stimulation of increased blood flow in the vessels of the penis. Mechanism of Action The physiological process underlying penile erection involves the release of nitric oxide (N0) in the cavernous body during sexual stimulation. Nitric oxide activates the enzyme guanylate cyclase, which leads to an increase in the concentration of cGMP and subsequent relaxation of smooth muscle cells of the cavernous body and contributes to its filling with blood. It does not have a direct relaxing effect on the isolated human cavernous body, but it enhances the effect of NO by inhibiting PDE-5, which is responsible for the breakdown of cGMP. When the NO/cGMP system is activated during sexual stimulation, inhibition of PDE5 by sildenafil leads to an increase in cGMP levels in the cavernous body. Sexual stimulation is absolutely necessary for the development of the desired pharmacological action of sildenafil. In vitro studies have shown that sildenafil is selective for PDE-5, which is involved in the development of an erection. Its activity against PDE-5 is superior to that of other known phosphodiesterases. Sildenafil is 10 times less selective for PDE-6, which is involved in retinal phototransmission. At the maximum recommended doses, sildenafil is 80 times less selective for PDE-1 and 700 times less selective for PDE-2,3,4,7,8,9,10 and 11. The activity of sildenafil against PDE-5 is approximately 4000 times higher than its activity against PDE-3 (cycloadenosine monophosphate (cAMP) – specific phosphodiesterase) involved 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 maximum decrease in systolic blood pressure in a horizontal position after taking sildenafil at a dose of 100 mg, on average, is 8.3 mm Hg, and diastolic blood pressure is 5.3 mm Hg. This decrease in blood pressure is due to the vasodilating effect of sildenafil, possibly associated with an increase in the concentration of cGMP in vascular smooth muscle cells. A single dose of sildenafil up to 100 mg is not associated with clinically significant changes in the electrocardiogram (ECG) in healthy volunteers. Sildenafil has no effect on cardiac output and does not alter blood flow through stenosed arteries. In patients with erectile dysfunction and stable angina who regularly took antianginal medications (other than nitrates), the time to angina attack during the exercise test did not significantly differ after taking sildenafil compared to placebo. In some patients,1 hour after taking 100 mg of sildenafil, the Farnsworth-Munsel 100 test revealed transient changes in the ability to distinguish shades of color (blue/green),2 hours after taking sildenafil these changes were absent. Inhibition of PDE-6 is considered to be the suggested mechanism of color perception disorders. Sildenafil has no effect on visual acuity or contrast perception, electroretinogram, intraocular pressure, or pupil diameter. It was noted that in patients with early age-related macular degeneration, sildenafil 100 mg once did not cause clinically significant visual changes assessed by special tests (visual acuity, Amsler grating, traffic light color difference, Humphrey’s perimetry, and photostress). A single 100 mg dose of sildenafil had no effect on sperm motility or morphology in healthy volunteers. Additional information on clinical trials In fixed-dose sildenafil trials, the proportion of men who reported improved erections was 62% (25 mg),74% (50 mg), and 82% (100 mg), compared to 25% in the placebo group. At the same time, the frequency of sildenafil withdrawal was low and comparable to that in the placebo group. In all studies, the proportion of patients who reported improved erections after taking sildenafil was as follows: psychogenic erectile dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly patients (67%), diabetes mellitus (59%), coronary heart disease (CHD) (69%), arterial hypertension (68%), transurethral resection of the prostate (61%), radical prostatectomy (43%), spinal cord injury (83%), depression (75%). Analysis of the international index of erectile dysfunction showed that in addition to improving erections, treatment with sildenafil also increased the quality of orgasm, allowed achieving satisfaction from sexual intercourse and overall satisfaction. The safety and efficacy of sildenafil were maintained with prolonged use. Pharmacokineticsabsorption of sildenafil is rapidly absorbed. The maximum concentration in blood plasma (Ctax) when taken on an empty stomach is reached within 30-120 minutes (median 60 minutes). Absolute bioavailability, on average, is about 41% (25-63%). The pharmacokinetics (area under the concentration-time curve (AUC) and Cmax) of sildenafil in the recommended dose range (25-100 mg) are linear. Food intake reduces the rate of absorption of sildenafil, and the time to reach the maximum concentration (TStax) is extended, on average, by 60 minutes, Cstax decreases, on average, by 29%. Distribution The volume of distribution (Vd) of sildenafil at steady state is, on average,105 liters. After a single oral dose of 100 mg of sildenafil, the Cmax is approximately 440 ng / ml (coefficient of variation (CV) 40%). Since sildenafil (and its main circulating N-demethylated metabolite) are 96% bound to plasma proteins, the average plasma concentration of the free fraction of sildenafil is 18 ng / ml (38 nM). In healthy volunteers, less than 0.0002% of the dose (on average,188 ng) is detected in semen 90 minutes after a single dose of 100 mg of sildenafil. Metabolism Sildenafil is mainly metabolized in the liver by microsomal cytochrome P 450 isoenzymes: CYP3A4 (main pathway) and CYP2C9 (secondary pathway). The main circulating active metabolite is formed as a result of N-demethylation of sildenafil. The selectivity of the metabolite to phosphodiesterases is comparable to that of sildenafil, and its activity against PDE-5 in vitro is approximately 50% of that of unchanged sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers is about 40% of the concentration of sildenafil. The N-demethylated metabolite undergoes further metabolism, its half-life (Jm) is about 4 hours. Elimination The total clearance of sildenafil is 41 l / h, and the final half-life (T 1/2) is 3-5 hours. Sildenafil is mainly excreted as metabolites by the intestines (approximately 80% of the dose) and, to a lesser extent, by the kidneys (approximately 13% of the dose). Pharmacokinetics of selected patient groups Elderly patients In healthy elderly patients (65 years and older), the clearance of sildenafil is reduced, and the concentration of sildenafil and its active N-demethylated metabolite in blood plasma is approximately 90% higher than in young patients (18-45 years). Taking into account the age-related features of binding to plasma proteins, the concentration of free sildenafil in blood plasma increases by about 40%. Renal impairment in patients with mild or moderate renal impairment (creatinine clearance 30-80 ml/min), the pharmacokinetics of sildenafil did not change after a single dose of 50 mg. Mean values of AUC and Cmax of the N-demethylated metabolite increased by 126% and 73%, respectively, compared with healthy patients of the same age. Due to the high inter-individual variability, these differences are statistically insignificant. In severe renal insufficiency (creatinine clearance less than 30 ml/min), sildenafil clearance decreases, which leads to approximately a twofold increase in AUC (100%) and Ctax (88%) compared to those in patients of the same age group without impaired renal function. Impaired liver function In patients with Child-Pugh class A and B cirrhosis, sildenafil clearance decreases, resulting in increased AUC (84%) and Cmax (47%) compared to patients with normal liver function in the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Interaction

Effect of other drugs on the pharmacokinetics of sildenafilin vitro studies: Sildenafil is mainly metabolized by cytochrome P450 isoenzymes: CYP3A4 (main pathway) and CYP2C9 (non-main pathway). Therefore, inhibitors of these isoenzymes may reduce the clearance of sildenafil. In vivo studies: A population pharmacokinetic analysis of the results of a clinical study revealed a decrease in the clearance of sildenafil with simultaneous use of inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, erythromycin, cimetidine). At the same time, there was no increase in the frequency of adverse events in these patients. Patients taking CYP3A4 inhibitors are recommended to start treatment with sildenafil at a dose of 25 mg. Concomitant use of sildenafil (100 mg once daily) with the HIV protease inhibitor ritonavir (500 mg twice daily) (a potent cytochrome P450 inhibitor) increases the Cmax and AUC of sildenafil in blood plasma by 300% (i. e. 4-fold) and 1000% (i. e. 11 – fold), respectively.After 24 hours, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml (with sildenafil alone-5 ng / ml). Given the results of a pharmacokinetic study, concomitant use of sildenafil with ritonavir is contraindicated. Co-use of the HIV protease inhibitor saquinavir (a CYP3A4 inhibitor) at steady state (1200 mg three times daily) with sildenafil (100 mg once daily) increases the Cmax and AUC of sildenafil by 140% and 210%, respectively. Sildenafil does not affect the pharmacokinetics of saquinavir. Probably, more potent inhibitors of the CYP3A4 isoenzyme (ketoconazole and itraconazole) have a more pronounced effect on the pharmacokinetics of sildenafil. When sildenafil (100 mg once) is co-administered with erythromycin (a specific inhibitor of the CYP3A4 isoenzyme) at steady state (500 mg twice daily for 5 days) The AUC of sildenafil increases by 182%. In healthy volunteers, azithromycin (500 mg daily for 3 days) does not cause changes in pharmacokinetic parameters (AUC, Ctax, TStax, elimination rate or Ti/2 of sildenafil or its main circulating metabolite. Cimetidine (a non-specific inhibitor of the CYP3A4 isoenzyme) (800 mg) in healthy volunteers increases the concentration of sildenafil (50 mg) in blood plasma by 56%. Grapefruit juice, a weak inhibitor of the isoenzyme CYP3A4 in the intestinal wall, can slightly increase the concentration of sildenafil in blood plasma. A single dose of an antacid (magnesium hydroxide and aluminum hydroxide) does not alter the bioavailability of sildenafil. Although interactions with the following drugs have not been specifically studied, population pharmacokinetic analysis did not reveal changes in the pharmacokinetics of sildenafil when co-administered with: CYP2C9 isoenzyme inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 isoenzyme inhibitors (such as: selective serotonin reuptake inhibitors and tricyclic antidepressants), thiazides and thiazide-like drugs. diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, beta-blockers or inducers of the CYP450 isoenzyme (such as rifampicin and barbiturates). Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the presence of nitrate in the composition of the drug, a serious interaction with sildenafil is possible. Effect of sildenafil on the pharmacokinetics of other drugs Studies in vitro Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1 A 2,2 C 9,2 C 19,2D6,2 E 1 and ZA 4 (IC50 > 150 mmol). The cmax of sildenafil after taking the recommended doses is approximately 1 mmol, so it is unlikely that sildenafil affects the clearance of substrates of these isoenzymes. There are no data on the interaction of sildenafil with non-specific phosphodiesterase inhibitors, such as theophylline or dipyridamole. In vivo studies Sildenafil has an effect on the NO/cGMP system, so it enhances the hypotensive effect of nitrates. Concomitant use with NO donors (such as: amyl nitrite) or nitrates in any form is contraindicated. In some patients, concomitant use of sildenafil with alpha-blockers may lead to the development of symptomatic hypotension. Arterial hypotension most often develops within 4 hours after taking sildenafil. Clinical studies have studied the use of sildenafil (25 mg,50 mg, or 100 mg) in combination with the 4 mg or 8 mg alpha-blocker doxazosin in patients with benign prostatic hyperplasia and stable hemodynamics. There was an additional decrease in blood pressure in the horizontal position of the patient, on average, by 7/7,9/5 and 8/4 mm Hg, respectively, and in the vertical position-on average, by 6/6,11/4 and 4/5 mm Hg. In patients with stable hemodynamics while taking doxazosin, when sildenafil was added to therapy, there were rare cases of symptomatic orthostatic hypotension, clinically manifested by dizziness, but without the development of syncope. Interactions of sildenafil (50 mg) with golbutamide (250 mg) or warfarin (40 mg), which are metabolized by the CYP2C9 isoenzyme, were not detected. Sildenafil (50 mg) does not cause additional prolongation of bleeding time when used simultaneously with acetylsalicylic acid (150 mg). Sildenafil (50 mg) did not potentiate the antihypertensive effect of ethanol in healthy volunteers (the average serum ethanol cmax was 80 mg / dl). Undesirable effects of antihypertensive drugs, including diuretics, beta-blockers, and ACE inhibitors. angiotensin II receptor antagonists, vasodilators, centrally acting drugs, adrenergic neuron blockers, slow calcium channel blockers, and alpha-blockers did not differ in patients treated with sildenafil or placebo. In a drug interaction study of the concomitant use of sildenafil (100 mg) with amlodipine in patients with arterial hypertension, an additional decrease in horizontal systolic blood pressure by 8 mm Hg and diastolic blood pressure by 7 mm Hg was noted. The additional decrease in blood pressure is comparable to that with sildenafil alone in healthy volunteers. Sildenafil (100 mg) at steady state did not affect the pharmacokinetic parameters of HIV protease inhibitors: saquinavir and ritonavir, which are substrates of the CYP3A4 isoenzyme.

Overdose

Symptoms: with a single dose of sildenafil in doses up to 800 mg, adverse reactions are similar to those with lower doses of the drug, while the severity and frequency increased. Taking sildenafil at a dose of 200 mg did not lead to an increase in effectiveness, but the frequency of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual disturbances) increased. Treatment: symptomatic. Hemodialysis is ineffective because sildenafil is strongly bound to plasma proteins and is not excreted by the kidneys.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 °C.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Sildenafil

Conditions of release from pharmacies

By prescription

Dosage form

granules