Maxigra pills 100mg №1

Active substance

Sildenafil

Composition

Pills

Active ingredient: Sildenafil citrate 70.24 mg or 140.48 mg (equivalent to sildenafil) 50.00 mg or 100.00 mg, respectively,

Excipients: mannitol, crospovidone (type A), povidone (K 25), silicon dioxide, colloidal starch, Magnesium stearate, sodium lauryl sulfate,

The composition of the shell: hypromellose (15 mPas), macrogol6000, titanium dioxide E171, talc, indigo carmine E132.

pharmachologic effect

Pharmacotherapeutic group: erectile dysfunction treatment agent - PDE5 inhibitor.

Pharmacological properties

Pharmacodynamics

Sildenafil - a drug for the treatment of erectile dysfunction. With sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5). Sildenafil does not have a direct relaxing effect on an isolated cavernous body, but actively enhances the relaxing effect of nitric oxide (NO) on this tissue, by inhibiting PDE5, which is responsible for the breakdown of cGMP in the cavernous body. When the pathway NO / cGMP is activated, inhibition of PDE5 under the influence of sildenafil leads to an increase in the level of cGMP in the cavernous body, resulting in muscle relaxation and increased blood flow in the cavernous body. The pharmacological effect is achieved only in the presence of sexual stimulation.

Activity against PDE5 is 10-10000 times greater than activity against other PDE isoenzymes (1-11).

In clinical studies, it was shown that the average time to achieve an erection resistant 60% (sufficient for sexual intercourse) was 25 minutes (range from 12 to 37 minutes).

Some patients after 1 hour after taking the drug in a dose of 100 mg using the Farnsworth-Munsell 100 test revealed a slight and transient impairment of the ability to distinguish colors (blue / green), 2 hours after taking the drug, these changes were absent. The mechanism of color vision impairment is considered 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.

In healthy volunteers, after a single dose of sildenafil at a dose of 100 mg, no effect on sperm motility or morphology was observed.

Pharmacokinetics

Suction

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages 41% (range 25–63%). The maximum concentration (Cmax) in plasma with a single fasting dose of 100 mg of the drug inside is 18 ng / ml (38 nM) and is achieved within 30-120 minutes (60 minutes on average).

When taking sildenafil with fatty foods, Cmax is reduced by 20-40% and is reached in 1.5-3 hours.

Distribution

The volume of distribution (Vd) of sildenafil in the equilibrium state is on average 105 liters.Sildenafil and its main circulating N-desmethyl metabolite approximately 96% bound to plasma proteins. Protein binding does not affect the total concentration of the drug.

In healthy volunteers receiving sildenafil (a single dose of 100 mg), 90 minutes after the administration, less than 0.0002% (average 188 ng) of the administered dose was detected in the semen.

Metabolism

Sildenafil is metabolized predominantly by microsomal liver isoenzymes CYP3A4 (main route) and CYP2C9 (secondary route). The main circulating metabolite is formed from sildenafil by N-demethylation. This metabolite has a selectivity profile for phosphodiesterase, similar to that of sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of the original preparation. The concentration of this metabolite in plasma is approximately 40% of the concentration of sildenafil. Subsequently, the metabolite N-desmethyl is metabolized, while its half-life (T½) is about 4 hours.

Removal

The total clearance of sildenafil is 41 l / h, and T½ in the terminal phase is 3-5 hours. After oral administration, sildenafil is excreted as metabolites mainly by the intestines (approximately 80% of the dose) and to a lesser extent by the kidneys (approximately 13% of the dose).

Pharmacokinetics in special clinical situations

In elderly (over 65 years) patients, the clearance of sildenafil is reduced, and the concentration of free active substance in plasma is approximately 40% higher than its concentration in young (18–45 years) patients.

In case of mild (CK 50-80 ml / min) and moderate (CK 30-49 ml / min) renal failure, the pharmacokinetic parameters of sildenafil once orally are taken once (50 mg) do not change.

With severe renal failure (CK ≤ 30 ml / min), the clearance of sildenafil is reduced, which leads to an approximately two-fold increase in AUC (100%) and Cmax (88%) compared with those in normal kidney function in patients of the same age group.

In patients with mild and moderate cirrhosis of the liver (class A and B on the Child-Pugh scale), the clearance of sildenafil decreases, leading to an increase in AUC (84%) and Cmax (47%) compared with those in normal liver function in patients same age group.

The pharmacokinetic parameters of sildenafil in patients with severely impaired liver function have not been studied.

Indications

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain an erection of the penis, to achieve or maintain an erection of the penis, sufficient for satisfactory sexual intercourse. The drug is 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, because sildenafil enhances the hypotensive effect of nitrates (seesection "Interaction with other drugs").

The safety and efficacy of sildenafil when used together with other means of treating erectile dysfunction have not been studied, therefore, the use of such combinations is not recommended (see section "Special Instructions").

According to the registered indication, sildenafil is not intended for use in children under 18 years of age.

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

Carefully

Anatomical deformity of the penis (including during angulation, cavernous fibrosis or Peyronie’s disease) (see section "Special Instructions").

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

Patients with episodes of anterior ischemic neuropathy of the optic nerve of non-inflammatory genesis in history.

Diseases accompanied by bleeding.

Exacerbation of gastric ulcer and duodenal ulcer.

Hereditary retinitis pigmentosa (see section "Special instructions")

Heart failure, unstable stenocardia, myocardial infarction, stroke or life-threatening arrhythmias, arterial hypertension (BP> 170/100 mm Hg) or hypotension (BP <90/50 mm Hg) in the last 6 months (see section "Special instructions").

Simultaneous reception of alpha-blockers.

Side effects

The frequency of side effects is given in accordance with the following classification: very often (≥ 1/10), often (≥1 / 100,<1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (<1/10000), the frequency is unknown (according to available data set the frequency of occurrence was not possible).

Immune system disorders: Infrequently, a hypersensitivity reaction.

Violations of the nervous system: very often - headache; often - dizziness; infrequently - hypoesthesia, drowsiness; rarely - stroke, fainting; frequency is unknown - intracerebral hemorrhage, transient ischemic attack, seizures, incl. recurrent.

Violations of the organ of vision: often - visual impairment, change in color perception; infrequently - conjunctivitis, impaired tearing, eye pain, photophobia, photopsia, eye redness / scleral injection, changes in the brightness of light perception; unknown frequency - anterior ischemic neuropathy of the optic nerve of non-inflammatory origin (NAION), retinal vascular occlusion, visual field defects.

Disturbances from an organ of hearing and labyrinth disturbances: infrequently - vertigo, tinnitus; rarely - deafness.

Violations of the cardiovascular system: often - "tides" of blood to the face; infrequently - palpitations, tachycardia; rarely, arterial hypertension, arterial hypotension, myocardial infarction, atrial fibrillation; the frequency is unknown - ventricular arrhythmia, unstable angina, sudden cardiac death.

Disturbances of the respiratory system, organs of the chest and mediastinum: often nasal congestion; rarely - nosebleeds.

Violations of the gastrointestinal tract: often - dyspepsia ; infrequently - vomiting, nausea, dry mouth.

Disorders of the liver and biliary tract: the frequency is unknown - hepatotoxicity (liver damage and increased levels of transaminases).

Violations of the skin and subcutaneous tissues: infrequently - skin rash, the frequency is unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disorders of the musculoskeletal and connective tissues: infrequently - myalgia.

Violations of the genital organs and the breast: infrequently - hematospermia, bleeding from the penis; frequency unknown - priapism, prolonged erection.

General disorders and disorders at the injection site: rarely - chest pain, fatigue.

Interaction

Effect of other drugs on the metabolism of sildenafil

Sildenafil metabolism occurs mainly in the liver under the influence of CYP3A4 isoenzymes (primary pathway) and CYP2C9 (secondary pathway), therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil.

When combined with inhibitors of CYP3A4 isoenzyme (such as Ketoconazole, Erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted.

A single dose of sildenafil in a dose of 100 mg together with erythromycin, a specific inhibitor of the isoenzyme CYP3A4 (at a dose of 500 mg 2 times a day for 5 days), under conditions of equilibrium concentration of erythromycin increases the AUC of sildenafil by 182%.

Cimetidine (800 mg), an inhibitor of cytochrome P450 and a nonspecific inhibitor of the CYP3A4 isoenzyme, when used together with sildenafil (50 mg) in healthy volunteers, caused an increase in plasma concentration of sildenafil by 56%.

Simultaneous use of sildenafil (once at a dose of 100 mg) and HIV protease inhibitor ritonavir (500 mg 2 times a day), a powerful inhibitor of cytochrome P450, in conditions of equilibrium concentrations of ritonavir in the blood led to an increase in Cmax of sildenafil by 300% (in 4 times), and Sildenafil AUC - by 1000% (11-fold). After 24 hours, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml compared to approximately 5 ng / ml with the use of sildenafil alone.

Simultaneous use of sildenafil (once at a dose of 100 mg) and HIV protease inhibitor saquinavir, which is an inhibitor of the CYP3A4 isoenzyme, under conditions of equilibrium concentration (at a dose of 1200 mg 3 times a day) led to an increase in Cmax of sildenafil by 140%, and AUD sildenafil 210%. Sildenafil had no effect on saquinavir pharmacokinetics.

More potent inhibitors of the isoenzyme CYP3A4, such as ketoconazole and itraconazole, can cause more pronounced changes in the pharmacokinetics of sildenafil.

CYP2C9 inhibitors (such as tolbutamide, Warfarin, phenytoin), CYP2D6 inhibitors (for example, selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, "loop" and potassium-sparing diuretics,angiotensin-converting enzyme inhibitors, beta-blockers, Calcium antagonists and CYP450 metabolism inducers (for example, rifampicin, barbiturates) do not affect the pharmacokinetics of sildenafil.

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

In healthy male volunteers, simultaneous administration of Azithromycin (500 mg per day for 3 days) does not affect the AUC, Cmax, Tmax, the rate constant for elimination and T½ of sildenafil or its main circulating metabolite.

Grapefruit juice is a weak inhibitor of the metabolism of the CYP3A4 isoenzyme in the wall of the gastrointestinal tract and can cause a moderate increase in the concentration of sildenafil in the blood plasma.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of isoenzymes of the cytochrome P450 system - 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IK50150 μmol). It is unlikely that sildenafil can affect the substrate clearance of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, therefore its combined use with nitric oxide donators or nitrates in any form is contraindicated.

In individual sensitive patients receiving alpha-blockers, the simultaneous use of sildenafil can lead to symptomatic hypotension. 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