Universal reference book for medicines
Product name: MAXIGRA (MAXIGRA)

Active substance: sildenafil

Type: The drug for the treatment of erectile dysfunction.
Inhibitor of PDE-5
Manufacturer: Pharmaceutical Works POLPHARMA (Poland)
Composition, form of production and packaging
The tablets covered with a film cover of
blue color, round, biconcave.

1 tab.

sildenafil citrate 35.21 mg,

which corresponds to the content of sildenafil 25 mg

Excipients: mannitol - 35.38 mg, crospovidone - 3 mg, povidone - 3 mg, corn starch - 5 mg, silicon dioxide colloid - 1 mg, sodium lauryl sulfate - 1 mg, magnesium stearate - 1.5 mg.

The composition of the membrane: hypromellose - 2.36 mg, macrogol 6000 - 0.74 mg, titanium dioxide - 0.52 mg, talc - 0.24 mg, indigocarmine (E132) - 0.14 mg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
The tablets covered with a film cover of blue color, round, biconcave.

1 tab.

sildenafil citrate 70.24 mg,

which corresponds to the content of sildenafil 50 mg

Excipients: mannitol - 70.76 mg, crospovidone - 6 mg, povidone - 6 mg, corn starch - 10 mg, silicon dioxide colloid - 2 mg, sodium lauryl sulfate - 2 mg, magnesium stearate - 3 mg.

The composition of the membrane: hypromellose - 4.13 mg, macrogol 6000 - 1.3 mg, titanium dioxide - 0.9 mg, talc - 0.43 mg, indigocarmine (E132) - 0.24 mg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
The tablets covered with a film cover of blue color, round, biconcave.

1 tab.

sildenafil citrate 140.48 mg,

which corresponds to the content of sildenafil 100 mg

Excipients: mannitol - 141.52 mg, crospovidone - 12 mg, povidone - 12 mg, corn starch - 20 mg, silicon dioxide colloid - 4 mg, sodium lauryl sulfate - 4 mg, magnesium stearate - 6 mg.

The composition of the membrane: hypromellose - 5.9 mg, macrogol 6000 - 1.85 mg, titanium dioxide - 1.3 mg, talc 0.6 mg, indigocarmine (E132) - 0.35 mg.

1 PC.
- blisters (1) - packs of cardboard.
4 things.
- blisters (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

The drug for the treatment of erectile dysfunction.
Sildenafil is a potent selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).
With sexual stimulation restores impaired erectile function by increasing the flow of blood to the penis.
Sildenafil does not have a direct relaxing effect on an isolated cavernous body, but actively enhances the relaxing effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the disintegration of cGMP in the cavernous body. When the NO / cGMP pathway is activated, the inhibition of PDE5 under the influence of sildenafil leads to an increase in the level of cGMP in the cavernous body, which results in relaxation of the smooth muscle tissue and increased blood flow in the cavernous body. The activity of sildenafil with respect to PDE5 is 10-10,000 times higher than that of other isoenzymes of PDE (1-11).
The pharmacological effect is achieved only with the presence of sexual stimulation.

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

In some patients, 1 hour after taking the drug at a dose of 100 mg with the Farnsworth-Munsell 100 test, a mild and transient impairment of the ability to distinguish between colors (blue / green) was detected, and 2 hours after taking the drug, these changes were absent.
It is believed that the violation of color vision is caused by the inhibition of PDE6, which is involved in the transmission of light in the retina of the eye. Sildenafil does not affect visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter.
In healthy volunteers, after a single dose of sildenafil in a dose of 100 mg, there was no effect on the motility or morphology of spermatozoa.

PHARMACOKINETICS

Suction

After ingestion, sildenafil is rapidly absorbed.
Absolute bioavailability averages 41% (25-63%). After a single administration of the drug, fasting in a dose of 100 mg Cmax is 18 ng / ml (38 nM) and is achieved within 30-120 minutes (60 minutes on the average).
When taking sildenafil in combination with fatty food, C max decreases by 20-40% and is reached after 1.5-3 hours.

Distribution

V d of sildenafil in the equilibrium state averages 105 liters.
The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is approximately 96% and is independent of the total concentration of sildenafil.
In healthy volunteers receiving sildenafil (once in a dose of 100 mg), 90 minutes after ingestion, less than 0.0002% (an average of 188 ng) of the administered dose was determined in the sperm.

Metabolism

Sildenafil is metabolized predominantly in the liver by the action of microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (a secondary pathway).
The main circulating metabolite is formed from sildenafil by N-desmethylation. By the selectivity of action on PDE, the metabolite is comparable to sildenafil, its activity in relation to PDE5 in vitro is approximately 50% of the activity of sildenafil. The concentration of the main metabolite in plasma is approximately 40% of the concentration of sildenafil. N-demethyl metabolite undergoes further metabolism, while its T 1/2 is about 4 hours.
Excretion

The total clearance of sildenafil is 41 l / h, and the final T 1/2 is 3-5 h. After ingestion, sildenafil is excreted as metabolites mainly through the intestine (approximately 80% of the dose) and to a lesser extent by the kidneys (approximately 13% of the dose).

Pharmacokinetics in specific patient groups

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

With renal insufficiency of light (KK 50-80 ml / min) and medium (KK 30-49 ml / min) severity, the pharmacokinetic parameters of sildenafil after single ingestion in a dose of 50 mg do not change.
With renal insufficiency of severe degree (CK-30 ml / min), the clearance of sildenafil decreases, which leads to approximately a two-fold increase in AUC (100%) and C max (88%) compared with those in normal kidney function in patients of the same age group .
In patients with cirrhosis of the liver of mild and moderate severity (class A and B on the Child-Pugh scale), the clearance of sildenafil decreases, which leads to an increase in AUC (84%) and C max (47%) compared with those for normal liver function in patients of the same age group.
The pharmacokinetic parameters of sildenafil in patients with severe impairment of liver function have not been studied.
INDICATIONS

- erectile dysfunction of various etiologies (organic, psychogenic, mixed), characterized by inability to achieve or maintain an erection penis sufficient for a satisfactory sexual intercourse.

Sildenafil is effective only with sexual stimulation.

DOSING MODE

The drug is taken orally, about 1 hour before the planned sexual activity.
When taken simultaneously with fatty foods, the onset of action of the drug may be delayed compared to taking on an empty stomach.
The recommended dose is 50 mg 1 time / day.
With regard to efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg.
The maximum single dose is 100 mg.
The maximum recommended frequency of application is 1 time / day.
In elderly patients, dose adjustment is not required.

In patients with severe renal insufficiency (CC <30 ml / min), the dose should be reduced to 25 mg.
With regard to efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.
In patients with impaired liver function, the dose should be reduced to 25 mg.
With regard to efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.
Joint use with other drugs

In patients receiving concomitant treatment with CYP3A4 inhibitors (with the exception of ritonavir, which is not recommended for simultaneous use of sildenafil), the initial dose of sildenafil should be 25 mg.

To minimize the possibility of orthostatic hypotension in patients taking alpha-adrenoblockers, treatment with sildenafil should be started after hemodynamic stabilization.
Consider the expediency of prescribing sildenafil in an initial dose of 25 mg.
SIDE EFFECT

The frequency of unwanted reactions is determined as follows: very often (> 1/10);
often (> 1/100, <1/10); sometimes (> 1/1000, <1/100); rarely (> 1/10 000, <1/1000).Within each gradation of frequency of occurrence undesirable phenomena are indicated according to reduction of their severity. The side effects registered in the postmarketing period, due to the lack of accurate frequency data, are marked as "unknown".
From the nervous system: very often - headache;
often - dizziness; sometimes - drowsiness, hypoesthesia; rarely - acute disturbance of cerebral circulation, fainting;unknown - transient ischemic attack, convulsions, repeated convulsions.
From the side of the organ of vision: often - impaired vision, changing the perception of color;
sometimes - violations of the conjunctiva, tearing disorders, other violations from the eyes; unknown - anterior ischemic neuropathy of the optic nerve of non-inflammatory genesis (NAION), occlusion of the retinal vessels, defect of the visual fields.
From the side of the organ of hearing: sometimes - ringing in the ears;
rarely - deafness.
From the side of the cardiovascular system: often - tides of blood to the face;
sometimes - palpitations, tachycardia; rarely - arterial hypertension, arterial hypotension, myocardial infarction, atrial fibrillation; unknown - ventricular arrhythmia, unstable angina, sudden cardiac death.
From the respiratory system: often - nasal congestion;
rarely - epistaxis.
From the side of the digestive system: often - indigestion;
sometimes - vomiting, nausea, dry mouth.
On the part of the reproductive system: unknown - priapism, prolonged erection.

From the musculoskeletal system: sometimes - myalgia.

From the skin and subcutaneous tissue: sometimes - skin rash.

From the immune system: rarely - hypersensitivity reactions.

Other: rarely - pain in the chest, fatigue.

CONTRAINDICATIONS

- simultaneous use of donators of nitric oxide or nitrates in any form;

- Hypersensitivity to any of the components of the drug.

With caution should be used in the preparation of anatomical deformation of the penis (including with angulation, cavernous fibrosis or Peyronie's disease);
with diseases predisposing to the development of priapism (such as sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); with diseases accompanied by bleeding; with exacerbation of peptic ulcer of the stomach and duodenum; hereditary pigment retinitis; heart failure, unstable angina, suffered in the last 6 months myocardial infarction, stroke, severe life-threatening arrhythmias, hypertension (blood pressure more than 170/100 mm Hg), or hypotension (blood pressure less than 90/50 mm Hg) .
PREGNANCY AND LACTATION

Sildenafil is not intended for use in women.

APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with severe renal insufficiency (CC <30 ml / min), the dose should be reduced to 25 mg.
With regard to efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with impaired liver function, the dose should be reduced to 25 mg.
With regard to efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.
APPLICATION FOR CHILDREN

Sildenafil is not intended for use in children and adolescents under the age of 18 years.

APPLICATION IN ELDERLY PATIENTS

In elderly patients, dose adjustment is not required.

SPECIAL INSTRUCTIONS

Before prescribing the drug, you need to collect a medical history and conduct a physical examination to diagnose erectile dysfunction and determine the possible causes of its development.

Since sexual activity represents a certain risk for heart disease, a doctor should conduct a survey of the patient's cardiovascular system before beginning any therapy for erectile dysfunction.

Sildenafil has the properties of a vasodilator, which leads to a slight and transient decrease in blood pressure.
Prior to the appointment of sildenafil, the risk of adverse effects of vasodilator action in patients with certain concomitant diseases should be carefully weighed, especially when combined with sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (for example, aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as a rare syndrome of multiple systemic atrophy, manifested severe violation of the regulation of blood pressure from the autonomic nervous system.
In rare cases, with the simultaneous use of sildenafil and other PDE5 inhibitors, visual impairment and the development of anterior ischemic neuropathy of the optic nerve of non-inflammatory genesis were noted.
In the event of a sudden impairment of vision, the patient should stop taking sildenafil and immediately consult a doctor.
Sildenafil should be administered with caution to patients taking alpha-blockers, as their combined use can lead to clinically pronounced hypotension in selected sensitive patients.
The most likely development of this effect within 4 hours after taking sildenafil. To minimize the possibility of developing orthostatic hypotension in patients taking alpha-adrenoblockers, treatment with sildenafil should begin after hemodynamics stabilization in these patients. Consider the expediency of prescribing sildenafil in an initial dose of 25 mg. In addition, patients should be informed what actions should be taken in case of symptoms of orthostatic hypotension.
Sildenafil enhances the antiaggregant effect of sodium nitroprusside on human platelets in vitro.

In clinical studies, there was no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular death rate (0.3 per 100 people per year) in patients receiving sildenafil compared to patients receiving placebo.

Drugs intended for the treatment of erectile dysfunction should not be given to men for whom sexual activity is undesirable.

Studies of the safety and effectiveness of combined use of sildenafil with other drugs for the treatment of erectile dysfunction were not conducted.
Therefore, the use of such combinations is not recommended.
Use in Pediatrics

Sildenafil is not intended for use in children and adolescents under the age of 18 years.

Impact on the ability to drive vehicles and manage mechanisms

The influence of sildenafil on the ability to drive vehicles and perform work that requires increased attention has not been studied.
However, during the period of application of the drug, care must be taken when driving vehicles and engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions. possibly dizziness and visual impairment.
OVERDOSE

Symptoms: with a single dose of the drug in a dose of up to 800 mg in studies in healthy volunteers, adverse events were comparable to those of sildenafil at lower doses, but their frequency and severity increased.
The use of the drug in a dose of 200 mg did not lead to an increase in efficacy, but the incidence of adverse events (headache, flushing, dizziness, indigestion, nasal congestion, visual impairment) increased.
Treatment: symptomatic therapy.
Sildenafil is not excreted in hemodialysis.
DRUG INTERACTION

The effect of other drugs on the metabolism of sildenafil

The metabolism of sildenafil occurs mainly in the liver under the action of CYP3A4 isoenzymes (main pathway) and CYP2C9 (a secondary pathway), so inhibitors of these isoenzymes may reduce the clearance of sildenafil.

With simultaneous use with inhibitors of CYP3A4 (such as ketoconazole, erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted.

A single dose of sildenafil 100 mg together with erythromycin, a specific inhibitor of CYP3A4 (when taking erythromycin 500 mg twice per day for 5 days), against the background of achieving a constant concentration of erythromycin in the blood leads to an increase in the AID of sildenafil by 182%.

Cimetidine (800 mg), which is a nonspecific inhibitor of CYP3A4, when co-administered with sildenafil (50 mg) in healthy volunteers caused an increase in the concentration of sildenafil in plasma by 56%.

Simultaneous use of sildenafil (once in a dose of 100 mg) and an inhibitor of ritonavir HIV protease (500 mg twice a day), which is a potent inhibitor of cytochrome P450 isozymes, against the background of achieving a constant concentration of ritonavir in the blood resulted in an increase in C max of sildenafil by 300 % (in 4 times), and AUC sildenafila - on 1000% (11-fold).
After 24 hours, the plasma sildenafil concentration was approximately 200 ng / ml (when sildenafil alone, approximately 5 ng / ml).
Simultaneous use of sildenafil (once in a dose of 100 mg) and an inhibitor of saquinavir HIV protease (1200 mg dose 3 times a day), which is an inhibitor of CYP3A4, in the presence of a constant concentration of saquinavir in the blood resulted in an increase in C max of sildenafil by 140%, a AUC sildenafila - by 210%.Sildenafil had no effect on the pharmacokinetics of saquinavir.

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

CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), inhibitors CYP2D (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide diuretics, "loop" and potassium-sparing diuretics, ACE inhibitors, beta-blockers, calcium antagonists and inductors isozymes of cytochrome P450 (eg, rifampicin, barbiturates) have no effect on the pharmacokinetics of sildenafil.
A single dose of antacid (hydroxide / magnesium hydroxide, aluminum) did not affect the bioavailability of sildenafil.
In healthy male volunteers simultaneous reception of azithromycin (500 mg / day for 3 days) did not affect the AUC, C max , T max , elimination rate constant and T1/2sildenafil or its main circulating metabolite.
Grapefruit juice is a weak inhibitor of CYP3A4, and may cause a moderate increase in levels of sildenafil in the blood plasma.
The effect of sildenafil on other drugs
Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC 50 150 micromolar). It is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.
Sildenafil nitrate enhances the hypotensive action therefore its combined use with nitric oxide donators or nitrates in any form is contraindicated.
In certain sensitive patients treated with alpha-adrenergic blockers, the simultaneous use of sildenafil may result in symptomatic hypotension. With simultaneous use of 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 haemodynamics average additional reduction in systolic / diastolic blood pressure in the supine position was 7 / 7 mmHg, 9/5 mmHg and 8.4 mmHg, respectively, while in a standing position - 6.6 mmHg, 11.4 mmHg and 5.4 mm Hg, respectively. It reported rare cases of such patients symptomatic orthostatic hypotension, manifested in the form of dizziness (without fainting).
No evidence of significant interaction sildenafil (50 mg), tolbutamide (250 mg) or warfarin (40 mg) are metabolized by CYP2C9, is not revealed.
Sildenafil 100 mg no effect on the pharmacokinetic parameters of HIV protease inhibitors at its constant concentration in the blood, such as saquinavir and ritonavir are simultaneously substrates CYP3A4.
Sildenafil dose of 50 mg did not cause an additional increase in bleeding time caused by taking aspirin at a dose of 150 mg.
Sildenafil dose of 50 mg of an ethanol enhances the hypotensive effect in healthy volunteers at the maximum blood concentration of ethanol in average 80 mg / dl.
Patients with signs of hypertension interaction sildenafil (100 mg) with amlodipine was not revealed. Average further reduction of blood pressure in the supine position was 8 mmHg (systolic) and 7 mm Hg (diastolic).
The use of sildenafil in combination with antihypertensive agents does not lead to additional side effects.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
The shelf life of tablets 25 mg - 3 years, tablets 50 mg and 100 mg - 4 years.
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