Universal reference book for medicines
Product name: TAXIER ® (TAXIER ® )

Active substance: sildenafil

Type: The drug for the treatment of erectile dysfunction.
Inhibitor of PDE-5
Manufacturer: ZENTIVA (Slovak Republic)
Composition, form of production and packaging
The tablets covered with a film cover of
yellow color, round, biconcave, with marking "50" on one side.

1 tab.

sildenafil citrate 70.24 mg,

which corresponds to the content of sildenafil 50 mg

[PRING] calcium hydrophosphate - 125.76 mg, microcrystalline cellulose - 70 mg, croscarmellose sodium - 8.4 mg, magnesium stearate - 5.6 mg.

The composition of the film sheath: sepiphilm 3048 yellow (hypromellose 40-45%, microcrystalline cellulose 30-40%, macrogol 40 stearate 4-12%, titanium dioxide 10-15%, dye quinoline yellow 0.15-0.5%) 12 mg, macrogol 6000 - 120 mcg.

1 PC.
- blisters (1) - packs of cardboard.
1 PC.
- blisters (4) - packs of cardboard.
4 things.
- blisters (2) - packs of cardboard.
The tablets covered with a film cover of yellow color, round, biconcave, with marking "100" on one side.

1 tab.

sildenafil citrate 140.48 mg,

which corresponds to the content of sildenafil 100 mg

[PRING] calcium hydrophosphate - 251.52 mg, microcrystalline cellulose - 140 mg, croscarmellose sodium - 16.8 mg, magnesium stearate - 11.2 mg.

The composition of the film sheath: sepiphilm 3048 yellow (hypromellose 40-45%, microcrystalline cellulose 30-40%, macrogol 40 stearate 4-12%, titanium dioxide 10-15%, dye quinoline yellow 0.15-0.5%) - 20 mg, macrogol 6000 - 240 mcg.

1 PC.
- blisters (1) - packs of cardboard.
1 PC.
- blisters (4) - packs of cardboard.
4 things.
- blisters (2) - 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, inhibitor PDE5.

Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP), a specific PDE5.
The realization 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 an isolated cavernous body in humans, but enhances the effect of NO by inhibiting PDE5, which is responsible for the degradation of cGMP. The use of sildenafil in recommended doses is ineffective in the absence of sexual stimulation.
Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is significantly superior to that of other known PDE isoenzymes.

PHARMACOKINETICS

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

Suction

After taking the drug, sildenafil is rapidly absorbed.
Absolute bioavailability averages 40% (25-63%). In vitro, sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) suppresses human PDE5 by 50%. After a single application of sildenafil inside at a dose of 100 mg, the average Cmax of free sildenafil in blood plasma is 18 ng / ml (38 nM) and is achieved on an empty stomach for an average of 60 min (30-120 min). When taken in combination with fatty foods, the rate of absorption decreases: C max decreases by an average of 29%, and T max increases by 60 min, but the degree of absorption does not change significantly (AUC decreases by 11%).
Distribution

V d of sildenafil in the equilibrium state averages 105 liters.
Sildenafil and its main circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Binding to proteins does not depend on the total concentration of sildenafil. Less than 0.0002% of the dose (an average of 188 ng) is found in the semen 90 minutes after taking sildenafil.
Metabolism

Sildenafil is metabolized mainly in the liver under the action of isoenzymes CYP3A4 (the main pathway) and CYP2C9 (a secondary pathway).
The main circulating metabolite, which is formed as a result of the N-demethylation of sildenafil, undergoes further metabolism. By the selectivity of action on PDE, the metabolite is comparable with sildenafil, and its activity in relation to PDE5 in vitro is approximately 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma is approximately 40% of the concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism. T 1/2 is about 4 hours.
Excretion

The total clearance of sildenafil is 41 l / h, and the final T 1/2 -
3-5 hours After ingestion, as well as after intravenous administration, sildenafil is excreted as metabolites, mainly by the intestine (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).
Pharmacokinetics in specific patient groups

In healthy elderly patients (over 65 years), the clearance of sildenafil is reduced, and the concentration of free sildenafil in blood plasma is approximately 40% higher than in young (18-45 years).
Age does not have a clinically significant effect on the incidence of side effects.
In mild (KK 50-80 ml / min) and moderate (KK 30-49 ml / min) degree of renal insufficiency, the pharmacokinetics of sildenafil after single administration in a dose of 50 mg does not change.
With a severe degree of renal failure (CK ≤ 30 mL / min), the clearance of sildenafil decreases, which leads to approximately a twofold increase in AUC (100%) and Cmax (88%) compared with the corresponding values ​​for normal kidney function in patients of the same age group.
In patients with cirrhosis of the liver (class A and B on the Child-Pugh scale), the clearance of sildenafil decreases, which leads to an increase in AUC (84%) andCmax (47%) compared with those for normal liver function in patients with the same age group.
The pharmacokinetics of sildenafil in patients with severe impairment of liver function (class C on the Child-Pugh scale) has not been studied.
INDICATIONS

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

The drug is effective only with sexual stimulation.

DOSING MODE

The drug is taken orally for 1 hour before sexual activity.
When taking Taxiere ® during meals, the onset of action of the drug may be delayed compared to taking on an empty stomach.
The recommended dose is 50 mg.
Given the efficacy and tolerability, this dose can be increased to 100 mg. The maximum recommended dose and frequency of application is 100 mg 1 time / day.
In elderly patients, dose adjustment is not required.

In patients with mild to moderate renal insufficiency (CK 30-80 ml / min), dose adjustment is not required.

In patients with impaired liver function (classes A and B on the Child-Pugh scale), the appointment of the drug should always be agreed with the attending physician.

Patients receiving concomitant treatment with other CYP3A4 isozyme inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole) should consult a physician before starting the drug.

To reduce the risk of orthostatic hypotension in patients taking alpha-adrenoblockers, the use of sildenafil should be started only after stabilizing the condition against the background of therapy with alpha-blockers.

SIDE EFFECT

Classification of the incidence of adverse events (WHO): very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100), rarely (> 1/10 000 to <1/1000), very rarely (from <1/10 000, including individual messages).

From the nervous system: very often - headache;
often - dizziness; infrequently - drowsiness, hypoesthesia; rarely - a stroke, a faint; frequency unknown - transient ischemic attack, convulsions, incl. recurrent.
From the cardiovascular system: often - hot flashes;
infrequent - a feeling of palpitations, tachycardia; rarely - increased or decreased blood pressure, myocardial infarction, atrial fibrillation; frequency unknown - ventricular arrhythmia, unstable angina, sudden death.
From the side of the organ of vision: often - impaired vision, violation of color perception;
infrequently - a lesion of the conjunctiva, a violation of lacrimation;frequency unknown - anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects.
From the side of the organ of hearing: infrequently - vertigo, noise in the ears;
rarely - deafness.
From the respiratory system: often - nasal congestion;
rarely - epistaxis.
From the side of the digestive system: often - indigestion;
infrequently - vomiting, nausea, dryness of the oral mucosa.
Allergic reactions: infrequent - skin rash;
frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).
On the part of the genitals: the frequency is unknown - priapism, prolonged erection.

Other: rarely - chest pain, fatigue.

CONTRAINDICATIONS

- simultaneous application of donators of nitric oxide or organic nitrates or nitrites in any dosage forms;

- simultaneous use of other drugs that stimulate erection, ritonavir;

- patients for whom sexual activity is undesirable (including with severe cardiovascular diseases, such as unstable angina, severe heart failure);

- arterial hypotension (blood pressure less than 90/50 mm Hg);

- recently suffered impairment of cerebral circulation;

- recently transferred myocardial infarction;

- hereditary degenerative diseases of the retina, incl.
pigment retinitis (a minority of these patients have a genetic impairment of the PDE of the retina);
hepatic failure of severe degree;

- children and adolescence under 18;

- female;

- hypersensitivity to sildenafil or to any component of the drug;

Caution should be applied to the preparation during anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease);
diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); diseases accompanied by bleeding; exacerbation of peptic ulcer of the stomach and duodenum; in patients taking alpha-adrenoblockers (the risk of developing orthostatic hypotension).
PREGNANCY AND LACTATION

According to the registered indications Taxi ® is not intended for use in women.

APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with mild to moderate renal insufficiency (CK 30-80 ml / min), dose adjustment is not required.

With a severe degree of renal failure (CK ≤ 30 mL / min), the clearance of sildenafil decreases, which leads to approximately a twofold increase in AUC (100%) and Cmax (88%) compared with the corresponding values ​​for normal kidney function in patients of the same age group.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindications: severe hepatic impairment.

In patients with impaired liver function (classes A and B on the Child-Pugh scale), the appointment of the drug should always be agreed with the attending physician.

APPLICATION FOR CHILDREN

Contraindicated in children and adolescents under 18 years.

APPLICATION IN ELDERLY PATIENTS

In elderly patients, dose adjustment is not required.

SPECIAL INSTRUCTIONS

Before the appointment of the drug for the diagnosis of erectile dysfunction, it is necessary to collect a complete medical history and conduct a physical examination.

Before beginning any treatment, erectile dysfunction should determine the cardiovascular status of the patient, since there is a certain degree of risk associated with sexual activity.
Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.
Taxiere ® has vasodilating properties, resulting in insignificant transient decreases in blood pressure.
However, increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (eg, aortic stenosis, hypertrophic obstructive cardiomyopathy), or in patients with a rare syndrome of multiple systemic atrophy, manifested severe violation of the regulation of blood pressure from the autonomic nervous system.
In the post-registration period, serious cardiovascular abnormalities were reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmias, cerebrovascular bleeding, transient ischemic attack, increase or decrease in blood pressure, which were in temporary communication with sildenafil.Most of these patients had cardiovascular risk factors.
It was reported that many phenomena occurred during or soon after intercourse, and only a small amount occurred shortly after taking sildenafil without sexual activity, so it is impossible to determine whether these phenomena are directly related to these or other factors.
Since the combined use of sildenafil and alpha-blockers can lead to symptomatic hypotension in selected sensitive patients, sildenafil should be used with caution in patients taking alpha-blockers.
To minimize the risk of orthostatic hypotension in patients taking alpha-adrenoblockers, the initiation of sildenafil should be started only after the stabilization of hemodynamics in these patients has been achieved. Consider the desirability of reducing the initial dose of sildenafil. In addition, patients should be informed about what should be done in case of symptoms of orthostatic hypotension.
Sildenafil enhances the antiplatelet effect of sodium nitroprusside (a donor of nitric oxide) on human platelets in vitro.
Information about the safety of the use of Taxiere ® in patients with internal bleeding or active peptic ulcer of the stomach is absent, therefore in such cases the drug should be used only after a thorough assessment of the relationship between the benefits and risks of therapy.
Impact on the ability to drive vehicles and manage mechanisms

Against the background of the use of the drug Taxi ® , there was no adverse effect on the ability to drive a car or other technical means.
However, since it is possible to reduce blood pressure, the development of chromatopsy, blurred vision, you should carefully consider the individual effect of the drug, especially at the beginning of treatment and when changing the dosage regimen, and take care when driving vehicles and engage in potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.
OVERDOSE

Symptoms: with a single application of the drug in a dose of up to 800 mg, the adverse reactions were the same as in the case of the drug in lower doses, but were more common.
When using the drug at a dose of 200 mg, there was no increase in efficacy, but the incidence of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual impairment) increased.
Treatment: conducting standard measures to maintain vital body functions;
symptomatic therapy. Dialysis does not accelerate clearance, because sildenafil is largely associated with plasma proteins and is not excreted in the urine.
DRUG INTERACTION

Metabolism of sildenafil occurs mainly in the liver under the action of isoenzymes CYP3A4 (the main pathway) and CYP2C9, so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil.
With the simultaneous use of inhibitors of the isoenzyme CYP3A4 (such as ketoconazole, erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted. Cimetidine (800 mg), which is a non-specific inhibitor of the isoenzyme CYP3A4, when used with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma by 56%. A single dose of sildenafil 100 mg concurrently with erythromycin, a specific inhibitor of the isoenzyme CYP3A4 (when erythromycin is administered 500 mg twice daily for 5 days), with the achievement of a constant erythromycin concentration in the blood leads to an increase in the AUC of sildenafil by 182%.
With the simultaneous use of sildenafil (at a dose of 100 mg once) and saquinavir, which is both an inhibitor of the HIV protease, and an inhibitor of the isoenzyme CYP3A4 (when saquinavir is administered at a dose of 1200 mg 3 times / day) against the background of C ss saquinavir in the blood, C max sildenafil in the blood increased by 140%, and the AUC increased by 210%.
Sildenafil had no effect on the pharmacokinetic parameters of saquinavir. More potent inhibitors of the CYP3A4 isoenzyme, such as ketoconazole or itraconazole, can cause more pronounced changes in the pharmacokinetics of sildenafil.
With the simultaneous use of sildenafil (once in a dose of 100 mg) and ritonavir, which is an inhibitor of HIV protease and a strong inhibitor of cytochrome P450 isoenzymes (when ritonavir is administered 500 mg twice a day), when the level of ritonavir in the blood is reached, C max sildenafil increased by 300% (4 times), and AUC by 1000% (11 times).
After 24 hours, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml (with a single application of one sildenafil - 5 ng / ml).
If sildenafil is taken at recommended doses, patients receiving simultaneously strong inhibitors of the isoenzyme CYP3A4, C max free sildenafil does not exceed 200 nM, and the drug is well tolerated.

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

CYP2C9 isoenzyme inhibitors (such as tolbutamide, warfarin), CYP2D6 isoenzymes (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors, and calcium antagonists have no effect on the pharmacokinetic parameters of sildenafil.

The simultaneous use of azithromycin (500 mg / day for 3 days) did not affect the AUC, C max , T max , elimination rate constant and T 1/2 sildenafil or its main circulating metabolite.
Sildenafil is a weak inhibitor of isozymes CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IK 50 > 150 mM). It is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.
Sildenafil increases the hypotensive effect of the nitrate as the long-term use, and when used on acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donators contraindicated.
With simultaneous use of alpha-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (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 9.5 mm Hg and 8/4 mm rt.ct. respectively, while in a standing position - 4.11 mm pt.ct. and 4/5 mm Hg respectively. It reported rare cases of such patients symptomatic postural hypotension, manifested in the form of dizziness (without fainting). In certain sensitive patients treated with alpha-adrenergic blockers, the simultaneous use of sildenafil may result in symptomatic hypotension.
No evidence of significant interaction with sildenafil tolbutamide (250 mg) or warfarin (40 mg) are metabolized by CYP2C9 isoenzyme not detected.
Cildenafil 100 mg no effect on the pharmacokinetic parameters of HIV protease inhibitors on the background of their C ss in the blood, such as saquinavir and ritonavir simultaneously are substrates isoenzyme CYP3A4.
Sildenafil (50 mg) does not cause an additional increase in bleeding time in the application of acetylsalicylic acid (150 mg).
Sildenafil (50 mg), does not potentiate the hypotensive effect of ethanol was in healthy volunteers in C max of ethanol in the blood on average 80 mg / dl.
Patients with signs of hypertension interaction sildenafil (100 mg) with amlodipine was not revealed. The use of sildenafil in combination with antihypertensive agents does not cause any 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.
Shelf life - 3 years.
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