Wiltedegra - instructions for use, dose, side effects, contraindications

Excipients (core): hypromellose - 110,0000 mg, lactose monohydrate (sugar milk) - 82,5200 mg, microcrystalline cellulose - 70.2400 mg, povidone - K25 - 14.0000 mg, magnesium stearate - 3.0000 mg.

Auxiliary substances (shell): Opapray II 85F240012 pink - 12,0000 mg, polyvinyl alcohol - 4,800 mg, macrogol-4000 - 2,9256 mg, iron-oxide red-0.0480 mg, iron-oxide oxide yellow-0.0264 mg, talc-1.7760 mg , titanium dioxide - 2.4240 mg.

Dosage of 100 mg:

Active substance: sildenafil citrate - 140,4800 mg, in terms of sildenafil base - 100,0000 mg.

Excipients (core): hypromellose - 110,0000 mg, lactose monohydrate (sugar milk) - 82,5200 mg, povidone - K25 - 14,0000 mg, magnesium stearate - 3.0000 mg.

Auxiliary substances (shell): Opapray II 85F205024 blue - 12,0000 mg, polyvinyl alcohol - 4,800 mg, macrogol-4000 - 2,4240 mg, aluminum lacquer with dyes indigo carmine and diamond blue - 0,7476 mg, iron oxide oxide yellow - 0.0324 mg, talc - 1.7760 mg, titanium dioxide - 2.2200 mg.

Description:

Dosage 50 mg:

Round biconvex tablets, covered with a film coat from pink to pale pink. On the cross section of the tablet, two layers are visible: a white or almost white core and a film membrane.

Dosage of 100 mg:

Round biconvex tablets, covered with a film shell of dark blue color. On the cross section of the tablet, two layers are visible: a white or almost white core and a film membrane.

Pharmacotherapeutic group:Erectile dysfunction remedy - PDE5-inhibitor

ATX: & nbsp

G.04.B.E Drugs for the treatment of erectile dysfunction

G.04.B.E.03 Sildenafil

Pharmacodynamics:

Sildenafil is a potent selective inhibitor of cyclic guanosine monophosphate (cGMP), a specific type 5 phosphodiesterase (PDE5).

Mechanism of action.

The implementation of the physiological mechanism of erection is associated with the release of nitric oxide (N0) in a 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 human body, but enhances the effect of nitric oxide (N0) by inhibiting PDE5, which is responsible for the degradation of cGMP.

Sildenafil is selective for PDE5 in vitro, its activity against PDE5 is higher than that of other known isoenzymes of phosphodiesterase: PDE6 - 10-fold; FDE1 - more than 80 times; PDE2, PDE4, PDE7-PDE11 - more than 700 times. Sildenafil is 4000 times more selective for PDE5 than for FDHD, which is of paramount importance, since FDEZ is one of the key enzymes in the regulation of myocardial contractility.

An essential condition for the effectiveness of sildenafil is sexual stimulation.

Pharmacokinetics:

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

Suction

After oral administration sildenafil quickly absorbed. Absolute bioavailability averages about 40% (from 25% to 63%). In vitro Sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) suppresses 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 (C_max) of men is about 18 ng / ml (38 nM). C_max when taking sildenafil inside fasting is achieved on average for 90 minutes. When taken in combination with fatty foods, the rate of absorption decreases: C_max decreases by an average of 29%, and the time to reach the maximum concentration (T_max) is increased by 60 min, but the degree of absorption does not change significantly (the area under the pharmacokinetic concentration-time curve (AUC) decreases by 11%).

Distribution

The volume of distribution of sildenafil in the equilibrium state averages 105 liters. Connection with plasma proteins of sildenafil and its main circulating N-detyl metabolite is approximately 96% and does not depend on the total drug concentration. Less than 0.0002% of the dose (an average of 188 ng) is found in the sperm 90 minutes after taking sildenafil.

Metabolism

Sildenafil is metabolized mainly in the liver under the action of the cytochrome isoenzyme CYP3A4 (main pathway) and cytochrome isoenzyme CYP2C9 (minor way).The main circulating active metabolite formed as a result of N-detylation of sildenafil, undergoes further metabolism. 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% activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. N-detyl metabolite undergoes further metabolism; its half-life (T_1/2) is about 4 hours.

Excretion

The total clearance of sildenafil is 41 liters / hour, and the final T_1/2 3-5 hours. After oral administration also 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 special patient groups:

Elderly patients

In elderly (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil in 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.

Renal impairment

With a mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-49 ml / min), the degree of renal failure pharmacokinetics of sildenafil after a single oral intake of 50 mg does not change. In severe renal failure (creatinine clearance ≤ 30 ml / min), the clearance of sildenafil decreases, which leads to an approximately twofold increase in the area under the pharmacokinetic concentration-time curve (AUC 100%) and C_max (88%) compared with those for normal kidney function in patients of the same age group.

Dysfunction of the liver

In patients with cirrhosis of the liver (stages A and B according to the Child-Pugh classification), the clearance of sildenafil decreases, which leads to an increase AUC (84%) and C_max (47%) compared with those for normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe impairment of liver function (Stage C according to the Child-Pugh classification) has not been studied.

Indications:

Treatment of erectile dysfunction characterized by an inability to achieve or maintain an erection penis sufficient for a satisfactory sexual intercourse. Sildenafil is effective only in the presence of sexual stimulation.

Contraindications:

Hypersensitivity to sildenafil or any other component of the drug.

Use in patients who receive permanently or intermittently donators of nitric oxide, organic nitrates or nitrites in any form, since sildenafil strengthens the hypotensive effect of nitrates (see 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 (arterial pressure less than 90/50 mm Hg).

Severe renal failure (CK <30 mL / min).

Hepatic insufficiency, cirrhosis.

Disturbed cerebral circulation or myocardial infarction during the last six months.

Hereditary degenerative diseases of the retina, including retinitis pigmentosa.

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Simultaneous reception of ritonavir (for dosages of 50 mg and 100 mg).

The safety and efficacy of sildenafil when used together with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see section "Special instructions").

According to the registered indication sildenafil Not suitable for use in children under 18 years of age.

According to the registered indication sildenafil not suitable for use in women.

Carefully:

Arterial hypertension (blood pressure> 170/100 mm Hg).

Heart failure.

Life-threatening arrhythmias.

Anatomic deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) (see section "Special instructions").

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

Patients with episodes of development of anterior non-arterial ischemic neuropathy of the optic nerve in anamnesis.

Diseases accompanied by bleeding.

Exacerbation of peptic ulcer of the stomach and duodenum.

Simultaneous reception of alpha-blockers.

Simultaneous reception with ritonavir the maximum single dose of sildenafil should not exceed 25 mg, the frequency of application every 48 hours (you need to use a pill with a dosage of 25 mg).

Simultaneous reception with inhibitors of cytochrome isoenzyme CYP3A4 (erythromycin, saquinavir, ketoconazole, itraconazole) the initial dose of sildenafil should be 25 mg (it is necessary to use a tablet with a dosage of 25 mg).

Pregnancy and lactation:

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

Dosing and Administration:

Inside.

The recommended dose for most adult patients is 50 mg about 1 hour before sexual activity. With regard to efficacy and tolerability, the dose can be increased to 100 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of application is once a day.

Renal impairment

With a mild and moderate degree of renal failure (CK 30-80 ml / min) dose adjustment is not required.

Joint use with other drugs

To minimize the risk of postural hypotension in patients taking α-adrenoblockers, the use of sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. It should also consider the desirability of reducing the initial dose of sildenafil (see Fig.sections "Special instructions" and "Interaction with other medicinal products").

Elderly patients

Correction of the dose of sildenafil is not required.

Side effects:

Classification of the incidence of adverse events (WHO): very often> 1/10, often> 1/100 to <1/10, infrequently from> 1/1000 to <1/100. rarely from> 1/10000 to <1/1000, very rarely from <1/10000, 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 - vasodilation ("hot flashes"); infrequent - a feeling of palpitations, tachycardia; rarely - increase or decrease in blood pressure, myocardial infarction, atrial fibrillation; frequency unknown - ventricular arrhythmia, unstable angina, sudden cardiac arrest.

On the part of the organs 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 organs of hearing: infrequently - vertigo, noise in the ears; rarely - a sudden decrease or loss of hearing.

From the respiratory system, chest and mediastinum: often - nasal congestion; rarely - epistaxis.

From the gastrointestinal tract: often - indigestion; infrequently - vomiting, nausea, dryness of the oral mucosa.

Allergic reactions: infrequent skin rash; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome).

On the part of the genitals: infrequently - hematospermia, bleeding from the penis, the frequency is unknown - priapism, prolonged erection.

From the musculoskeletal system: infrequently - myalgia.

Other: rarely - chest pain, fatigue.

Overdose:

With a single dose of the drug in a dose of up to 800 mg, adverse events were comparable to those observed with lower doses, but were more common. Treatment is symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, since the latter actively binds to plasma proteins and is not excreted by the kidneys.

Interaction:

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome isoenzymes CYP3A4 (main path) and CYP2C9, so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. There was a decrease in clearance of sildenafil with simultaneous use of cytochrome isoenzyme inhibitors CYP3A4 (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome isoenzyme CYP3A4, with a joint admission with sildenafil (50 mg) causes an increase in the concentration of sildenafil in plasma 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 isoenzyme CYP3A4, against the background of the achievement of a constant concentration of erythromycin in the blood, leads to an increase AUC sildenafil by 182%. With the joint administration of sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 once a day), HIV protease inhibitor and cytochrome isoenzyme CYP3A4, against the background of achieving a constant concentration of saquinavir in the blood C_max sildenafil increased by 140%, a AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. More potent inhibitors of cytochrome isoenzyme CYP3A4, such as ketoconazole and itraconazole, can cause and stronger changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (single dose 100 mg) and RTV (500 mg, 2 times a day), HIV protease inhibitor and a potent inhibitor of cytochrome P450, against the backdrop of a constant concentration in the blood leads to an increase of ritonavir C_max sildenafil by 300% (4 times), a AUC on 1000% (in 11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng / ml (after a single application of one sildenafil - 5 ng / ml).

If sildenafil take in recommended doses of patients receiving simultaneously strong inhibitors of the cytochrome isoenzyme CYP3A4, then C_max free sildenafil does not exceed 200 nM, and the drug is well tolerated.

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

Inhibitors of cytochrome isoenzyme CYP2C9 (tolbutamide, warfarin), cytochrome isoenzyme CYP2D6 (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics,ACE inhibitors and calcium antagonists, do not affect the pharmacokinetics of sildenafil. Azithromycin (500 mg / day for 3 days) does not affect AUC, C_max, T_max, the rate constant of excretion and T_1/2sildenafil or its main circulating metabolite.

With the simultaneous use of an antagonist of endothelin receptors, bosentan and sildenafil, there was a decrease AUC and C_max sildenafil by 62.6% and 52.4% respectively.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IR₅₀> 150 μmol). When taking sildenafil in the recommended doses of its Cmah is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of the substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with prolonged use of the latter, and when they are prescribed for acute indications. In this regard, the application of sildenafil in combination with nitrates or donators of nitric oxide is contraindicated.

With the simultaneous administration of α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) inpatients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic / diastolic blood pressure in the supine position was 7/7 mm Hg. st., 9/5 mm Hg. Art. and 8/4 mm Hg. st., respectively, and in the standing position - 6/6 mm Hg. st., 11/4 mm Hg. Art. and 4/5 mm Hg. art., respectively. We report rare cases of development in these patients of symptomatic postural hypotension, manifested as dizziness (without syncope). In individual sensitive patients receiving α-blockers, simultaneous use of sildenafil can lead to symptomatic hypotension.

Signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome isoenzyme CYP2C9, not found. Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease, saquinavir and ritonavir inhibitors that are substrates of the cytochrome isoenzyme CYP3A4, 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 enhancethe hypotensive effect of alcohol in healthy volunteers with a maximum alcohol concentration in the blood averaged 0.08% (80 mg / dL).

In patients with arterial hypertension, there was no evidence of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the prone position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic).

The use of sildenafil in combination with antihypertensive drugs does not lead to additional side effects.

With the simultaneous use of sildenafil with bosentan (inductor of isoenzymes CYP3A4, CYP2C9) there was a decrease AUC and C_maxsildenafil by 62.6% and 52.4% respectively. Sildenafil increased AUC and C_max bosentan by 49.8% and 42% respectively.

Special instructions:

To diagnose erectile dysfunction, determine their possible causes and choose an adequate treatment, you must collect a complete medical history and conduct a thorough physical examination. Means of treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).see "With caution").

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

If the erection persists for more than 4 hours, seek medical attention. If priapism therapy is not performed in a timely manner, it can lead to damage to the penile tissue and an irreversible loss of potency.

Sexual activity represents a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient to a cardiovascular system examination. Sexual activity is undesirable in patients with heart failure, unstable angina, suffered in the last 6 months by myocardial infarction or stroke, life-threatening arrhythmias, hypertension (BP> 170/100 mm Hg), or hypotension (BP <90/50 mm Hg. st.). In clinical studies, there was no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or mortality from cardiovascular disease (0.3 per 100 people per year) in patients who received sildenafil, compared with patients receiving placebo.

Cardiovascular complications

During the postmarketing use of sildenafil, serious adverse events such as myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension were reported for the treatment of erectile dysfunction, such as serious cardiovascular complications ), which had a temporary connection with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events were observed soon after sexual activity, and some of them were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish the presence of a direct link between the observed undesirable phenomena and these or other factors.

Hypotension

Viagra has systemic vasodilatory effect resulting in a transient decrease in blood pressure that is not clinically significant phenomenon and does not lead to any consequences in most patients.However, before the appointment of sildenafil the physician should carefully evaluate the risk of possible undesirable manifestations of vasodilating action in patients with the corresponding diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with a rare syndrome of multiple systemic atrophy, manifested severe violation of the regulation of blood pressure from the autonomic nervous system. Since the combined use of sildenafil and α-blockers can lead to symptomatic hypotension in selected sensitive patients, the drug should be used with caution in patients taking α-blockers (see "Interactions with Other Drugs"). To minimize the risk of postural hypotension in patients taking α-adrenoblockers, sildenafil should be taken only after stabilization of hemodynamic parameters in these patients has been achieved. It should also consider the desirability of reducing the initial dose of sildenafil (see Fig.See section "Dosing and Administration"). The doctor should inform patients about what actions should be taken in case of symptoms of postural hypotension.

Visual disorders

Rare cases of development of anterior non-artery ischemic neuropathy of the optic nerve were noted as a cause of impairment or loss of vision against the background of the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, such as optic disc excavation, age over 50, diabetes, hypertension, ischemic heart disease, hyperlipidemia and smoking. A small number of patients with hereditary pigment retinitis have genetically determined impairments of the functions of the retina phosphodiesterase. Information on the safety of sildenafil in patients with retinitis pigmentosa absent.

Hearing Impairment

Some post-marketing and clinical studies report cases of sudden deterioration or hearing loss associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing.The causal relationship between the use of PDE5 inhibitors and sudden deterioration of hearing or loss of hearing is not established. In the event of a sudden deterioration in hearing or hearing loss, taking sildenafil should immediately consult a doctor.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a donator of nitric oxide, on human platelets in vitro. Data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of peptic ulcer of the stomach and duodenum are absent, therefore sildenafil these patients should be used with caution (see "With caution"). The frequency of nasal bleeding in patients with PH associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). In patients who received sildenafil in combination with a vitamin K antagonist, the incidence of nasal bleeding was higher (8.8%) than in patients who did not take a vitamin K antagonist (1.7%).

Application in conjunction with other treatments for erectile dysfunction

The safety and efficacy of sildenafil in conjunction with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended (see "Contraindications").

Effect on the ability to drive transp. cf. and fur:

Since the use of sildenafil may reduce blood pressure, the development of chromatopsy, blurred vision, etc. side effects, you should carefully consider the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen and to be careful when driving vehicles and engage in potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Tablets with prolonged release, coated with a film coat of 50 mg and 100 mg.

Packaging:

According to 1, 2, 4 or 10 tablets in a contour cell pack of film polyvinylchloride and aluminum foil printed lacquered.

For 10, 20, 40, 50 or 100 tablets in cans of polyethylene terephthalate for medicines, sealed with caps screwed on with a first opening control or by a "push-turn" system of polypropylene or polyethylene, or polymeric cans for medicines,Corked with lids pulled with the control of the first opening of polyethylene.

One jar or 1, 2, 4, or 10 contour mesh packages together with the instruction for use are placed in a cardboard package (bundle).

It is allowed to bundle 2 or 3 cardboard packages (packs) into a group package (shipping container) from cardboard for consumer packaging.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003418

Date of registration:18.01.2016

Expiration Date:18.01.2021

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp15.02.2017

Illustrated instructions

Instructions

Wilderegra (Vildegra)