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

cellulose microcrystalline 81,13 / 162,26 / 324,52 mg; calcium hydrophosphate 22.5 / 45/90 mg; croscarmellose sodium 9/18/36 mg; Magnesium stearate 2.25 / 4.5 / 9 mg.

Sheath: Opadrai II 85F20464 blue 3/6/12 mg (polyvinyl alcohol 1.2 / 2.4 / 4.8 mg, macrogol-3350 0.606 / 1.212 / 2.424 mg, titanium dioxide 0.54 / 1.08 / 2, 16 mg, talc 0.444 / 0.888 / 1.776 mg, indigocarmine aluminum varnish 0.21 / 0.42 / 0.84 mg).

Description:Tablets 50 mg: Oval tablets covered with a film coating of blue color.
Tablets 100 mg: Oval tablets covered with a film shell of blue color, with an engraving "+" on one side.

Pharmacotherapeutic group:treatment of erectile dysfunction 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 cyclo-guanosine monophosphate (cGMP) - a specific type 5 phosphodiesterase (PDE5).

The physiological mechanism of erection is associated with the release of nitric oxide (N0) 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 human body, but enhances the effect of 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 with respect to PDE5 than with FDES, which is extremely important, as FDEZ is one of the key enzymes for the regulation of myocardial contractility.

A mandatory condition for the effectiveness of sildenafil is sexual stimulation.
Clinical data

Cardiac examinations

The use of sildenafil in doses up to 100 mg did not lead to clinically significant changes in the ECG in healthy volunteers. The maximum decrease in systolic blood pressure (SBP) in the supine position after taking sildenafil in a dose of 100 mg was 8.3 mm Hg. st, and diastolic blood pressure (DBP) - 5.3 mm Hg. Art. A more pronounced but also transient influence on blood pressure (BP) was noted in patients taking nitrates (see the sections "Contraindications" and "Interaction").

In a study of the hemodynamic effect of sildenafil in a single dose of 100 mg in 14 patients with severe ischemic heart disease (CHD) (more than 70% of patients had stenosis, at least one coronary artery), SBP and DBP at rest decreased by 7 and 6 %, respectively, and pulmonary systolic pressure decreased by 9%. Sildenafil did not affect cardiac output and did not interfere with blood flow in stenosed coronary arteries, and also led to an increase (approximately 13%) of adenosine-induced coronary flow in both stenotic and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina treated with antianginal drugs (except nitrates) were exercising until the angina symptom severity decreased. The duration of exercise was significantly higher (19.9 s, 0.9-38.9 s) in patients taking sildenafil in a single dose of 100 mg, compared with patients receiving a placebo.

In a randomized, double-blind, placebo-controlled study, the effect of changing the dose of sildenafil (up to 100 mg) in men (n = 568) with erectile dysfunction and hypertension taking more than two antihypertensive drugs was studied. Sildenafil improved erection in 71% of men compared with 18% in the placebo group. The frequency of adverse effects was comparable to that in the other groups of patients, as well as in people taking more than three antihypertensive drugs.
Research of visual disorders

In some patients, an easy and transient impairment in the ability to distinguish between shades of color (blue / green) was detected 1 hour after taking 100 mg of sildenafil with the Farnsworth-Munssel test 100. After 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 did not affect visual acuity, contrast perception, electroretinogram, intraocular pressure or pupil diameter.

In a placebo-controlled, cross-sectional study of patients with proven early age macular degeneration (n = 9) sildenafil in a single dose of 100 mg was tolerated well. There were no clinically significant visual changes assessed by special visual tests (visual acuity, Amsler grating, color perception, color flow modeling, Humphrey perimeter and photostress).
Efficiency

The efficacy and safety of sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months in 3000 patients aged 19 to 87 years with erectile dysfunction of different etiology (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using the diary of erections, the international index of erectile function (a validated questionnaire on the status of sexual function), and a partner survey.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for a satisfactory sexual intercourse, has been demonstrated in all studies conducted and has been confirmed in long-term studies lasting 1 year. In studies using a fixed dose, the ratio of patients who reported that the therapy improved their erection was 62% (the dose of sildenafil - 25 mg), 74% (the dose of sildenafil - 50 mg) and 82% (the dose of sildenafil - 100 mg) compared with 25% in the placebo group. Analysis of the international index of erectile function showed that, in addition to improving the erection, sildenafil treatment also increased the quality of orgasm, it was possible to achieve satisfaction from sexual intercourse and general satisfaction.

According to generalized data, among patients who reported an improvement in erectile dysfunction with sildenafil were 59% of patients with diabetes mellitus, 43% of patients undergoing radical prostatectomy, and 83% of patients with spinal cord injuries (compared with 16%, 15% and 12% in placebo group, respectively).

Pharmacokinetics:

The pharmacokinetics of sildenafil in the recommended dose range is linear.After oral administration sildenafil quickly absorbed from the gastrointestinal tract (GIT). Absolute bioavailability is 25-63%, an average of 40%. In vitro, sildenafil at a concentration of about 1.7 ng / ml (3.5 nM) suppresses human PDE5 activity by 50%. After a single intake of sildenafil in a dose of 100 mg, the average maximum concentration of free sildenafil in the blood plasma (Cmax) of men is about 18 ng / ml (38 nM). Stam when taking sildenafil inward on an empty stomach is achieved on average for 60 minutes (from 30 to 120 min). When taken in combination with fatty foods, the absorption rate slows down, the Stax decreases by an average of 29%, and the time of its attainment (Tmax) increases by 60 min, but the degree of absorption does not change significantly (the area under the pharmacokinetic curve of the plasma drug concentration versus time AUC) is reduced by 11%).

The volume of distribution (Vd) of sildenafil in the equilibrium state averages 105 liters.

The connection with plasma proteins of sildenafil and its main circulating N-demethyl metabolite is about 96% and does not depend on the total drug concentration. Less than 0.0002% of the dose of sildenafil (an average of 188 ng) was found in the sperm 90 minutes after taking the drug.

Sildenafil is metabolized mainly in the liver with the participation of CYP3A4 isoenzymes (main pathway) and CYP2C9 (a secondary pathway) of cytochrome P450. The main circulating active metabolite is formed as a result of N-demethylation of sildenafil and undergoes further metabolism. By selectivity of action against PDE, the metabolite is comparable with sildenafil, and the metabolite activity in relation to PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of metabolite in the blood plasma of healthy volunteers is approximately 40% of the concentration of sildenafil. N-demethyl metabolite undergoes further metabolism, its half-life (T1 / 2) is about 4 hours.

The total clearance of sildenafil is 41 liters / hour, and the final T1 / 2 is 3-5 hours. After oral administration as well as after intravenous administration sildenafil is excreted as metabolites in the main 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
Elderly patients

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.

Impaired renal function

In mild (creatinine clearance 50 to 80 ml / min) and moderate (KK 30-49 ml / min) degree of renal insufficiency, the pharmacokinetics of sildenafil after single ingestion at a dose of 50 mg does not change. In severe renal failure (CK <30 ml / min), the clearance of sildenafil decreases, which leads to approximately a two-fold increase in AUC (100%) and Cmax (88%), as compared with those in normal kidney function in patients of the same age group .

Impaired liver function

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 in AUC (84%) and Cmax (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 with 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").

Joint use with other drugs (drugs) for the treatment of erectile dysfunction. The safety and efficacy of sildenafil in such combinations has not been studied, so the use of such combinations is not recommended (see section "Special instructions").

It is not recommended simultaneous use of sildenafil with ritonavir.

The drug is not intended for use on a registered indication in children under 18 years of age.

The drug is not intended for use on a recorded indication in women.

Carefully:

Restrictions on the use are: anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), diseases predisposing to the development of priapism (myeloma, sickle cell anemia, leukemia, thrombocytopenia) (see below).(See section "Special instructions"), increased tendency to bleeding, exacerbation of peptic ulcer of the stomach and duodenum, hereditary retinitis pigmentosa, heart failure, unstable angina, myocardial infarction (MI), stroke or life-threatening arrhythmias, arterial hypertension (AH> 170/110 mm Hg) and hypotension (BP <90/50 mm Hg) (see section "Special instructions"), episodes of development in patients of anterior non-artery ischemic neuropathy of the visual a nerve (in the anamnesis).

Pregnancy and lactation:

The drug is not indicated for use in pregnant women and women during breastfeeding.

Dosing and Administration:

The drug should be taken orally. 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 or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of application is 1 time per day.

Renal impairment

With a mild and moderate degree of renal failure (CK 30-80 ml / min) dose adjustment is not required, with severe renal failure (CK <30 ml / min) - the dose of sildenafil should be reduced to 25 mg.

Dysfunction of the liver

Since the excretion of sildenafil is disrupted in patients with liver damage (in particular, with cirrhosis), the dose of sildenafil should be reduced to 25 mg.

Joint application with other drugs

When combined with ritonavir, the maximum single dose of sildenafil should not exceed 25 mg, and the frequency of application - 1 every 48 hours (see the section "Interaction"), When combined with inhibitors of the cytochrome isoenzyme CYP3A4 (erythromycin, saquinavir, ketoconazole, itraconazole) the initial dose of the drug should be 25 mg (see section "Interaction").

To minimize the risk of postural hypotension in patients taking a-adrenergic blockers, Erexelas should be taken only after hemodynamics stabilization has been achieved in these patients. It should also consider the desirability of reducing the initial dose of sildenafil (see section "Special instructions" and "Interaction").

Elderly patients

Adjusting the dose of Erexel is not required.

Side effects:

Usually the side effects of sildenafil are weak or moderate and are transient.

In studies using a fixed dose, it has been shown that the incidence of certain adverse events increases with increasing doses.

Organs and organ systems	Adverse Events	Sildenafil,%	Placebo,%
The most common side effects (> 1/10)
Nervous system	Headache	10,8	2,8
Cardiovascular system	Vasodilation ("tides" of blood to the skin of the face)	10,9	1,4
Frequent side effects (> 1/100 and <1/10)
Nervous system	Dizziness	2,9	1,0
Body of sight	Visual impairment (blurred vision, change in sensitivity to light)	2,5	0,4
Body of sight	Chromatopsia (mild and transient, mainly a change in the perception of color shades)	1,1	0,03
Cardiovascular system	Cardiopalmus	1,0	0,2
Respiratory system	Rhinitis (nasal congestion)	2,1	0,3
Gastrointestinal tract	Dyspepsia	3,0	0,4

When sildenafil was used in doses exceeding the recommended levels, the adverse events were similar to those noted above, but were usually more common.

General condition disorders: reactions of hypersensitivity (including skin rash).

Changes from the central and peripheral nervous systems: convulsions.
Changes from the CAS: tachycardia, decreased blood pressure, fainting, epistaxis.
Disorders of the digestive tract: vomiting.
Changes from the organ of vision: pain in the eyes, redness of the eyes / injection of the sclera.
Disorders from the reproductive system: prolonged erection and / or priapism.

Overdose:

With a single admission of sildenafil at a dose of 800 mg, adverse events were comparable to those when taking the drug at lower doses, but were more common.
Symptoms: Increased severity of side effects was noted.

Treatment is symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, tk. 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 (the main pathway) and CYP2C9, so inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inductors, respectively, increase the clearance of sildenafil. A decrease in the clearance of sildenafil with simultaneous application of inhibitors of the cytochrome isoenzyme CYP3A4 (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome isoenzyme CYP3A4, when co-administered 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 CYP3A4 isoenzyme, in the presence of an equilibrium erythromycin concentration in the blood, increases the sildenafil AUC by 182%. With the simultaneous administration of sildenafil (once 100 mg) and saquinavir (1200 mg / day 3 times a day), the HIV protease inhibitor and the cytochrome CYP3A4 isoenzyme, while achieving an equilibrium concentration of saquinavir in the blood, Cmax sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir. More potent cytochrome CYP3A4 isoenzyme inhibitors, such as ketoconazole and itraconazole, can cause and stronger changes in the pharmacokinetics of sildenafil.

Simultaneous use of sildenafil (once 100 mg) and ritonavir (500 mg twice a day), an HIV protease inhibitor and a strong inhibitor of cytochrome P450, in the presence of an equilibrium concentration (Css) of ritonavir in the blood leads to an increase in Cmax sildenafil by 300% in 4 times), and 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 only 5 ng / ml).

If sildenafil take in recommended doses of patients receiving simultaneously strong inhibitors of the cytochrome isoenzyme CYP3A4, then Cmax of 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 the cytochrome isoenzyme CYP2C9 (tolbutamide, warfarin), cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists have no effect on the pharmacokinetics of sildenafil.

Azithromycin (500 mg / day for 3 days) has no effect on AUC, Cmax, Tmax, rate of elimination rate and T1 / 2 sildenafil or its main circulating metabolite.

Influence of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 - 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 isoenzymes (IC50> 150 μmol). When taking sildenafil in recommended doses, its Cmax 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 use of sildenafil in combination with nitrates or donators of nitric oxide is contraindicated.

At simultaneous reception α(4 or 8 mg) and sildenafil (25, 50 or 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in SBP and DBP in the supine position was 7/7, 9/5 and 8 / 4 mm of mercury. st., respectively, and in the standing position - 6/6, 11/4 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). Some sensitive patients receiving α- adrenoblockers, 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 isoenzyme of cytochrome CYP2C9, have not been identified. Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease, saquinavir and ritonavir inhibitors that are substrates of the cytochrome CYP3A4 isoenzyme 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 increase the hypotensive effect of alcohol in healthy volunteers at Cmax alcohol in the blood, on average 0.08% (80 mg / dL).

In patients with hypertension, there was no evidence of interaction between sildenafil (100 mg) and amlodipine. The average additional decrease in blood pressure in the supine position on the back is 8 mm Hg. Art. (SBP) and 7 mm Hg. Art. (DBP).

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

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.

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 (CAS) examination. Sexual activity is undesirable in patients with heart failure, unstable angina, MI or stroke, life-threatening arrhythmias, AH (BP> 170/100 mm Hg), or hypotension (BP <90/50 mm Hg. ).In clinical studies, there was no difference in the incidence of MI (1.1 per 100 people per year) or the incidence of CVD (0.3 per 100 people per year) in patients who received sildenafil compared with patients receiving placebo.

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

Sildenafil has a systemic vasodilator effect, leading to a transient decrease in blood pressure. This effect is not clinically significant and does not lead to any consequences in most patients. However, prior to prescribing the doctor should carefully evaluate the risk of possible undesirable manifestations of vasodilator action in patients with related diseases, especially

background of sexual activity. Increased sensitivity 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 by a severe violation of the regulation of blood pressure from the autonomic nervous system.

There were rare cases of development of anterior ischemic neuropathy of the optic nerve of non-arterial genesis as a cause of worsening 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 excavating the optic nerve head, age over 50 years, diabetes, AH, IHD, hyperlipidemia and smoking. The causal relationship between the intake of PDE5 inhibitors and the development of anterior ischemic neuropathy of the optic nerve of non-arterial genesis has not been revealed. The doctor should inform the patient about the increased risk of development of anterior ischemic neuropathy of the optic nerve of non-arterial genesis, if previously this condition was already noted. Since the joint use of sildenafil and α-adrenoconjugators may lead to symptomatic hypotension in selected sensitive patients, sildenafil should be administered with caution to patients receiving α-adrenoconvertors (see section "Interaction"). To minimize the risk of postural hypotension in patients taking αadrenoblockers, sildenafil should be started only after achieving hemodynamic stabilization in these patients. It should also consider the desirability of reducing the initial dose of the drug (see the section "Dosage regimen, mode of administration"). The doctor should inform patients about what actions should be taken in case of symptoms of postural hypotension.

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 pigment retinitis is absent, therefore sildenafil should be used with caution.

Sildenafil enhances the anti-aggregation effect of sodium nitroprusside (donor N0) on human platelets in vitro. Information on the safety of sildenafil in patients with internal bleeding or active peptic ulcers of the stomach is not available, so it should be used with caution.

Means for treating 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).

The safety and effectiveness of the use of sildenafil in conjunction with other drugs for the treatment of erectile dysfunction has not been studied, so the use of such combinations is not recommended (see the section "Contraindications"),

In some post-marketing and clinical trials using all PDE5 inhibitors, including sildenafil, reported a sudden decrease or loss of hearing in patients. However, most of these patients had risk factors for this pathology, and there was no correlation between the use of PDE5 inhibitors and sudden decline or loss of hearing. In case of sudden decrease or loss of hearing, stop sildenafil and immediately consult a doctor.

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

Against the background of taking sildenafil, there was no adverse effect on the ability to drive a car or other technical means. However, since the use of sildenafil may reduce blood pressure, the development of chromatopsy, blurred vision, and the like.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.

Form release / dosage:

Film-coated tablets 25 mg, 50 mg, 100 mg.

Packaging:

1 tablet in a blister of PVC / PVDC / / PVDH / aluminum foil. 1 blister together with instructions for use in a cardboard pack.

4 tablets in a PVC / PVDC blister. // PVDC / aluminum foil. 1 or 2 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiration date stated on the package

Terms of leave from pharmacies:On prescription

Registration number:LP-002461

Date of registration:13.05.2014

Manufacturer: & nbsp

West Pharma Produces de Especialidades Farmaceuticas, S.A. Portugal

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp28.10.2014

Illustrated instructions

Instructions

Erexel® (Erexesil®)