Maxigra, pills 50mg 1pc

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Active ingredient:	Sildenafil
Dosage form:	Pills
Indications for use:	Erectile dysfunction

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Categories: Genitourinary system, Impotence, Medication

Description
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Composition

Tablets

Active ingredient:

sildenafil citrate 70.24 mg or 140.48 mg (equivalent to sildenafil) 50.00 mg or 100.00 mg, respectively,

Auxiliary substances:

mannitol,

crospovidone (type A),

povidone (K 25),

silicon dioxycolloid,

corn starch,

magnesium stearate,

sodium lauryl sulfate,

Shell composition:

hypromellose (15 MPas),

macrogol 6000,

titanium dioxide E 171,

talc,

indigo carmine E 132.

Pharmacological action

Pharmacotherapeutic group: treatment for erectile dysfunction-PDE5-inhibitor.

ATX code: [G04BE03].

Pharmacological properties

Pharmacodynamics

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

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

The activity of PDE5 is 10-10000 times higher than that of other PDE isoenzymes [1-11].

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

In some patients,1 hour after taking the drug at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a slight and transient violation of the ability to distinguish colors (blue/green),2 hours after taking the drug these changes were absent. The mechanism of color vision impairment is considered to be inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil has no effect on visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

No effects on sperm motility or morphology were observed in healthy volunteers after a single 100 mg dose of sildenafil.

Pharmacokinetics

Suction

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

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

Distribution

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

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

Metabolism

Sildenafil is primarily metabolized by microsomal liver isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The main circulating metabolite is formed from sildenafil by N-demethylation. This metabolite has a phosphodiesterase selectivity profile similar to that of sildenafil, and its activity against PDE5 in vitro is approximately 50% of that of the parent drug. The plasma concentration of this metabolite is approximately 40% of that of sildenafil. Subsequently, the metabolite N-desmethyl is metabolized, and its half-life (half-life) is about 4 hours.

Deduction

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

Pharmacokinetics in special clinical cases

Elderly patients

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

Patients with renal insufficiency

In patients with mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal insufficiency, the pharmacokinetic parameters of sildenafil after oral use of a single dose (50 mg) do not change.

In severe renal insufficiency (creatinine clearance < 30 ml/min), sildenafil clearance decreases, resulting in approximately a twofold increase in AUC (100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

Patients with hepatic insufficiency

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

The pharmacokinetic parameters of sildenafil in patients with severe hepatic impairment have not been studied.

Indications

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain a penile erection, to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

The drug is effective only for sexual stimulation.

Contraindications

Hypersensitivity to sildenafil or any other component of the drug.

Use in patients receiving continuous or intermittent nitric oxide donors, organic nitrates or nitrites in any form, as sildenafil increases the hypotensive effect of nitrates (see the section “Interaction with other drugs”).

The safety and efficacy of sildenafil when co-administered 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 is not intended for use in children under 18 years of age.

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

With caution

Anatomical deformity of the penis (including angulation, cavernous fibrosis, or Peyronie’s disease) (see the section “Special instructions”).

Diseases that predispose to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia) (see the section “Special instructions”).

Patients with a history of anterior ischemic optic neuropathy of non-inflammatory origin.

Diseases accompanied by bleeding.

Exacerbation of peptic ulcer of the stomach and duodenum.

Hereditary retinitis pigmentosa (see section “Special instructions”)

Heart failure, unstable angina, myocardial infarction, stroke or life-threatening arrhythmias in the last 6 months, hypertension (BP > 170/100 mm Hg) or hypotension (BP >

Simultaneous use of alpha-blockers.

Side effects

The frequency of side effects is given according to the following classification: very common (≥ 1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (

Immune system disorders: infrequently – hypersensitivity reaction.

Nervous system disorders: very often – headache; often-dizziness; infrequently-hypesthesia, drowsiness; rarely-stroke, fainting; frequency unknown-intracerebral hemorrhage, transient ischemic attack, convulsions, including recurrent ones.

Visual disorders: often – visual impairment, color perception changes; infrequently-conjunctivitis, lacrimation disorders, eye pain, photophobia, photopsia, redness of the eyes/sclera injections, changes in light perception brightness; frequency unknown – anterior ischemic neuropathy of the optic nerve of non-inflammatory origin (NAION), retinal vascular occlusion, visual field defects.

Hearing disorders and labyrinth disorders: infrequently-vertigo, tinnitus; rarely-deafness.

Disorders of the cardiovascular system: often – “hot flashes” of blood to the face; infrequently – palpitation, tachycardia; rarely – arterial hypertension, hypotension, myocardial infarction, atrial fibrillation; frequency unknown – ventricular arrhythmia, unstable angina, sudden cardiac death.

Respiratory, thoracic, and mediastinal disorders: often nasal congestion; rarely nosebleeds.

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

Liver and biliary tract disorders: frequency unknown-hepatotoxicity (liver damage and increased transaminase levels).

Skin and subcutaneous tissue disorders: infrequently-skin rash, frequency unknown-Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: infrequently-myalgia.

Genital and breast disorders: infrequently-hematospermia, penile bleeding; frequency unknown-priapism, prolonged erection.

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

Interaction

Effect of other drugs on the metabolism of sildenafil

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

When co-administered with inhibitors of the CYP3A4 isoenzyme (such as ketoconazole, erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted.

A single dose of 100 mg of sildenafil in combination with erythromycin, a specific inhibitor of the CYP3A4 isoenzyme (at a dose of 500 mg 2 times a day for 5 days), at steady-state concentrations of erythromycin leads to an increase in the AUC of sildenafil by 182%.

Cimetidine (800 mg), a cytochrome P450 inhibitor and a non-specific inhibitor of the CYP3A4 isoenzyme, when co-administered with sildenafil (50 mg) in healthy volunteers caused an increase in the concentration of sildenafil in plasma by 56%.

Concomitant use of sildenafil (a single 100 mg dose) and the HIV protease inhibitor ritonavir (500 mg twice daily), which is a potent cytochrome P450 inhibitor, at steady-state blood concentrations of ritonavir resulted in a 300% (4-fold) increase in sildenafil Cmax and an 11-fold increase in sildenafil AUC. After 24 hours, the concentration of sildenafil in the blood plasma was approximately 200 ng / ml, compared with approximately 5 ng / ml when using sildenafil alone.

Concomitant use of sildenafil (a single dose of 100 mg) and the HIV protease inhibitor saquinavir, which is an inhibitor of the CYP3A4 isoenzyme, at steady-state concentrations (at a dose of 1200 mg 3 times a day) resulted in an increase in sildenafil Cmax by 140%, and sildenafil AUC by 210%. Sildenafil had no effect on the pharmacokinetics of saquinavir.

Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

CYP2C9 inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, calcium antagonists and metabolic inducers CYP450 agents (e. g. rifampicin, barbiturates) do not affect the pharmacokinetics of sildenafil.

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

In healthy male volunteers, concomitant use of azithromycin (500 mg daily for 3 days) had no effect on the AUC, Cmax, Tmax, elimination rate constant, and half-life of sildenafil or its main circulating metabolite.

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

Effect of sildenafil on other medications

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes-1A2,2C9,2C19,2D6,2E1, and 3A4 (IC50150 mmol). It is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

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

In some sensitive patients receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension. When the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg,50 mg and 100 mg) were co – administered in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional reduction in systolic/diastolic blood pressure in the supine position was 7/7 mm Hg,9/5 mm Hg and 8/4 mm Hg, respectively, and in the standing position-6/6 mm Hg.,11/4 mmHg and 4/5 mmHg, respectively. Rare cases of symptomatic orthostatic hypotension have been reported in such patients, which manifested itself in the form of dizziness (without fainting).

There were no significant interactions of sildenafil (50 mg) when co-administered with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.

Sildenafil (100 mg) had no effect on the pharmacokinetic parameters of HIV protease inhibitors at steady state, such as saquinavir and ritonavir, both CYP3A4 substrates.

Sildenafil (50 mg) did not cause an additional increase in bleeding time caused by taking acetylsalicylic acid (150 mg).

Sildenafil (50 mg) did not enhance the hypotensive effect of alcohol in healthy volunteers with a maximum blood alcohol concentration of 80 mg/dl on average.

In patients with arterial hypertension, there were no signs of interaction between sildenafil (100 mg) and amlodipine. The average additional reduction in blood pressure in the supine position is: systolic – by 8 mm Hg, diastolic-by 7 mm Hg.

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

How to take, course of use and dosage

Inside, approximately 1 hour before the planned sexual activity. The maximum recommended frequency of use is once a day.

A single dose for adults is 50 mg once a day. Depending on the efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg. The maximum single dose is 100 mg.

When taking sildenafil together with fatty foods, the onset of its action may be delayed compared to taking it on an empty stomach.

Use in elderly patients

No dose adjustment is required in elderly patients.

Use in patients with impaired renal function

In mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), no dose adjustment is required; in severe renal insufficiency (creatinine clearance < 30 ml/min), the dose of sildenafil should be reduced to 25 mg.

Depending on the effectiveness and tolerability, the dose can be increased to 50 mg and 100 mg.

Use in patients with impaired liver function

In case of impaired liver function, the dose of the drug should be reduced to 25 mg.

Depending on the effectiveness and tolerability, the dose can be increased to 50 mg and 100 mg.

Application in patients receiving other drugs

with the exception of ritonavir for which co-use sildenafil is not recommended in patients receiving concomitant treatment with inhibitors of CYP3A4, the initial dose should be 25 mg.

to minimize the possibility of orthostatic hypotension in patients receiving alpha-blockers, treatment sildenafilom should be started after stabilization of hemodynamic parameters in these patients. In addition, consideration should be given to the use of sildenafil at an initial dose of 25 mg.

Overdose

With a single dose of the drug up to 800 mg in studies on healthy volunteers, adverse events were comparable to those with sildenafil in lower doses, but their frequency and severity increased.

The use of sildenafil at a dose of 200 mg did not lead to an increase in effectiveness, but the frequency of adverse events increased (headache, “hot flashes” of blood to the face, dizziness, dyspepsia, nasal congestion, visual impairment).

Treatment: symptomatic. It is not excreted during hemodialysis.

Special instructions

Before prescribing treatment, it is necessary to collect a medical history and conduct a physical examination in order to diagnose erectile dysfunction and determine the possible causes of its development.

Treatment of erectile dysfunction should be used with caution in patients with anatomical deformity of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see the section “With caution”).

If your erection persists for more than 4 hours, seek immediate medical attention. If priapism therapy is not carried out in a timely manner, it can lead to damage to penile tissues and irreversible loss of potency.

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

Since sexual activity poses a certain risk in the presence of heart disease, before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the patient’s cardiovascular system.

Sexual activity is undesirable in patients with heart failure, unstable angina, a history of myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP >

Clinical studies have shown no differences in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients treated with sildenafil compared to patients treated with placebo.

Cardiovascular complications

Adverse events such as severe cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with the use of sildenafil have been reported during post-marketing use of sildenafil for the treatment of erectile dysfunction. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some of them were observed after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct link between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing sildenafil, the doctor should carefully assess the risk of possible undesirable manifestations of vasodilating effects 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 exit tract (for example, aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare multiple systemic atrophy syndrome, manifested by a severe violation of blood pressure regulation by the autonomic nervous system.

Sildenafil should be administered with caution in patients taking alpha-blockers, as their combined use may lead to symptomatic hypotension in some sensitive patients.

This effect is most likely to develop within 4 hours after taking sildenafil. To minimize the risk of postural hypotension in patients taking alpha-blockers, treatment with sildenafil should be initiated after the hemodynamic parameters in these patients have stabilized. Consideration should also be given to reducing the initial dose of sildenafil. The doctor should inform patients what actions should be taken in case of symptoms of postural hypotension.

Visual impairments

When using all PDE5 inhibitors, including sildenafil, rare cases of anterior ischemic neuropathy of the optic nerve of non-inflammatory origin were noted, as a cause of deterioration or loss of vision. Most of these patients had risk factors such as a reduced ratio of excavation diameters to the optic disc (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, and smoking. In case of sudden deterioration of vision, the patient should be advised to stop taking sildenafil and immediately consult a doctor.

A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase functions. There is no information on the safety of sildenafil in patients with retinitis pigmentosa.

Hearing loss

Some post-marketing and clinical studies have reported cases of sudden hearing impairment or 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. No causal relationship has been established between the use of PDE5 inhibitors and sudden deterioration or loss of hearing. In case of sudden deterioration or loss of hearing while taking sildenafil, you should immediately consult a doctor.

Bleeding issues

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of using sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so sildenafil should be used with caution in these patients (see the section “With caution”). The incidence of nosebleeds 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 treated with sildenafil in combination with a vitamin K antagonist, the incidence of nosebleeds was higher (8.8%) than in patients who did not take a vitamin K antagonist (1.7%).

Use in conjunction with other treatments for erectile dysfunction

The safety and efficacy of the combined use of sildenafil with other PDE5 inhibitors, or other drugs for the treatment of pulmonary hypertension containing sildenafil, or other agents for the treatment of erectile dysfunction have not been studied, so the use of such combinations is not recommended.

Influence on the ability to drive vehicles and work with mechanisms.

The effect of sildenafil on the ability to drive a car and perform work that requires increased attention has not been studied.

However, during the period of taking the drug, care should be taken when driving vehicles and engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions, since dizziness and visual impairment may occur.