Sildenafil-SZ, 50 mg 20 pcs

Sildenafil is a potent selective inhibitor of cGMP-specific FDE-5.

The mechanism of action

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpora cavernosa during sexual stimulation. This in turn leads to an increase in cGMP levels, a subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE-5, which is responsible for the breakdown of cGMP.

Sildenafil is selective against FDE-5 in vitro, its activity against FDE-5 exceeds activity against other known FDE isoenzymes: FDE-6 – 10 times; FDE-1 – more than 80 times; FDE-2, FDE-4, FDE-7 – FDE-11 – more than 700 times. Sildenafil is 4,000 times more selective against FDE-5 compared to FDE-3, which is very important because FDE-3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiology studies. Use of sildenafil in doses up to 100 mg did not result in clinically significant ECG changes in healthy volunteers. The maximum decrease in resting BP after sildenafil administration at a dose of 100 mg was 8.3 mmHg, and in resting BP, 5.3 mmHg. A more pronounced, but also transient effect on BP was observed in patients taking nitrates (see “Contraindications”, “Interactions”).

In a study of the hemodynamic effects of sildenafil in a single dose of 100 mg in 14 patients with severe CHD (more than 70% of patients had stenosis of at least one coronary artery), resting BP and MAP decreased by 7 and 6%, respectively, and pulmonary BP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenosed coronary arteries, and also resulted in an increase (by approximately 13%) in adenosine-induced coronary flow in both stenosed and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until the severity of angina symptoms decreased. Exercise duration was significantly longer (19.9 s; 0.9-38.9 s) in patients taking sildenafil in a single dose of 100 mg compared with patients receiving placebo.

The randomized, double-blind, placebo-controlled study examined the effect of a variable dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and arterial hypertension who were taking more than two antihypertensive drugs. Sildenafil improved erections in 71% of men compared with 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in those taking more than three antihypertensive drugs.

Studies on visual impairment. Mild and transient impairment in the ability to distinguish shades of color (blue/green) was detected in some patients 1 h after taking sildenafil at a dose of 100 mg using the Farnsworth-Mansell 100 test. These changes were absent 2 h after drug administration. The color vision impairment is thought to be caused by inhibition of FDE-6, which is involved in the transmission of light in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.

In a placebo-controlled, cross-over study of patients with proven early-onset macular degeneration (n=9), sildenafil at a single dose of 100 mg was well tolerated. No clinically significant changes in vision as assessed by specific visual tests (visual acuity, Amsler grid, color perception, color passage simulation, Humphrey perimeter, and photostress) were identified.

The efficacy and safety of sildenafil were 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 various etiologies (organic, psychogenic, or mixed). Efficacy of the drug was evaluated globally using an erection diary, the International Erectile Function Index (a validated sexual function questionnaire), and a partner survey.

The efficacy of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportion of patients who reported that therapy improved their erections was 62% (sildenafil dose – 25 mg), 74% (sildenafil dose – 50 mg) and 82% (sildenafil dose – 100 mg) versus 25% in the placebo group). Analysis of the International Index of Erectile Function showed that in addition to improved erections, sildenafil treatment also improved the quality of orgasm, allowed to achieve satisfaction of sexual intercourse and overall satisfaction.

The data summarized showed that among the patients who reported improved erections with sildenafil treatment, 59% had diabetes, 43% had radical prostatectomy, and 83% had spinal cord injury (versus 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics:

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

Intake

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (25% to 63%). In-vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%. After a single sildenafil dose of 100 mg, the average maximum plasma concentration (Cmax) of free sildenafil in men is about 18 ng/ml (38 nM). Cmax when sildenafil is taken orally on an empty stomach is reached on average within 60 min (from 30 min to 120 min). When taken in combination with fatty food absorption rate is reduced: Cmax is reduced by 29 % on average, and time to maximum concentration (Tmax) is increased by 60 min, but absorption degree does not change significantly (area under the pharmacokinetic curve concentration-time (AUC) is reduced by 11 %).
Distribution
Sildenafil distribution volume in equilibrium is on average 105 l. Binding of sildenafil and its main circulating N-demethyl metabolite with blood plasma proteins is about 96 % and does not depend on total drug concentration. Less than 0.0002% of the sildenafil dose (188 ng on average) is detected in semen 90 min after taking the drug.

Metabolism

Sildenafil is metabolized primarily in the liver by the cytochrome CYPCA4 isoenzyme (major pathway) and cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism. Selectivity of this metabolite against FDE is comparable with that of sildenafil, and its activity against FDE5invitro is about 50% of sildenafil activity.

The plasma concentration of the metabolite in healthy volunteers was about 40% of that of sildenafil. The N-demethyl metabolite is further metabolized; its half-life (T1/2) is about 4 hours.

The total clearance of sildenafil is 41 l/hour and the final T1/2 is 3-5 hours. After oral administration 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 special patient groups

Elderly patients

Healthy elderly patients (over 65 years of age) have reduced sildenafil clearance and plasma free sildenafil concentrations are about 40% higher than those of younger patients (18-45 years of age). Age has no clinically significant effect on the incidence of side effects.

Renal impairment

In mild (creatinine clearance (CK) 50-80 ml/min) and moderate (CK 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal impairment (CKD ≤ 30 ml/min) sildenafil clearance is decreased, resulting in approximately twofold increase of AUC (100%) and Cmax (88%) compared to normal renal function in patients of the same age group.

Hepatic disorders

In patients with cirrhosis (Child-Pugh stages A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) and Cmax (47%) compared to normal hepatic function in patients in the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh stage C) has not been studied.

Indications

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

Sildenafil is effective only with sexual stimulation.

Active ingredient

Sildenafil

Composition

• active ingredient:
• sildenafil citrate in terms of sildenafil – 50 mg;
• accessory substances (core):
• cellulose microcrystalline – 54.0 mg;
• lactose monohydrate (milk sugar) – 74.0 mg;
• croscarmellose sodium (primellose) – 10.0 mg;
• povidone (Polyvinylpyrrolidone medium molecular) – 10.0 mg;
• magnesium stearate – 2.0 mg;
• accompanied substances (coating):
• Opadray II (polyvinyl alcohol, partially hydrolyzed – 2.4 mg; titanium dioxide E 171 – 1.374 mg; macrogol (polyethylene glycol 3350) – 1.212 mg;
• talcum powder – 0.888 mg; Brilliant blue alumina varnish – 0.1152 mg; iron oxide (II) yellow E 172 – 0.0102 mg; iron oxide (II) black E 172 – 0.0006 mg.)

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How to take, the dosage

Ingestion.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Renal dysfunction

In mild to moderate renal failure (CKR 30-80 ml/min), no dose adjustment is necessary; in severe renal failure (CKR < 30 ml/min), the sildenafil dose should be reduced to 25 mg.

Hepatic disorders

Because sildenafil excretion is impaired in patients with liver damage (particularly in cirrhosis), the dose of sildenafil should be reduced to 25 mg.

Combined use with other medicinal products

When combined with ritonavir, the maximum single dose of Sildenafil should not exceed 25 mg and the frequency of use should be once every 48 hours (see “Interaction with other medicinal products”).

In co-administration with cytochrome CYPCA4 inhibitors (erythromycin, saquinavir, ketoconazole, itraconazole), the starting dose of Sildenafil should be 25 mg (see “Interaction with other medicinal products”).

In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, Sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. It should also be considered to reduce the starting dose of sildenafil (see sections “Special Precautions” and “Interaction with other medicinal products”).

Elderly patients

There is no need to adjust the dose of sildenafil.

Interaction

Influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYPCA4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance. There was observed a decrease in sildenafil clearance when concomitant use of inhibitors of cytochrome CYPCA4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of cytochrome СYPZA4 isoenzyme, when taken together with sildenafil (50 mg) increases sildenafil concentration in plasma by 56%. Simultaneous use of sildenafil 100 mg in combination with erythromycin (500 mg/day two times a day for 5 days), a specific inhibitor of cytochrome CYPCA4 isoenzyme, on the background of achieving constant concentration of erythromycin in blood, leads to increase of AUC of sildenafil by 182 %.

When taking sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, together, against achieving a constant concentration of saquinavir in the blood Cmax of sildenafil was increased by 140 % and AUC was increased by 210 %. Sildenafil has no effect on the pharmacokinetics of saquinavir.

The stronger inhibitors of cytochrome CYPCA4 isoenzyme, such as ketoconazole and itraconazole, can also cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P450 inhibitor, on reaching a steady blood concentration of ritonavir results in a 300% (4-fold) increase in Cmax of sildenafil and a 1000% (11-fold) increase in AUC. After 24 hours, plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml), which is consistent with the information on the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates. Sildenafil has no effect on the pharmacokinetics of ritonavir. Combined use of sildenafil with ritonavir is not recommended.

If sildenafil is taken in recommended doses in patients receiving concomitant strong sildenafil cytochrome CYPCA4 isoenzyme inhibitors, the Cmax of free sildenafil does not exceed 200 nM and the drug is well tolerated.

A single administration of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.
Inhibitors of cytochrome CYP2C9 isoenzyme (tolbutamide, warfarin), cytochrome CYP2D6 isoenzyme (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not influence sildenafil pharmacokinetics.

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

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and WA4 (IK50>150 μmol). When sildenafil is taken at the recommended doses, its Cmax is about 1 μmol, so it is unlikely that sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates both with long-term use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were used concomitantly in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic/diastolic BP in the supine position was 7/7 mm Hg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension, manifested as dizziness (without fainting), have been reported in these patients. In certain sensitive patients receiving α-adrenoblockers, concomitant use of sildenafil may result in symptomatic hypotension.

There are no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by cytochrome CYP2C9 isoenzyme.

Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of cytochrome CYPCA4, when their blood levels are constant.

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 a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average

In patients with arterial hypertension, there is no evidence of interaction between sildenafil (100 mg) and amlodipine. The mean additional reduction of BP in the supine position is 8 mmHg (systolic) and 7 mmHg (diastolic).

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

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Special Instructions

To diagnose erectile dysfunction, determine its possible causes, and choose an adequate treatment, a complete medical history and a thorough physical examination must be taken. Erectile dysfunction treatments should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

The drugs intended to treat erectile dysfunction should not be prescribed for men for whom sexual activity is undesirable.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any erectile dysfunction therapy. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg) (see section “Caution”). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality (0.3 per 100 people per year) in patients treated with Sildenafil compared to patients treated with placebo.

Cardiovascular Complications

In the postmarketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmias, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) that were temporarily associated with sildenafil use. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after sildenafil administration without subsequent sexual activity. A direct relationship between these adverse events and these or other factors cannot be established.

Hypotension

Sildenafil has a systemic vasodilatory effect resulting in a transient decrease in BP, which is not clinically significant and has no effect in most patients. Nevertheless, before prescribing Sildenafil, the physician should carefully assess the risk of possible adverse vasodilatory effects in patients with related conditions, especially during sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with rare syndrome of multiple systemic atrophy manifested by severe BP regulation disorder of the autonomic nervous system.
Since co-administration of sildenafil and α-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, Sildenafil should be prescribed with caution in patients taking α-adrenoblockers (see section “Interaction with other medicinal products”). To minimize the risk of postural hypotension in patients taking α-adrenoblockers, Sildenafil should be started only after hemodynamic stabilization is achieved in these patients. It should also be considered to reduce the starting dose of Sildenafil (see section “Dosage and administration”). The physician should inform patients about what actions should be taken if symptoms of postural hypotension occur.

Visual impairment

Rare cases of development of anterior nonarteritic ischemic optic neuropathy as a cause of visual impairment or loss have been reported with all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as optic disc excavation (deepening), age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease, hyperlipidemia, and smoking. No causal relationship between the intake of FDE5 inhibitors and the development of anterior nonarteritic ischemic optic neuropathy has been identified. The physician should inform the patient about the increased risk of anterior nonarteritic ischemic optic neuropathy if this condition has already been reported. In case of sudden loss of vision, patients should be treated immediately. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase functions. There is no information about the safety of Sildenafil in patients with retinitis pigmentosa, so Sildenafil should be used with caution (see section “Caution”).

Hearing impairment

Some postmarketing and clinical studies have reported cases of sudden hearing impairment or loss associated with use of all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or hearing loss. A causal relationship between the use of FDE5 inhibitors and sudden hearing impairment or hearing loss has not been established. If there is sudden hearing loss or hearing loss while taking sildenafil, consult a physician immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on safety of sildenafil administration in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcer, therefore Sildenafil should be used with caution in these patients (see section “Caution”). The incidence of nasal bleeding in patients with LH associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). Patients who received sildenafil in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).

Performance in combination with other treatments for erectile dysfunction.

The safety and effectiveness of Sildenafil with other erectile dysfunction drugs have not been studied, so this combination is not recommended (see section “Contraindications”).

Influence on driving and operating ability

There have been no adverse effects on the ability to drive or operate machinery while taking sildenafil.

However, since taking sildenafil may result in decreased blood pressure, chromatopsia, blurred vision, and other adverse events, careful consideration should be given to the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosing regimen.

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Contraindications

• High sensitivity to sildenafil or any other drug component
• Application in patients receiving nitric oxide donors, organic nitrates or nitrites in any form continuously or intermittently, as sildenafil enhances the hypotensive effects of nitrates (see “Interaction with other drugs.
• Safety and effectiveness of Sildenafil combined with other treatments for erectile dysfunction have not been studied, therefore such combinations are not recommended (see
• Specific information

).

• Sildenafil is not indicated for use in children under 18 years of age
• About the registered indicationSildenafil is not indicated for use in women
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
• Do not use sildenafil concomitantly with ritonavir.

With caution:

• Anatomical deformity of the penis (angulation, cavernous fibrosis, or Peyronie’s disease) (see “Special Precautions”).
• Diseases predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia)
• (see section “Special Indications”).
• Diseases accompanied by bleeding.
• Elevation of gastric and duodenal ulcer.
• Hereditary retinitis pigmentosa (see section “Special Indications”).
• Heart failure, unstable angina pectoris, myocardial infarction, stroke or life-threatening arrhythmias within the last 6 months, arterial hypertension (BP > 170/100 mm Hg), or hypotension.104 mm Hg) or hypotension (BP < 90/50 mm Hg) (see Special Precautions).
• Patients with a history of anterior nonarteritic ischemic optic neuropathy.
  

Side effects

Sildenafil side effects are usually mild to moderate and transient.

In fixed-dose studies, the incidence of some adverse events has been shown to increase with increasing dose.

When using Sildenafil in doses higher than recommended, adverse events were similar to those noted above, but tended to be more common.

General condition disorders: facial edema, photosensitivity reactions, shock, asthenia, pain, chills, abdominal pain, chest pain.

Allergic reactions: hypersensitivity reactions (including skin rash), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome).

Central and peripheral nervous system disorders: somnolence, insomnia, hypoesthesia, paraesthesia, ataxia, neuralgia, neuropathy, tremor, depression, unusual dreams, decreased reflexes, stroke, transient ischemic attack, convulsions, including recurrent ones.

Cardiovascular system disorders: tachycardia, increased or decreased BP, myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, AV-blockade, cerebral vascular thrombosis, heart failure, ECG disorders, cardiomyopathy, sudden death, syncope.

Respiratory disorders: nasal bleeding, asthma, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum secretion, increased cough.

Gastrointestinal disorders: vomiting, nausea, dry oral mucosa, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, rectal bleeding, gingivitis.

Visual organ disorders: eye pain, eye redness/sclerae injection, conjunctival lesions, lacrimation disorders, anterior ischemic optical neuropathy, retinal vascular occlusion, visual field defects, mydriasis, cataracts, eye pain.

Hearing disorders: vertigo, tinnitus, tinnitus pain, deafness.

Blood and lymphatic system disorders: anemia, leukopenia.

Metabolism and nutrition disorders: thirst, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatriemia.

Musculoskeletal system disorders: arthritis, arthrosis, myalgia, tendon rupture, tendovaginitis, bone pain, myasthenia, synovitis.

Skin and subcutaneous tissue disorders: urticaria, herpes simplex, itching, sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.

Urogenital system disorders: cystitis, nycturia, frequent urination, gynecomastia, urinary incontinence, ejaculation disorders, genital edema, anorgasmia.

Reproductive system disorders: prolonged erection and/or priapism.

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Overdose

Single administration of Sildenafil in doses up to 800 mg resulted in adverse events comparable to, but more frequent than, those associated with lower doses.

The treatment is symptomatic. Hemodialysis does not accelerate clearance of sildenafil, because the latter is actively bound to plasma proteins and is not excreted by the kidneys.

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Similarities

Viagra, Dynamico, Sildenafil NW, Effex, Visarsin, Visarsin Ku-tab, Effex Sildenafil, Sildenafil, Wildegra, Gent