Pharmacological properties
Pharmacodynamics. Sildenafil is an oral therapeutic agent used to treat erectile dysfunction in men. In particular, upon sexual stimulation, it restores a failed erection by increasing blood flow to the penis.
The physiological mechanism of penile erection is the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates the enzyme guanylate cyclase, which causes an increase in cGMP levels, relaxation of the smooth muscles of the corpus cavernosum, and increased blood flow to them.
Sildenafil is a potent, selective inhibitor of specific cGMP phosphodiesterase-5 in the corpus cavernosum, where PDE5 is responsible for the breakdown of cGMP. Sildenafil has a peripheral center of action on erection. Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum, but significantly enhances the relaxing effect of NO on this tissue. When the NO/cGMP pathway is activated, which occurs during sexual stimulation, inhibition of PDE5 by sildenafil leads to an increase in cGMP levels in the corpus cavernosum. Therefore, sexual stimulation is necessary for sildenafil to have its targeted positive pharmacological effect.
In vitro studies have shown that sildenafil is selective for PDE5, which is involved in the process of erection. Its effect is more pronounced on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity for PDE6, which is involved in the process of photoconversion in the retina. At the maximum recommended doses, there is an 80-fold selectivity for PDE1 and more than 700-fold selectivity for PDE2, -3, -4, -7, -8, -9, -10 and -11. In particular, sildenafil has more than 4000-fold selectivity for PDE5 than PDE3, the cGMP-specific isoform of phosphodiesterase, which is involved in the control of cardiac contraction.
Pharmacokinetics. Absorption. Sildenafil is rapidly absorbed. The observed Cmax was achieved within 30-120 min (mean 60 min) after oral administration in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral administration of sildenafil, AUC and Cmax increase proportionally with increasing dose within the recommended dosage range (25-100 mg).
When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 min and a mean decrease in Cmax of 29%.
Distribution. The mean steady-state volume of distribution (Vd) for sildenafil is 105 L, indicating tissue distribution. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) are 96% bound to plasma proteins, this results in a mean Cmax of free sildenafil in plasma of 18 ng/mL (38 Nm). Protein binding is independent of total drug concentration.
In healthy volunteers who took sildenafil (100 mg once), less than 0.0002% (average 188 ng) of the administered dose was detected in the ejaculate 90 minutes after dosing.
Metabolism: Sildenafil is primarily metabolized by the hepatic microsomal isoenzymes CYP 3A4 (major pathway) and CYP 2C9 (minor pathway). The major circulating metabolite is formed by N-demethylation of sildenafil. This metabolite has a PDE selectivity similar to sildenafil and an in vitro activity for PDE5 of approximately 50% of the parent drug. The plasma concentration of this metabolite is approximately 40% of that observed for sildenafil. The N-desmethyl metabolite is further metabolized with a terminal T½ of approximately 4 h.
Excretion. The total clearance of sildenafil is 41 l / h with a terminal phase T ½ of 3-5 h. After oral or intravenous administration, sildenafil is excreted as metabolites, mainly in the feces (approximately 80% of the oral dose) and to a lesser extent in the urine (approximately 13% of the oral dose).
Pharmacokinetics in special patient groups
Elderly patients: In healthy elderly volunteers (65 years or older), reduced clearance of sildenafil was observed, resulting in higher (approximately 90%) plasma concentrations of the N-desmethyl metabolite of sildenafil compared to those observed in healthy young volunteers (aged 18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentrations was approximately 40%.
Hepatic impairment: In volunteers with mild to moderate liver cirrhosis (Child-Pugh grades A and B), sildenafil clearance was reduced, resulting in increased AUC (84%) and C max (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.
Indication
Vizarsin Q-tab is recommended for use in men with erectile dysfunction, which is defined as the inability to achieve or maintain a penile erection sufficient for successful sexual intercourse. Sexual arousal is required for Vizarsin Q-tab to be effective.
Application
The drug is intended for oral use in adult men.
The tablet should be placed in the mouth on the tongue, where it quickly dissolves in saliva and can then be easily swallowed. The tablet can be taken with or without liquid. It is difficult to remove a dispersible tablet from the mouth whole. Since the tablet is fragile, it should be taken immediately after opening the blister.
Dispersible tablets may be an alternative to Vizarsin film-coated tablets for patients who have difficulty swallowing film-coated tablets. If a 100 mg dose is required, the second tablet should be taken only after the first tablet has completely disintegrated.
Adults. The recommended dose is 50 mg, taken as needed approximately 1 hour before sexual intercourse. Based on efficacy and tolerability, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of administration is once daily. The efficacy of Vizarsin Q-Tab may be delayed when taken with food compared to when taken on an empty stomach.
Elderly patients: No dosage adjustment is required for elderly patients.
Patients with renal impairment. In patients with mild to moderate renal insufficiency (creatinine clearance 30-80 ml/min), the dosage regimen is not changed. Since sildenafil clearance is reduced in patients with severe renal insufficiency (creatinine clearance 30 ml/min), the drug should be started with a dose of 25 mg. Depending on the effectiveness and tolerability of the drug, the dose can be gradually increased to 50 and 100 mg if necessary.
Patients with impaired liver function. Since sildenafil clearance is reduced in patients with hepatic insufficiency, for example, in cirrhosis, the drug should be started at a dose of 25 mg. Depending on the effectiveness and tolerability of the drug, the dose can be gradually increased to 50 and 100 mg if necessary.
Patients taking other medications: If patients are taking CYP 3A4 inhibitors concomitantly (see Interactions with other drugs), a starting dose of 25 mg should be considered (except for ritonavir, the use of which with sildenafil is not recommended, see Precautions).
To minimize the potential for postural hypotension in patients taking α-blockers, their condition should be stabilized with α-blockers before initiating sildenafil. A starting dose of 25 mg should also be considered (see Precautions and Interactions).
Contraindication
Hypersensitivity to the active substance or any other component of the drug.
By affecting the NO/cGMP exchange, sildenafil enhances the hypotensive effect of nitrates, therefore its simultaneous administration with NO donors (such as amyl nitrite) or nitrates in any form is contraindicated.
Drugs for the treatment of erectile dysfunction, including sildenafil, should not be used in patients for whom sexual activity is undesirable (e.g. patients with severe cardiovascular disease, such as unstable angina or severe heart failure).
Loss of vision in one eye due to non-arterial anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of phosphodiesterase-5 inhibitors or not.
The presence of diseases such as severe liver dysfunction, arterial hypotension (BP 90/50 mm Hg), recent stroke or myocardial infarction, and known hereditary degenerative retinal diseases such as retinitis pigmentosa (a small number of such patients have genetic disorders of retinal PDE), since the safety of sildenafil has not been studied in such subgroups of patients.
Side effects
The most common adverse reactions reported in clinical trials in patients taking sildenafil were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia and blurred vision. Information on adverse reactions in the framework of post-marketing surveillance of sildenafil was collected for more than 10 years. Below are listed all clinically important adverse reactions identified in clinical trials at a frequency higher than when taking placebo, by body system and frequency: very common (≥1 / 10), common (≥1 / 100, 1/10), uncommon (≥1 / 1000, 1/100), rare (≥1 / 10,000, 1/100).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infectious and invasive diseases: infrequently - rhinitis.
On the part of the immune system: infrequently - hypersensitivity.
From the nervous system: very often - headache; often - dizziness; infrequently - drowsiness, hypoesthesia; rarely - stroke, transient ischemic attack, convulsions *, recurrent convulsions *, syncope.
From the organ of vision: often - color perception disorders **, visual impairment, blurred vision; infrequently - lacrimation disorders ***, eye pain, photophobia, photopsia, ocular hyperemia, visual brightness, conjunctivitis; rarely - non-arterial anterior ischemic optic neuropathy *, retinal vascular occlusion *, retinal hemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, decreased visual acuity, myopia, asthenopia, floating vitreous opacities, iris disorders, mydriasis, the appearance of luminous circles around the light source (halo) in the field of vision, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal sensations in the eyes, eyelid edema, sclera discoloration.
From the organs of hearing and vestibular apparatus: infrequently - dizziness, tinnitus; rarely - deafness.
On the part of the heart: infrequently - tachycardia, palpitations; rarely - sudden cardiac death *, myocardial infarction, ventricular arrhythmia *, atrial fibrillation, unstable angina.
Vascular: often - flushing, hot flashes; infrequently - hypertension, arterial hypotension.
From the respiratory system, chest and mediastinum: often - nasal congestion; infrequently - nosebleeds, sinus congestion; rarely - a feeling of tightness in the throat, swelling of the nasal mucosa, dryness in the nose.
From the gastrointestinal tract: often - nausea, dyspepsia; infrequently - gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rarely - oral hypoesthesia.
Skin and subcutaneous tissue disorders: infrequently - rash; rarely - Stevens-Johnson syndrome*, toxic epidermal necrolysis*.
Musculoskeletal and connective tissue disorders: uncommon - muscle pain, pain in extremities.
From the urinary system: infrequently - hematuria.
From the reproductive system and mammary glands: rarely - bleeding from the penis, priapism *, hematospermia, prolonged erection.
General disorders and administration site conditions: uncommon - chest pain, fatigue, feeling hot; rare - irritation.
Examination: infrequently - increased heart rate.
* Reported only in post-marketing studies.
** Color perception disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.
*** Lacrimation disorders: dry eyes, lacrimation disorders and increased lacrimation.
The following events were reported in 2% of patients in controlled clinical trials; causality has not been established. The reports included events that had a probable relationship to the drug. The events that were not listed were mild and the reports were too imprecise to be of significance.
General: Facial edema, photosensitivity, shock, asthenia, pain, sudden fall, abdominal pain, sudden injury.
Cardiovascular system: angina pectoris, AV block, migraine, postural hypotension, myocardial ischemia, cerebral thrombosis, sudden cardiac arrest, changes in ECG results, cardiomyopathy.
On the part of the digestive system: glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding, gingivitis.
From the blood and lymphatic system: anemia, leukopenia.
Metabolism and nutrition disorders: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.
Musculoskeletal system: arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia gravis, synovitis.
Nervous system: ataxia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, abnormal dreams, decreased reflexes.
From the respiratory system: asthma, shortness of breath, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.
Skin: urticaria, herpes, itching, increased sweating, skin ulcers, contact dermatitis, exfoliative dermatitis.
Specific sensations: sudden decrease or loss of hearing, earache, hemorrhage in the eye, cataract, dry eyes.
From the urogenital system: cystitis, nocturia, increased frequency of urination, breast enlargement, urinary incontinence, ejaculation disorders, swelling of the genitals, anorgasmia.
Cardiovascular and cerebrovascular events. Serious cardiovascular, cerebrovascular and vascular events, including cerebrovascular haemorrhage, subarachnoid and intracerebral haemorrhage and pulmonary haemorrhage, have been reported in temporal association with sildenafil use. Most, but not all, patients had cardiovascular risk factors. Many of these events have been reported to occur during or shortly after sexual activity, and a few have occurred immediately following sildenafil use without sexual activity. Others have developed over the hours or days following sildenafil use and sexual activity. It is not possible to determine whether these events are directly related to the drug, sexual activity, pre-existing risk factors or a combination of these factors or other factors.
Blood and lymphatic system: Vaso-occlusive crisis. In a small, prematurely terminated study of sildenafil in patients with pulmonary hypertension secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were reported more frequently than with placebo. The clinical significance of this information for patients taking sildenafil for the treatment of erectile dysfunction is unknown.
Nervous system: anxiety, transient global amnesia.
Specific sensations. Hearing. Cases of sudden hearing loss or hearing impairment have been reported in the post-marketing setting in association with sildenafil use. In some cases, underlying medical conditions and other factors that may have contributed to the development of hearing adverse reactions have been reported. In many cases, follow-up information is not available. It is not possible to determine whether these events are directly related to sildenafil use, to pre-existing risk factors for hearing loss, to a combination of these factors, or to other factors.
Vision: Temporary loss of vision, eye redness, burning in the eyes, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, vitreous detachment.
Rare cases of non-arteritic anterior ischemic optic neuropathy, which causes visual impairment, including permanent vision loss, have been reported in post-marketing experience and have been associated with the use of phosphodiesterase-5 inhibitors, including sildenafil. Many, but not all, of the patients had anatomical or vascular risk factors for the development of non-arteritic anterior ischemic optic neuropathy, including (but not necessarily limited to) the following: low optic disc diameter ratio (congestive optic disc), age over 50 years, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are directly related to the use of phosphodiesterase-5 inhibitors or to the existing anatomical or vascular risk factors, a combination of all these factors, or to other factors.
Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the balance between benefits and risks associated with the use of this medicine. Physicians should report any suspected adverse reactions in accordance with legal requirements.
Special instructions
To diagnose erectile dysfunction, determine possible causes of the disease, and prescribe adequate treatment, it is necessary to carefully study the patient's medical history and conduct a thorough medical examination.
Cardiovascular risk factors. Before starting any treatment for erectile dysfunction, the cardiovascular status of the patient should be considered, as there is a certain cardiovascular risk associated with sexual activity. Sildenafil has vasodilator properties, which leads to a slight and transient decrease in blood pressure. Before prescribing sildenafil, the physician should carefully weigh the risk of undesirable manifestations of vasodilator action in patients with certain concomitant diseases against the background of sexual activity. Increased sensitivity to vasodilators is observed in patients with left ventricular obstruction (e.g. aortic stenosis, obstructive hypertrophic cardiomyopathy) or patients with a rare syndrome of multiple system atrophy, one of the manifestations of which is severe dysregulation of blood pressure by the autonomic nervous system.
During the period after the introduction of the drug into widespread medical practice, serious cardiovascular complications were reported, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension and hypotension. Most, but not all, of these patients had a history of cardiovascular risk factors. The vast majority of such cases were registered during or immediately after sexual activity, a small part - after a short period of non-sexual activity after taking sildenafil. It is not possible to establish a direct relationship of such cases with the use of sildenafil, sexual activity, concomitant cardiovascular diseases, a combination of these factors, or other factors.
Priapism. Drugs intended for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) or in patients with conditions that contribute to the development of priapism (sickle cell anemia, multiple myeloma or leukemia).
Concomitant use with other phosphodiesterase-5 inhibitors or other drugs for the treatment of erectile dysfunction. The safety and efficacy of concomitant use of sildenafil with other phosphodiesterase-5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil, or with other treatments for erectile dysfunction have not been studied, therefore such combinations are not recommended.
Effects on vision. Visual defects and cases of non-arterial anterior ischemic optic neuropathy have been reported in association with sildenafil and other phosphodiesterase-5 inhibitors (see Adverse Reactions). Patients are advised to discontinue Vizarsin Q-Tab in the event of sudden visual impairment and seek medical advice immediately (see Adverse Reactions).
Ritonavir: Concomitant use of sildenafil and ritonavir is not recommended (see Interactions with other medicinal products).
Alpha-blockers. Sildenafil should be used with caution in patients receiving concomitant alpha-blockers as it may occasionally lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. To minimise the risk of postural hypotension, blood pressure should be stabilised with alpha-blockers before sildenafil administration. A starting dose of 25 mg should also be considered (see section 4.2). Patients should also be advised what to do if they experience symptoms of orthostatic hypotension.
Effects on bleeding: In vitro studies with human platelets have shown that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside. There is no safety information regarding the use of sildenafil in patients with a bleeding tendency or with acute gastric ulcer, therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.
After administration of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed (see Pharmacodynamics).
Hearing loss. Patients should discontinue use of phosphodiesterase-5 inhibitors, including Vizarsin Q-Tab, and seek immediate medical attention if they experience sudden decrease or loss of hearing. These events, which may also be accompanied by tinnitus and dizziness, have been reported in association with the use of phosphodiesterase-5 inhibitors, including Vizarsin Q-Tab. It is not possible to determine whether these events are directly related to the use of phosphodiesterase-5 inhibitors or to other factors.
Concomitant use with antihypertensive drugs. Vizarsin Q-Tab has a systemic vasodilator effect and may further reduce blood pressure in patients taking antihypertensive drugs. In a separate drug interaction study, the simultaneous use of amlodipine (5 mg or 10 mg) and Vizarsin Q-Tab (100 mg) orally resulted in an average additional decrease in blood pressure of 8 mm Hg. Art. and diastolic blood pressure - 7 mm Hg. Art.
Sexually transmitted diseases. Use of Vizarsin Q-Tab does not protect against sexually transmitted diseases. Consideration should be given to instructing patients on the necessary precautions to protect against sexually transmitted diseases, including HIV.
Vizarsin Q-Tab contains aspartame (E951), which is a source of phenylalanine. The drug may be harmful for men with phenylketonuria.
Vizarsin Q-Tab contains sorbitol (E420). Men with rare hereditary problems of fructose intolerance should not use this medicine.
Use during pregnancy and breastfeeding. Vizarsin Q-Tab is not intended for use in women.
Ability to influence the reaction rate when driving vehicles or working with other mechanisms. Studies of the effect of the drug on the ability to drive a car and work with mechanisms have not been conducted. Since during clinical studies of the use of sildenafil, cases of dizziness and visual disturbances were reported, before driving vehicles or working with other mechanisms, patients should find out what their individual reaction to the use of the drug Vizarsin Q-Tab is.
Interactions
Effects of other drugs on sildenafil
In vitro studies: Sildenafil metabolism is mediated primarily by cytochrome P450 (CYP) isoforms 3A4 (major pathway) and 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil elimination.
In vivo studies: Studies have shown a decrease in sildenafil clearance with concomitant administration of CYP 3A4 inhibitors (ketoconazole, erythromycin, cimetidine).
Although no increase in the incidence of adverse events has been observed with the concomitant use of sildenafil and CYP 3A4 inhibitors, a starting dose of 25 mg of sildenafil should be considered.
Co-administration of an HIV protease inhibitor, which is a highly specific P450 inhibitor, at steady-state (500 mg twice daily) with sildenafil (100 mg once) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil AUC in plasma. After 24 h, the plasma concentration of sildenafil was approximately 200 ng/ml, while with sildenafil its concentration reached 5 ng/ml. This is due to ritonavir-induced effects on P450 isoenzymes. Sildenafil did not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic results, co-administration of sildenafil with ritonavir is not recommended, however, the maximum dose of sildenafil should not exceed 25 mg within 48 h under any circumstances.
Co-administration of the HIV protease inhibitor saquinavir, a CYP 3A4 inhibitor, at steady state (1200 mg 3 times daily) with sildenafil (100 mg once daily) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil did not appear to affect the pharmacokinetics of saquinavir (see Dosage & Administration). More potent CYP 3A4 inhibitors such as ketoconazole and itraconazole are expected to have a more pronounced effect.
When a single dose of 100 mg sildenafil was administered with erythromycin, a specific CYP 3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In healthy male volunteers, there was no effect of azithromycin (500 mg/day for 3 days) on the AUC, C max, T max, elimination rate constant, and subsequent T ½ of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and nonspecific CYP 3A4 inhibitor) at a dose of 800 mg when co-administered with sildenafil at a dose of 50 mg in healthy volunteers resulted in a 56% increase in plasma concentrations of sildenafil.
Grapefruit juice is a weak inhibitor of CYP 3A4 in the intestinal wall and may cause a modest increase in plasma levels of sildenafil.
Single administration of antacids (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Although specific drug interaction studies have not been conducted, population pharmacokinetic analysis showed that sildenafil pharmacokinetics were not altered by concomitant use with drugs belonging to the CYP 2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP 2D6 inhibitor group (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, calcium antagonists, β-blockers or inducers of CYP 450 metabolism (rifampicin, barbiturates).
In a study in healthy male volunteers, co-administration of the endothelin antagonist bosentan (a moderate inducer of CYP 3A4, CYP 2C9 and possibly CYP 2C19) at steady state (125 mg twice daily) and sildenafil at steady state (80 mg three times daily) resulted in a 62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Therefore, co-administration of potent CYP 3A4 inducers such as rifampicin may result in a more pronounced decrease in sildenafil plasma concentrations.
Nicorandil is a hybrid calcium channel activator and nitrate. Due to the nitrate component, it has the potential for serious interactions with sildenafil.
Effect of sildenafil on other drugs
In vitro studies: Sildenafil is a weak inhibitor of cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 150 μM). Given that the Cmax of sildenafil in plasma is approximately 1 μM, it is unlikely that the drug can affect the clearance of substrates of these isoenzymes.
There are no data on the interaction of sildenafil and nonspecific phosphodiesterase inhibitors, such as theophylline or dipyridamole.
Concomitant use of sildenafil and α-blockers may lead to symptomatic hypotension in some susceptible patients. This reaction has often occurred within 4 hours of sildenafil administration (see Dosage and Administration and Precautions). In 3 specific drug interaction studies, the α-blockers doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) were administered concomitantly to patients with benign prostatic hyperplasia who were stabilized on doxazosin. In these populations, mean additional reductions in supine blood pressure of 7/7; 9/5 and 8/4 mm Hg and mean reductions in standing blood pressure of 6/6; 11/4 and 4/5 mm Hg, respectively, were observed. Symptomatic orthostatic hypotension has occasionally been reported with concomitant use of sildenafil and doxazosin in patients stabilized on doxazosin. These reports included dizziness and fainting, but without syncope.
No significant interactions were observed with the simultaneous use of sildenafil (50 mg), tolbutamide (250 mg) and warfarin (40 mg), which are metabolized by CYP 2C9.
Sildenafil (50 mg) does not increase the duration of bleeding caused by acetylsalicylic acid (150 mg).
Sildenafil (50 mg) potentiated the hypotensive effect of alcohol in healthy volunteers at mean maximum blood ethanol levels of 80 mg/dl.
In patients receiving sildenafil, no differences in the side effect profile were found compared to placebo when using such classes of antihypertensive drugs as diuretics, β-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neuron blockers, calcium channel blockers and α-blockers. In a special interaction study, when sildenafil (100 mg) was used concomitantly with amlodipine in patients with arterial hypertension, an additional decrease in supine blood pressure of 8 mm Hg was observed. The decrease in diastolic blood pressure was 7 mm Hg. This additional decrease in blood pressure was comparable in magnitude to that observed when sildenafil was used alone in healthy volunteers (see Pharmacological properties).
Sildenafil at a dose of 100 mg did not affect the pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, which are substrates of CYP 3A4.
In healthy male volunteers, the use of sildenafil at steady state (80 mg 3 times a day) resulted in an increase in AUC and C max of bosentan (125 mg 2 times a day) by 49.8 and 42%, respectively.
Overdose
In clinical trials involving volunteers, when using a single dose of sildenafil up to 800 mg, adverse reactions were similar to those noted when using sildenafil in lower doses, but occurred more often and were more severe. The use of sildenafil in a dose of 200 mg led to increased efficacy, but caused an increase in the number of cases of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).
In case of overdose, if necessary, resort to the usual supportive measures. Acceleration of sildenafil clearance during hemodialysis is unlikely due to the high degree of binding of the drug to plasma proteins and the lack of elimination of sildenafil in the urine.
Storage conditions
At a temperature not exceeding 30 °C in the original packaging to protect from moisture.
