Instructions for Integra IS film-coated tablets 100 mg No. 1
Composition
active ingredient: sildenafil citrate;
1 tablet contains sildenafil citrate (as sildenafil) 25 mg (0.025 g), 50 mg (0.05 g) or 100 mg (0.1 g);
excipients: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, potato starch, croscarmellose sodium, sodium bicarbonate, gelatin, colloidal anhydrous silica, talc, magnesium stearate, hypromellose (hydroxypropylmethylcellulose), polyethylene glycol (macrogol), titanium dioxide (E 171), acesulfame potassium, candurin (for 25 mg tablets – potassium aluminosilicate (E 555), red iron oxide (E 172); for 50 mg tablets – potassium aluminosilicate (E 555), titanium dioxide (E 171); for 100 mg tablets – potassium aluminosilicate (E 555), titanium dioxide (E 171), red iron oxide (E 172)).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated, bronze (dosage 0.025 g) or silver (dosage 0.05 g) or golden (dosage 0.1 g) color.
Pharmacotherapeutic group
Drugs used for erectile dysfunction. Sildenafil. ATX code G04B E03.
Pharmacological properties
Pharmacodynamics.
Mechanism of action.
Sildenafil is an oral medication used to treat erectile dysfunction. During sexual arousal, the drug restores impaired erectile function by increasing blood flow to the penis.
The physiological mechanism that causes an erection involves the release of nitric oxide (NO) in the corpora cavernosa during sexual arousal. The released nitric oxide activates the enzyme guanylate cyclase, which stimulates an increase in cyclic guanosine monophosphate (cGMP), which in turn causes relaxation of the smooth muscle of the corpora cavernosa, facilitating blood flow.
Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for the breakdown of cGMP. The effects of sildenafil on erection are peripheral in nature. Sildenafil does not have a direct relaxant effect on isolated human corpus cavernosum, but it potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, sildenafil's inhibition of PDE5 leads to an increase in cGMP levels in the corpus cavernosum. Thus, sexual arousal is required for sildenafil to produce the desired pharmacological effect.
Effect on pharmacodynamics.
In vitro studies have shown that sildenafil is selective for PDE5, which is actively involved in the erection process. The effect of sildenafil on PDE5 is more potent than on other known phosphodiesterases. This effect is 10 times more potent than the effect on PDE6, which is involved in photoconversion processes in the retina. When using the maximum recommended doses, the selectivity of sildenafil for PDE5 is 80 times higher than its selectivity for PDE1, 700 times higher than for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10 and PDE11. In particular, the selectivity of sildenafil for PDE5 is 4000 times higher than its selectivity for PDE3 - a cAMP-specific isoform of phosphodiesterase involved in the regulation of cardiac contractility.
Pharmacokinetics.
Absorption.
Sildenafil is rapidly absorbed. Peak plasma concentrations are reached within 30-120 minutes (median 60 minutes) after oral administration in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). Over the recommended dose range (25-100 mg), the AUC and Cmax of sildenafil increase proportionally with dose after oral administration.
When sildenafil is taken with food, the extent of absorption is reduced with a mean prolongation of Tmax to 60 minutes and a mean decrease in Cmax by 29%.
Distribution.
The average equilibrium volume of distribution (Vd) is 105 liters, which indicates the distribution of the drug in the tissues of the body. After a single oral dose of sildenafil at a dose of 100 mg, the average maximum total plasma concentration of sildenafil is approximately 440 ng/ml (the coefficient of variation is 40%). Since the binding of sildenafil and its main N-desmethyl metabolite to plasma proteins reaches 96%, the average maximum plasma concentration of free sildenafil reaches 18 ng/ml (38 nmol). The degree of binding to plasma proteins does not depend on the total concentrations of sildenafil.
In healthy volunteers who used sildenafil once at a dose of 100 mg, less than 0.0002% (average 188 ng) of the administered dose was detected in the ejaculate after 90 minutes.
Biotransformation.
Sildenafil is metabolized primarily by the hepatic microsomal isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway). The major circulating metabolite is formed by N-demethylation of sildenafil. The selectivity of the metabolite for PDE5 is comparable to that of sildenafil, and the in vitro activity of the metabolite for PDE5 is approximately 50% of that of the parent compound. Plasma concentrations of this metabolite are approximately 40% of those of sildenafil in plasma. The N-demethylated metabolite undergoes further metabolism and has a half-life of approximately 4 hours.
The total clearance of sildenafil is 41 l/h, resulting in a half-life of 3-5 hours. After both oral and intravenous administration, sildenafil is excreted as metabolites mainly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Pharmacokinetics in special patient groups.
Elderly patients.
In healthy elderly volunteers (aged 65 years and older), a decrease in sildenafil clearance was observed, which resulted in an increase in plasma concentrations of sildenafil and its active N-demethylated metabolite by approximately 90% compared with the corresponding concentrations in healthy younger volunteers (18-45 years). Due to age-related differences in plasma protein binding, the corresponding increase in plasma concentrations of free sildenafil was approximately 40%.
Kidney failure.
In volunteers with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), sildenafil pharmacokinetics were unchanged after a single oral dose of 50 mg. The mean AUC and Cmax of the N-desmethyl metabolite were increased by a maximum of 126% and a maximum of 73%, respectively, compared with those in age-matched volunteers without renal impairment. However, due to high interindividual variability, these differences were not statistically significant. In volunteers with severe renal impairment (creatinine clearance below 30 ml/min), sildenafil clearance was reduced, resulting in mean increases in AUC and Cmax of 100% and 88%, respectively, compared with age-matched volunteers without renal impairment. In addition, the AUC and Cmax of the N-desmethyl metabolite were significantly increased by 200% and 79%, respectively.
Liver failure.
In volunteers with mild to moderate liver cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increased AUC (84%) and Cmax (47%) compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.
Indication
INTAGRA® IS is recommended for use in men with erectile dysfunction, which is defined as the inability to achieve or maintain a penile erection necessary for successful sexual intercourse.
For INTAGRA® IS to be effective, sexual arousal is required.
Contraindication
Hypersensitivity to the active substance or to any other component of the drug.
Concomitant use with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated, as sildenafil is known to affect the nitric oxide/cyclic guanosine monophosphate (cGMP) metabolic pathways and potentiate the hypotensive effect of nitrates.
The concomitant use of PDE5 inhibitors (including sildenafil) with guanylate cyclase stimulators such as riociguat is contraindicated as it may lead to symptomatic hypotension (see section 4.5).
Conditions in which sexual activity is not recommended (e.g. severe cardiovascular disorders such as unstable angina or severe heart failure).
Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this pathology is associated with previous use of phosphodiesterase 5 (PDE5) inhibitors.
The presence of diseases such as severe liver dysfunction, arterial hypotension (blood pressure below 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 phosphodiesterases), as the safety of sildenafil has not been studied in these subgroups of patients.
Interaction with other medicinal products and other types of interactions
Effects of other drugs on sildenafil.
In vitro studies.
Sildenafil is metabolized primarily by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers of these isoenzymes may increase sildenafil clearance.
In vivo studies.
Co-administration of the HIV protease inhibitor ritonavir, a very potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (single dose of 100 mg) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil systemic exposure (AUC). After 24 hours, plasma sildenafil levels were still approximately 200 ng/ml compared to approximately 5 ng/ml with sildenafil alone, consistent with the significant effect of ritonavir on a wide range of P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Based on these pharmacokinetic data, co-administration of sildenafil and ritonavir is not recommended (see section 4.4); In any case, the maximum dose of sildenafil should under no circumstances exceed 25 mg within 48 hours.
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a steady-state dose (1200 mg three times daily) with sildenafil (100 mg once daily) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on the pharmacokinetics of saquinavir (see section 4.2). More potent CYP3A4 inhibitors such as ketoconazole and itraconazole are expected to have a greater effect.
When sildenafil (100 mg once) and erythromycin, a moderate CYP3A4 inhibitor, were administered at steady state (500 mg twice daily for 5 days), an increase in sildenafil AUC by 182% was observed. In healthy male volunteers, there was no effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, and subsequent half-life of sildenafil or its major circulating metabolite. Cimetidine (a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor) at a dose of 800 mg when co-administered with sildenafil at a dose of 50 mg in healthy volunteers resulted in an increase in plasma concentrations of sildenafil by 56%.
Grapefruit juice is a weak inhibitor of CYP3A4 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 performed, population pharmacokinetic analysis suggests that sildenafil pharmacokinetics were not altered by concomitant use of drugs belonging to the CYP2C9 inhibitor group (tolbutamide, warfarin, phenytoin), CYP2D6 inhibitor group (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, loop and potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, calcium antagonists, β-adrenoceptor antagonists, or inducers of CYP450 metabolism (such as rifampicin, barbiturates).
In a study in healthy male volunteers, co-administration of the endothelin antagonist bosentan (a moderate CYP3A4 inducer, CYP2C9 and possibly CYP2C19 inducer) at steady state (125 mg twice daily) with 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 CYP3A4 inducers such as rifampin may result in a more pronounced decrease in sildenafil plasma concentrations.
Nicorandil is a hybrid of a calcium channel activator and a nitrate. The nitrate component makes it possible for it to have a serious interaction with sildenafil.
Effects 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 μmol). Since peak plasma concentrations of sildenafil are approximately 1 μmol, the effect of INTAGRA® IC on the clearance of substrates of these isoenzymes is unlikely when used in the recommended dose range.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.
In vivo studies.
Since sildenafil is known to have an effect on nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, sildenafil has been shown to potentiate the hypotensive effect of nitrates, and its concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section 4.3).
Concomitant use of sildenafil and α-adrenergic blockers may lead to symptomatic hypotension in some susceptible patients. This reaction most often occurred within 4 hours of sildenafil administration (see sections 4.2 and 4.4). In 3 specific drug interaction studies, the α-adrenergic blocker 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 mmHg, 9/5 mmHg and 8/4 mmHg and mean reductions in standing blood pressure of 6/6 mmHg, 11/4 mmHg and 11/4 mmHg were observed. Art., 4/5 mm Hg. Art., respectively. With the simultaneous use of sildenafil and doxazosin in patients whose condition was stabilized on doxazosin, the development of symptomatic orthostatic hypotension has sometimes been reported. These reports included cases of dizziness and fainting, but without syncope.
No significant interactions were observed with the concomitant use of sildenafil (50 mg) and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9.
Sildenafil (50 mg) did not prolong bleeding time induced by acetylsalicylic acid (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers at mean maximum blood ethanol levels of 80 mg/dL.
In patients taking sildenafil, no differences in the side effect profile were observed compared to placebo when using such classes of antihypertensive drugs as diuretics, β-adrenergic blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neurone blockers, calcium channel blockers and α-adrenergic blockers.
In a specific interaction study, co-administration of sildenafil (100 mg) and amlodipine in hypertensive patients resulted in an additional reduction in supine systolic blood pressure of 8 mm Hg. The corresponding reduction in diastolic blood pressure was 7 mm Hg. These additional reductions in blood pressure were comparable in magnitude to those observed with sildenafil alone in healthy volunteers.
Sildenafil at a dose of 100 mg did not affect the pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, which are CYP3A4 substrates.
In healthy male volunteers, administration of sildenafil at steady state (80 mg three times daily) resulted in an increase in the AUC and Cmax of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.
Single-dose sildenafil administration to hypertensive patients receiving a combination of sacubitril/valsartan, the pharmacokinetic parameters of which have reached steady state, was associated with significantly greater reductions in blood pressure compared with sacubitril/valsartan alone. Therefore, caution should be exercised when initiating sildenafil in patients receiving sacubitril/valsartan therapy.
Application features
Before starting therapy, the patient's medical history should be collected and a physical examination should be performed to diagnose erectile dysfunction and determine its possible causes.
Risk factors for cardiovascular disease.
Since sexual activity carries a certain cardiac risk, the physician should assess the patient's cardiovascular status before initiating any treatment for erectile dysfunction. Sildenafil has a vasodilating effect, which is manifested by a mild and transient decrease in blood pressure. Before prescribing sildenafil, the physician should carefully consider whether this effect may adversely affect patients with certain underlying diseases, especially in combination with sexual activity. Patients with increased sensitivity to vasodilators include patients with obstruction of the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy) or patients with the rare syndrome of multiple system atrophy, one of the manifestations of which is severe dysregulation of blood pressure by the autonomic nervous system.
Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, fatal sudden cardiovascular event, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, and hypotension, have been reported in the postmarketing setting in association with sildenafil use. Most, but not all, patients had cardiovascular risk factors. Many of these adverse reactions occurred during or shortly after sexual intercourse, and only a few occurred shortly after sildenafil use in the absence of sexual activity. Therefore, it is not possible to determine whether these adverse reactions are directly related to the risk factors or whether they are caused by other factors.
Priapism.
Erectile dysfunction drugs, including sildenafil, should be prescribed with caution in patients with anatomical deformities of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or in patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Cases of prolonged erection and priapism have been reported since the introduction of sildenafil into the market. If an erection lasts more than 4 hours, patients should seek immediate medical attention. If not treated promptly, priapism can lead to damage to the tissues of the penis and permanent loss of potency.
Concomitant use with other PDE5 inhibitors or other drugs for the treatment of erectile dysfunction.
The safety and efficacy of concomitant use of sildenafil with other PDE5 inhibitors or other sildenafil-containing drugs for the treatment of pulmonary arterial hypertension, or with other drugs for the treatment of erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.
Effects on vision.
Spontaneous reports of visual defects have been reported in association with the use of sildenafil and other PDE5 inhibitors (see section 4.8). Cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported spontaneously and in an observational study in association with the use of sildenafil and other PDE5 inhibitors (see section 4.8). Patients should be advised that in the event of sudden visual impairment, sildenafil should be discontinued and a physician should be consulted immediately (see section 4.8).
Concomitant use with ritonavir.
The simultaneous use of sildenafil and ritonavir is not recommended (see section "Interaction with other medicinal products and other types of interactions").
Concomitant use with α-adrenergic blockers.
Sildenafil should be used with caution in patients taking α-adrenergic blockers, as the combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. To minimize the potential for postural hypotension in patients taking α-adrenergic blockers, patients should be stabilized with α-adrenergic blockers prior to initiating sildenafil. A starting dose of 25 mg should also be considered (see Dosage and Administration). Patients should also be instructed on how to respond to symptoms of orthostatic hypotension.
Effect on bleeding.
Studies in human platelets have shown that sildenafil potentiates the antiaggregatory effects of sodium nitroprusside in vitro. There is no information on the safety of sildenafil in patients with coagulation disorders or acute peptic ulcer. Therefore, sildenafil should only be used in these patients after careful consideration of the benefit-risk ratio.
The drug contains lactose, so it should not be used in men with rare hereditary disorders such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
After administration of a dose of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed (see section "Pharmacological properties. Pharmacodynamics").
Hearing loss.
Physicians should advise patients to discontinue use of PDE5 inhibitors, including sildenafil, and seek immediate medical attention if they experience sudden hearing loss or hearing loss. These events, which may also be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE5 inhibitors, including sildenafil. It is not possible to determine whether these events are directly related to the use of PDE5 inhibitors or to other factors.
Concomitant use with antihypertensive drugs.
Sildenafil has systemic vasodilator effects and may further reduce blood pressure in patients taking antihypertensive medications. In a separate drug interaction study, concomitant administration of amlodipine (5 mg or 10 mg) and oral sildenafil (100 mg) resulted in a mean additional reduction in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.
Use of INTAGRA® IC 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 human immunodeficiency virus.
Use during pregnancy or breastfeeding
INTAGRA® IS is not intended for use in women.
Ability to influence reaction speed when driving vehicles or other mechanisms
INTAGRA® IC may have a minor influence on the ability to drive or use machines. Since dizziness and visual disturbances have been reported in clinical studies with sildenafil, patients should be advised to assess their individual response to INTAGRA® IC before driving or operating machinery.
Method of administration and doses
The drug should be administered orally.
Adults.
The recommended dose of INTAGRA® IC is 50 mg and is administered, if necessary, approximately 1 hour before sexual activity. Depending on the effectiveness and tolerability of the drug, the dose can be increased to 100 mg or reduced to 25 mg. The maximum recommended dose is 100 mg. The frequency of use of the maximum recommended dose of the drug is 1 time per day. When INTAGRA® IC is administered with food, the effect of the drug may occur later than when administered on an empty stomach.
Elderly patients.
There is no need for dose adjustment in elderly patients (≥ 65 years).
Patients with renal failure.
For patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min), the recommended dose is the same as given above in the Adults section.
Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min), a dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg and 100 mg if necessary.
Patients with liver failure.
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), a dose of 25 mg should be considered. Depending on efficacy and tolerability, the dose may be increased gradually to 50 mg and 100 mg if necessary.
Patients taking other medications.
If patients are concomitantly taking CYP3A4 inhibitors (see section 4.5), a starting dose of 25 mg should be considered (except for ritonavir, the use of which with sildenafil is not recommended, see section 4.4).
To minimise the potential for postural hypotension in patients taking α-adrenergic blockers, their condition should be stabilised with α-adrenergic blockers before starting sildenafil. A starting dose of 25 mg should also be considered (see sections 4.4 and 4.5).
Children.
The drug is not indicated for use in persons under 18 years of age.
Overdose
In clinical trials in volunteers, adverse reactions following single doses of sildenafil up to 800 mg were similar to those seen with lower doses of sildenafil, but were more frequent and severe. Sildenafil 200 mg did not improve efficacy, but did increase the incidence of adverse reactions (headache, hot flushes, dizziness, dyspepsia, nasal congestion, visual disturbances).
Treatment: In case of overdose, usual supportive measures should be employed as necessary. 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.
Adverse reactions
In double-blind, placebo-controlled clinical trials, the most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, visual disturbances, cyanopsia, and blurred vision.
All clinically significant adverse reactions observed in clinical trials at an incidence greater than placebo are listed below by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1,000 - < 1/100) and rare (≥ 1/10,000 - < 1/1,000). In addition, the frequency of clinically significant adverse reactions reported during post-marketing experience with sildenafil is defined as unknown. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Infectious and invasive diseases: uncommon - rhinitis.
Nervous system disorders: very common - headache; common - dizziness; uncommon - drowsiness, hypoesthesia; rare - stroke, transient ischemic attack, convulsions*, recurrent convulsions*, syncope.
On the part of the organs of vision: often - color perception disorders (chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia), visual disorders, blurred vision; infrequently - lacrimation disorders (dry eyes, lacrimation disorders and increased lacrimation), eye pain, photophobia, photopsia, eye hyperemia, visual brightness, conjunctivitis; Rare: non-arteritic 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, halos in the field of vision, eye edema, eye swelling, eye disorders, conjunctival hyperemia, eye irritation, abnormal eye sensation, eyelid edema, sclera discoloration.
From the organs of hearing and vestibular apparatus: infrequently - dizziness, tinnitus; rarely - deafness.
Cardiac disorders: uncommon – tachycardia, palpitations; rare – fatal cardiovascular event*, myocardial infarction, ventricular arrhythmia*, atrial fibrillation, unstable angina.
Vascular disorders: often – hot flashes; infrequently – hypertension, hypotension.
Respiratory, thoracic and mediastinal disorders: common: nasal congestion; uncommon: epistaxis, sinus congestion; rare: feeling of tightness in the throat, swelling of the nasal mucosa, dry nose.
Gastrointestinal: often - nausea, dyspepsia; infrequently - gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth; rarely - oral hypoesthesia.
Skin and subcutaneous tissue disorders: uncommon - rash; rare - Stevens-Johnson syndrome*, toxic epidermal necrolysis*.
Musculoskeletal and connective tissue disorders: uncommon – myalgia, pain in the extremities.
From the urinary system: infrequently - hematuria.
Reproductive system and breast disorders: rarely - penile bleeding, priapism*, hematospermia, prolonged erection.
General disorders and administration site conditions: uncommon – chest pain, fatigue, feeling hot; rare – irritation.
Examination: uncommon – increased heart rate.
* Only reported during post-marketing surveillance of sildenafil.
The following events were observed in < 2% of patients in controlled clinical trials of sildenafil; causality has not been established. The reports included events that had a probable relationship to sildenafil use. Events that were not listed were mild and the reports were too imprecise to be of significance.
General: facial edema, photosensitivity reactions, 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, ECG abnormalities, cardiomyopathy.
Gastrointestinal: 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: 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, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.
Skin: urticaria, herpes, itching, 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.
Post-market application experience.
The following adverse reactions have been identified during post-marketing experience with sildenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to accurately estimate the
