Instructions for Novagra Euro tablets 50 mg No. 1
Composition
active ingredient: sildenafil;
1 tablet contains sildenafil citrate equivalent to 50 mg sildenafil
or 1 tablet contains sildenafil citrate equivalent to 100 mg of sildenafil;
Excipients: croscarmellose sodium; calcium hydrogen phosphate (dihydrate); microcrystalline cellulose; magnesium stearate; purified talc; Opadry red II 85G55231 (contains Ponceau 4R dye (E 124).
Dosage form
Film-coated tablets.
Main physicochemical properties: purple-red, triangular-shaped, biconvex, film-coated tablets with embossing "50" or "100" on one side.
Pharmacotherapeutic group
Drugs used for erectile dysfunction. Sildenafil. ATX code G04B E03.
Pharmacological properties
Pharmacodynamics.
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 cause a direct relaxant effect on isolated human corpus cavernosum, but 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.
In vitro studies have shown the selectivity of sildenafil for PDE 5, which is actively involved in the erection process. The effect of sildenafil on PDE 5 is more potent than on other known phosphodiesterases. This effect is 10 times more potent than the effect on PDE 6, which is involved in photoconversion processes in the retina. When using the maximum recommended doses, the selectivity of sildenafil for PDE 5 is 80 times higher than its selectivity for PDE 1, 700 times higher than for PDE 2, PDE 3, PDE 4, PDE 7, PDE 8, PDE 9, PDE 10 and PDE 11. In particular, the selectivity of sildenafil for PDE 5 is 4000 times higher than its selectivity for PDE 3 - a cGMP-specific isoform of phosphodiesterase, which is involved in the regulation of cardiac contractility.
Specific clinical studies have been conducted to assess the time it takes for sildenafil to produce an erection in response to sexual stimulation. In clinical studies in patients taking sildenafil in the fasted state, the median time to onset of erection in patients who achieved an erection of 60% rigidity (sufficient for sexual intercourse) using phalloplethysmography was 25 minutes (range 12–37 minutes). Another study showed that sildenafil was still able to produce an erection 4–5 hours after administration.
Sildenafil causes a mild and transient decrease in blood pressure, which in most cases is not clinically evident. The mean maximum decrease in supine systolic blood pressure after oral administration of sildenafil at a dose of 100 mg was 8.4 mm Hg. The corresponding change in supine diastolic blood pressure was 5.5 mm Hg. This decrease in blood pressure is consistent with the vasodilatory effect of sildenafil, possibly due to an increase in cGMP levels in vascular smooth muscle. Single oral doses of sildenafil up to 100 mg in healthy volunteers did not cause any clinically significant changes in the electrocardiogram.
In a study of the hemodynamic effects of a single oral dose of sildenafil 100 mg in patients with severe coronary artery disease (CAD) (with stenosis of at least one coronary artery >70%), mean resting systolic and diastolic blood pressure decreased by 7% and 6%, respectively, from baseline. Mean pulmonary systolic pressure decreased by 9%. Sildenafil did not alter cardiac output or reduce blood flow in stenosed coronary arteries.
Mild and transient color vision impairment (blue/green) was observed in some patients 1 hour after administration of sildenafil 100 mg. These effects completely disappeared 2 hours after administration of the drug. The possible mechanism of this change in color vision is associated with inhibition of PDE 6, which is involved in the photoconversion cascade of reactions in the retina. Sildenafil does not affect visual acuity or contrast sensitivity. In studies involving patients with documented macular degeneration, the use of sildenafil (single dose of 100 mg) did not cause significant changes in the results of visual tests (visual acuity, Amsler grid, simulated traffic light color recognition, Humphrey perimeter and photostress).
A single oral dose of sildenafil 100 mg in healthy volunteers had no effect on sperm motility or morphology.
In clinical studies, sildenafil was used in patients aged 19 to 87 years. The following patient groups were represented: elderly patients, patients with arterial hypertension, patients with diabetes mellitus, coronary heart disease, hyperlipidemia, spinal cord injury, depression, transurethral resection of the prostate, radical prostatectomy. The following patient groups were not adequately represented or included in clinical studies: patients after pelvic surgery, patients after radiation therapy, patients with severe renal or hepatic insufficiency, and patients with certain cardiovascular diseases.
In fixed-dose studies, the number of patients reporting improvement in erectile function was higher than in the placebo group. In studies, the number of sildenafil withdrawals was low and similar to that in the placebo group.
In all these studies, patients reported improvements with sildenafil in psychogenic erectile dysfunction, mixed erectile dysfunction, organic erectile dysfunction, in the elderly, in diabetes mellitus, ischemic heart disease, hypertension, transurethral resection of the prostate, radical prostatectomy, spinal cord injury, and depression. The safety and efficacy of sildenafil were confirmed by data from these long-term studies.
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), sildenafil AUC and Cmax increase in proportion to 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 mean steady-state volume of distribution (Vd) is 105 liters, indicating distribution of the drug into body tissues. After a single oral dose of 100 mg sildenafil, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL (coefficient of variation is 40%). Since the binding of sildenafil and its major N-desmethyl metabolite to plasma proteins reaches 96%, the mean maximum plasma concentration of free sildenafil reaches 18 ng/mL (38 nmol). The extent of binding to plasma proteins is independent of 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 applied dose was detected in the ejaculate after 90 minutes.
Metabolism. 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 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.
Elimination: 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 primarily 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).
Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30 to 80 ml/min), the pharmacokinetics of sildenafil were unchanged after a single oral dose of 50 mg. The mean AUC and Cmax of the N-dimethylated metabolite were increased by 126% and 73%, respectively, compared with those in age-matched volunteers without renal impairment. However, due to high intersubject 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 values of the N-demethylated metabolite were significantly increased by 200% and 79%, respectively.
Hepatic impairment: In volunteers with mild to moderate liver cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in an 84% increase in AUC and a 47% increase in Cmax compared to age-matched volunteers without hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.
Indication
Treatment of erectile dysfunction, defined as the inability to achieve or maintain a penile erection necessary for successful sexual intercourse.
Sexual arousal is required for the drug to be effective.
Contraindication
- Hypersensitivity to the active substance or to any of the excipients 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).
- Erectile dysfunction medications, including sildenafil, are contraindicated in men for whom sexual activity is not recommended (e.g., patients with severe cardiovascular disorders such as unstable angina and severe heart failure).
- Loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy, regardless of whether this pathology is related to previous use of PDE5 inhibitors.
- Severe hepatic impairment; 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) - 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 metabolism is primarily mediated by cytochrome P450 (CYP) isoform 3A4 (major pathway) and isoform 2C9 (minor pathway). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance, and inducers of these isoenzymes may increase sildenafil clearance.
In vivo studies: Population pharmacokinetic analysis of clinical trial data has shown a decrease in sildenafil clearance when co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). Although no increase in adverse events was observed when sildenafil was co-administered with CYP3A4 inhibitors, the recommended starting dose of sildenafil is 25 mg.
Co-administration of the HIV protease inhibitor ritonavir, a very potent P450 inhibitor, at steady state (500 mg once 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 plasma AUC. After 24 hours, sildenafil plasma 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.
When sildenafil (100 mg once daily) was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), a 182% increase in systemic exposure (AUC) to sildenafil 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 a 56% increase in plasma concentrations of sildenafil.
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) does not affect the bioavailability of sildenafil.
Although specific drug interaction studies have not been conducted, 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 (ACE) inhibitors, calcium antagonists, beta-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 inducer of CYP3A4, CYP2C9 and possibly CYP2C19) 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.
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 the drug on the clearance of substrates of these isoenzymes is unlikely.
There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline and dipyridamole.
Since sildenafil is known to have an effect on nitric oxide/cyclic guanosine monophosphate (cGMP) metabolism, it has been found that this drug potentiates the hypotensive effect of nitrates, therefore its simultaneous use with nitric oxide donors or with nitrates in any form is contraindicated (see section "Contraindications").
Riociguat. Preclinical studies have shown an additive systemic blood pressure lowering effect when PDE5 inhibitors are used concomitantly with riociguat. Clinical studies have shown that riociguat potentiates the hypotensive effect of PDE5 inhibitors. No beneficial clinical effect was observed in patients who participated in the study when PDE5 inhibitors were used concomitantly with riociguat. Concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section 4.3).
In some susceptible patients, concomitant use of sildenafil and alpha-blockers may result in symptomatic hypotension, most often occurring within 4 hours of sildenafil administration (see sections 4.2 and 4.4). In a specific drug interaction study, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) were co-administered to patients with benign prostatic hyperplasia (BPH) who were stabilised on doxazosin. In these study populations, mean additional reductions in supine blood pressure of 7/7 mmHg, 9/5 mmHg and 8/4 mmHg were observed, and mean reductions in standing blood pressure of 6/6 mmHg. Art., 11/4 mm Hg. 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 concerned cases of dizziness and presyncope, 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).
In patients taking sildenafil, no differences in the side effect profile compared to placebo were observed when such classes of antihypertensive drugs as diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists, antihypertensive drugs (vasodilators and centrally acting), adrenergic neurone blockers, calcium channel blockers and alpha-adrenergic blockers were used concomitantly. In a specific interaction study, when sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, an additional reduction in supine systolic blood pressure of 8 mm Hg was observed. The corresponding reduction in diastolic blood pressure was 7 mm Hg. This additional reduction in blood pressure was comparable to that observed with sildenafil alone in healthy volunteers (see section 5.1).
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 3 times daily) resulted in an increase in the AUC and Cmax of bosentan (125 mg 2 times daily) by 49.8% and 42%, respectively.
The addition of a single dose of sildenafil to sacubitril/valsartan at steady state in hypertensive patients 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.
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.
Cardiovascular risk factors. 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, manifested by a mild and transient decrease in blood pressure (see section "Pharmacodynamics"). Before prescribing sildenafil, the physician should carefully consider whether this effect may have an adverse effect on 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), and 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.
The drug potentiates the hypotensive effect of nitrates (see the "Contraindications" section).
Serious cardiovascular adverse reactions, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, and hypotension, have been reported in association with sildenafil use. Most 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) and in patients with conditions predisposing to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
The safety and efficacy of concomitant use of sildenafil with other treatments for erectile dysfunction have not been studied, therefore the use of such combinations is not recommended.
Cases of prolonged erection and priapism have been reported since sildenafil was marketed. If an erection lasts longer than 4 hours, patients should seek immediate medical attention. If not treated promptly, priapism can lead to penile tissue damage and permanent loss of potency.
Effects on vision: There have been spontaneous reports of visual defects associated with the use of sildenafil and other PDE5 inhibitors (see section 4.8). From spontaneous reports and observational studies, cases of non-arteritic anterior ischemic optic neuropathy, a rare condition, have been reported 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 medical advice should be sought immediately (see section 4.8).
Concomitant use with ritonavir: Concomitant use of sildenafil and ritonavir is not recommended (see section 4.5).
Concomitant use with α-adrenergic blockers. Sildenafil should be used with caution in patients taking alpha-adrenergic blockers, as the combination may lead to symptomatic hypotension in some susceptible patients. Symptomatic hypotension usually occurs within 4 hours of sildenafil administration. Due to the risk of orthostatic hypotension, sildenafil therapy should only be initiated in haemodynamically stable patients taking alpha-adrenergic blockers. The recommended starting dose for such patients is 25 mg sildenafil (see section 4.2). Patients should also be advised what to do if they experience symptoms of orthostatic hypotension.
Effects on bleeding. Studies on 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.
After administration of a dose of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed (see section "Pharmacodynamics").
Hearing loss. Physicians should advise patients to discontinue use of inhibitors
PDE5 inhibitors, including NOVAGRA EURO, and seek immediate medical attention in cases of 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 PDE5 inhibitors, including NOVAGRA EURO. 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. The drug has a systemic vasodilator effect and may further reduce blood pressure in patients taking antihypertensive drugs. In a separate drug interaction study, concomitant administration of amlodipine (5 mg or 10 mg) and sildenafil (100 mg) orally resulted in an average additional reduction in systolic blood pressure of 8 mm Hg and diastolic blood pressure of 7 mm Hg.
Sexually transmitted diseases. Sildenafil does not protect against sexually transmitted diseases. Patients should be advised to take appropriate precautions to protect against sexually transmitted diseases, including human immunodeficiency virus.
The film coating of NOVAGRA EURO tablets contains the dye Ponceau 4R (E 124). May cause allergic reactions.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially sodium-free. Patients on a controlled sodium diet may be informed of this.
Use during pregnancy or breastfeeding
The drug is not intended for use by women.
Ability to influence reaction speed when driving vehicles or other mechanisms
Novagra Euro 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 Novagra Euro before driving or operating machinery.
Method of administration and doses
The drug should be administered orally.
Sexual arousal is required for the drug to be effective.
Adults.
The recommended dose of the drug is 50 mg and is used, if necessary, approximately 1 hour before sexual intercourse. 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 maximum recommended frequency of use of the drug is 1 time per day. When the drug is used with food, the effect of the drug may occur later than when it is used on an empty stomach.
Elderly patients.
There is no need for dose adjustment for elderly patients (≥ 65 years).
Patients with renal failure.
Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance below 30 ml/min), the recommended dose is 25 mg.* Depending on the efficacy and tolerability of the drug, the dose may be increased to 50 mg and 100 mg.
Patients with liver failure.
Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis), the recommended dose is 25 mg.* Depending on efficacy and tolerability, the dose may be increased to 50 mg and 100 mg.
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 risk of orthostatic hypotension, patients taking alpha-blockers should be stabilised before starting sildenafil. A starting dose of 25 mg sildenafil* should also be considered (see sections 4.4 and 4.5).
* - use medicines with the active ingredient sildenafil in the appropriate dosage.
Children.
The drug is not indicated for use in persons under 18 years of age.
Overdose
When using a single dose of sildenafil up to 800 mg, adverse reactions were similar to those observed with the use of sildenafil at lower doses, but occurred more frequently and were more severe. The use of sildenafil at a dose of 200 mg did not lead to increased efficacy, but caused an increase in the number of cases of adverse reactions (headache, hot flashes, dizziness, dyspepsia, nasal congestion, visual disturbances, described in the section "Adverse reactions").
In the event of overdose, standard supportive measures should be taken. 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
The most commonly reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flashes, 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 (≥ 1/1000 - < 1/100) and rare (≥ 1/10000 - < 1/1000). Adverse reactions are listed in order of decreasing frequency.
- Infectious and invasive diseases.
Uncommon: Rhinitis.
Uncommon: Hypersensitivity reactions.
- Nervous system disorders.
Very common: headache,
Common: dizziness,
Uncommon: drowsiness, hypoaesthesia,
Rare: stroke, syncope, transient ischemic attack, seizures*, recurrent seizures*, syncope.
- Disorders of the organs of vision.
Common: visual disturbances, colour vision disturbances**, blurred vision,
Uncommon: lacrimation disorder***, eye pain, photophobia, photopsia, ocular hyperaemia, visual acuity reduced, conjunctivitis,
Rare: non-arteritic anterior ischemic optic neuropathy*, retinal vascular occlusion*, retinal haemorrhage, arteriosclerotic retinopathy, retinal disorders, glaucoma, visual field defects, diplopia, visual acuity reduced, myopia, asthenopia, floating vitreous opacities, iris disorders, mydriasis, halos, eye oedema, eye swelling, eye disorders, conjunctival hyperaemia, eye irritation, abnormal eye sensation, eyelid oedema, sclera discolouration.
- Disorders of the hearing and vestibular system.
Uncommon: vertigo, tinnitus,
Rare: deafness*.
