Vivaira chewable tablets 100 mg No. 4

Vivaira chewable tablets 100 mg No. 4

Composition

Active ingredient: sildenafil citrate;

1 chewable tablet contains sildenafil 50 mg in the form of sildenafil citrate 70.24 mg or

1 chewable tablet contains sildenafil 100 mg in the form of sildenafil citrate 140.48 mg;

Excipients: potassium polacrilin; magnesium stearate; colloidal anhydrous silicon dioxide; aspartame (E 951); croscarmellose sodium; peppermint flavor; lactose monohydrate; povidone K-30.

Dosage form

Chewable tablets.

Main physicochemical properties: triangular biconvex white 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 NO activates the enzyme guanylate cyclase, which stimulates an increase in cyclic guanosine monophosphate (cGMP), causing relaxation of the smooth muscle of the corpora cavernosa and promoting 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 inhibition of PDE5 leads to an increase in cGMP levels in the corpus cavernosum. Thus, sexual arousal is required for the necessary pharmacological effect of sildenafil to occur.

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 area under the plasma concentration-time curve (AUC) and maximum concentration (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 delay in time to maximum concentration (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 (the 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 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 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).

Pharmacokinetics in special patient groups.

Renal impairment. In volunteers with mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the pharmacokinetics of sildenafil were unchanged after a single oral dose of 50 mg. The mean AUC and Cmax of the N-desmethyl metabolite were increased by 126% and 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 to 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.

Hepatic impairment: 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

The drug 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.

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 NO/cGMP metabolic pathways and potentiate the hypotensive effect of nitrates.

- 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 “Interaction with other medicinal products and other forms of interaction”).

˗ 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 PDE5 inhibitors or not.

˗ The presence of the following diseases: severe liver dysfunction, arterial hypotension (blood pressure below 90/50 mm Hg), recent stroke or myocardial infarction, and 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 the presence of such diseases.

Interaction with other medicinal products and other types of interactions

Effects of other drugs on sildenafil

In vitro studies

Sildenafil is metabolized primarily by the 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

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, a starting dose of 25 mg sildenafil should be considered.

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at a steady-state dose (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 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 used 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 nonspecific 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 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, 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 inducer of CYP3A4, CYP2C9 and possibly CYP2C19) 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 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 μM). Since peak plasma concentrations of sildenafil are approximately 1 μM, the drug is unlikely to affect the clearance of substrates of these isoenzymes.

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 NO/cGMP metabolism, sildenafil has been shown to potentiate the hypotensive effect of nitrates, therefore its concomitant use with nitric oxide donors or nitrates in any form is contraindicated (see section "Contraindications").

Riociguat: Preclinical studies have demonstrated an additive systemic blood pressure lowering effect when PDE5 inhibitors are co-administered with riociguat. Clinical studies have demonstrated that riociguat potentiates the hypotensive effects of PDE5 inhibitors.

No positive clinical effect was observed in patients participating in the study from the concomitant use of PDE5 inhibitors with riociguat. The concomitant use of riociguat with PDE5 inhibitors (including sildenafil) is contraindicated (see section "Contraindications").

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 a mean maximum blood ethanol level 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 dedicated 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 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 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.

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) 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.

Sildenafil potentiates the hypotensive effect of nitrates (see section "Contraindications").

In the post-marketing period, serious adverse reactions from the cardiovascular system, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension and hypotension, have been reported, which coincided in time with the use of sildenafil. The majority of patients had risk factors for cardiovascular disease. Many of these adverse reactions were observed during or immediately after sexual intercourse, and only a few occurred shortly after use of the drug without sexual activity. Therefore, it is not possible to determine whether the development of such adverse reactions is directly related to the risk factors or whether their development is due to other factors.

Priapism

Erectile dysfunction drugs, including sildenafil, should be prescribed with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) and in patients with conditions predisposing to the development of priapism (sickle cell anemia, multiple myeloma or leukemia).

Cases of prolonged erection and priapism have been reported in post-marketing experience. Patients should seek immediate medical attention if an erection lasts more than 4 hours. If not treated promptly, priapism can lead to penile tissue damage 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

Visual defects and cases of non-arteritic anterior ischemic optic neuropathy 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, the drug 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").

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. Therefore, the patient's haemodynamic parameters should be stable on α-adrenergic blockers before starting sildenafil. A starting dose of 25 mg sildenafil should be considered (see section 4.2). Patients should also be advised what to do if they experience 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, the use of sildenafil in these patients should only be considered after careful consideration of the benefit-risk ratio.

Hearing loss

Physicians should advise patients to discontinue use of PDE5 inhibitors, including Vivaray, 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 temporal association with the use of PDE5 inhibitors, including Vivaray. 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

Vivaray 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 Vivaray (100 mg) orally resulted in a mean additional reduction in systolic blood pressure of 8 mmHg and diastolic blood pressure of 7 mmHg.

Sexually transmitted diseases

Use of Vivaray does not protect against sexually transmitted diseases. Patients should be instructed on the necessary precautions to protect against sexually transmitted diseases, including human immunodeficiency virus.

Fertility

After administration of a dose of 100 mg to healthy volunteers, no effect on sperm morphology or motility was observed.

Vivaira contains lactose, if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Aspartame (E 951) in the medicine is a derivative of phenylalanine, which is dangerous for patients with phenylketonuria.

Use during pregnancy or breastfeeding .

The drug is not intended for use by women.

The ability to influence the reaction speed when driving vehicles or other mechanisms.

No studies have been conducted on the effect of the drug on the ability to drive vehicles and work with other mechanisms.

Since dizziness and visual disturbances have been reported in clinical trials with sildenafil, patients should be aware of their individual reaction to the drug before driving or operating machinery.

Method of administration and doses

The drug is administered orally.

The tablet should be chewed and swallowed completely.

Adults

If necessary, Vivaira should be used 1 hour before sexual activity. The recommended dose is 50 mg. Since simultaneous use of the drug with food delays absorption and slows down the effect of the drug (see section "Pharmacokinetics"), it is recommended to use the drug on an empty stomach.

Depending 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 use of the drug is 1 time per day.

Elderly patients

There is no need for dose adjustment in elderly patients (aged 65 years and over).

Patients with renal insufficiency

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 gradually increased to 50 mg and 100 mg if necessary.

Patients with hepatic insufficiency

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 gradually increased 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).

Due to the risk of postural hypotension in patients taking α-adrenergic blockers, it is necessary to ensure that their condition is stable before starting sildenafil. A starting dose of 25 mg* should also be considered (see sections 4.5 and 4.4).

* Use in appropriate dosage.

Children.

The drug is not indicated for use in persons under 18 years of age.

Overdose

In clinical studies in adult volunteers, after a single dose of sildenafil up to 800 mg, adverse reactions were similar to those observed with lower doses of sildenafil, 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, flushing, dizziness, dyspepsia, nasal congestion, visual disturbances).

In case of overdose, usual supportive measures should be employed if 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.

Side effects

The safety profile of sildenafil is based on data from 74 double-blind, placebo-controlled clinical trials (9570 patients). The most frequently reported adverse reactions were headache, flushing, dyspepsia, nasal congestion, back pain, dizziness, nausea, hot flushes, visual disturbances, cyanopsia and blurred vision. Post-marketing data on adverse reactions were collected over a period of more than 10 years. As not all adverse reactions were reported to the applicant and not all adverse reactions were included in the safety database, the frequency of such reactions cannot be reliably estimated.

All clinically significant adverse reactions observed in clinical trials at a frequency greater than that observed with placebo are listed below by system organ class and frequency: very common (≥1/10), common (≥1/100 - <1/10), uncommon (≥1/1000 - <1/100), rare (≥1/10000 - <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data). The frequency of clinically significant adverse reactions reported during post-marketing surveillance is defined as unknown. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infectious and invasive diseases

Uncommon: rhinitis.

On the part of the immune system

Uncommon: hypersensitivity reactions.

From the nervous system

Very common: headache.

Common: dizziness.

Uncommon: drowsiness, hypoesthesia.

Rare: stroke, syncope, transient ischemic attack, seizures, recurrent seizures.

From the organs of vision

Common: color perception disorders*, visual disturbances, blurred vision.

Uncommon: lacrimation disorder**, eye pain, photophobia, photopsia, ocular hyperemia, visual acuity reduced, 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 side of the organs of hearing and vestibular apparatus

Uncommon: dizziness, vertigo, tinnitus.

Rare: deafness.

Cardiovascular system

Common: flushing, hot flushes.

Uncommon: tachycardia, palpitations, hypertension, hypotension.

Rare: sudden cardiac death, myocardial infarction, ventricular arrhythmia, atrial fibrillation, unstable angina.

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 tract

Common: nausea, dyspepsia.

Uncommon: gastroesophageal reflux disease, vomiting, upper abdominal pain, dry mouth.

Rare: 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 extremity.

From the urinary system

Uncommon: hematuria.

Reproductive system and breast disorders

Rare: penile bleeding, priapism, hematospermia, prolonged erection.

General disorders and administration site conditions

Uncommon: chest pain, fatigue, feeling hot.

Rare: irritation.

Laboratory tests

Uncommon: increased heart rate.

* Color perception disorders: chloropsia, chromatopsia, cyanopsia, erythropsia, xanthopsia.

** Lacrimation disorders: dry eyes, lacrimation disorders and lacrimation increased.

The following events occurred in < 2% of patients in controlled clinical trials; causality has not been established. Reports included events that had a probable relationship to drug 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 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, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased salivation, increased cough.

Skin disorders: 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.

Post-marketing experience. The following adverse reactions have been identified during post-marketing experience. Because these reactions are reported voluntarily and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events were reported because of their seriousness, frequency of reporting, lack of a clear alternative relationship, or a combination of these factors.

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. The majority of patients had pre-existing 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 occurred in the hours or days following