Viagra^® (Tablets) Instructions for Use

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).

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

Sildenafil does not have a direct relaxing effect on the isolated human corpus cavernosum but enhances the effect of NO by inhibiting PDE5, which is responsible for the breakdown of cGMP.

Sildenafil is selective for PDE5 in vitro; its activity against PDE5 exceeds its activity against other known phosphodiesterase isoenzymes: PDE6 – by 10 times; PDE1 – by more than 80 times; PDE2, PDE4, PDE7-PDE11 – by more than 700 times. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of utmost importance since PDE3 is one of the key enzymes regulating myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation. Sildenafil restores impaired erectile function under conditions of sexual stimulation by increasing blood flow to the corpus cavernosum of the penis.

Clinical data

Cardiological studies

The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in systolic blood pressure in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mmHg, and diastolic blood pressure – 5.3 mmHg. A more pronounced, but also transient, effect on blood pressure was noted in patients taking nitrates.

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

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina pectoris taking antianginal drugs (except nitrates) performed physical exercises until the severity of angina symptoms decreased. The duration of exercise was significantly longer (19.9 seconds; 0.9-38.9 sec) in patients taking Sildenafil in a single dose of 100 mg compared to patients receiving placebo.

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

Visual impairment studies

In some patients, 1 hour after taking sildenafil at a dose of 100 mg, a mild and transient impairment of the ability to distinguish shades of color (blue/green) was detected using the Farnsworth-Munsell 100 test. Two hours after taking the drug, these changes were absent. It is believed that the color vision impairment is caused by inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil did not affect visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset age-related macular degeneration (n=9), Sildenafil in a single 100 mg dose was well tolerated. No clinically significant changes in vision were detected, assessed by special visual tests (visual acuity, Amsler grid, color perception, color transit simulation, Humphrey perimeter, and photostress).

Efficacy

The efficacy and safety of sildenafil were evaluated in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic, or mixed). The efficacy of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire on sexual function status), and a partner survey.

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

According to summarized data, among patients reporting improvement in erection with sildenafil treatment were 59% of patients with diabetes mellitus, 43% of patients who underwent radical prostatectomy, and 83% of patients with spinal cord injuries (compared with 16%, 15%, and 12% in the placebo group, respectively).

Pharmacokinetics

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

Absorption

After oral administration, Sildenafil is rapidly absorbed. The absolute bioavailability averages 40% (25-63%). In vitro, Sildenafil at a concentration of approximately 1.7 ng/ml (3.5 nM) inhibits human PDE5 by 50%. After a single dose of sildenafil 100 mg, the mean C_max of free sildenafil in blood plasma is 18 ng/ml (38 nM) and is achieved when taken on an empty stomach on average within 60 min (30-120 min).

When taken with fatty food, the rate of absorption decreases; C_max decreases by an average of 29%, T_max increases by 60 min. However, the extent of absorption does not change significantly (AUC decreases by 11%).

Distribution

The V_d of sildenafil at steady state averages 105 L. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is about 96% and does not depend on the total concentration of sildenafil. Less than 0.0002% of the dose (average 188 ng) was found in semen 90 minutes after taking the drug.

Metabolism

Sildenafil is metabolized mainly in the liver under the action of isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway). The main circulating active metabolite, which is formed as a result of N-demethylation of sildenafil, undergoes further metabolism. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil, and its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil. The plasma concentration of the metabolite is approximately 40% of the concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism; its T_1/2 is about 4 hours.

Excretion

The total clearance of sildenafil is 41 L/h, and the terminal T_1/2 is 3-5 hours. After oral administration, as well as after intravenous administration, Sildenafil is excreted as metabolites, mainly in the feces (approximately 80% of the dose) and to a lesser extent in the urine (approximately 13% of the dose).

Pharmacokinetics in special clinical cases

In healthy elderly people (over 65 years of age), the clearance of sildenafil is reduced, and the plasma concentration of the free active substance is approximately 40% higher than its concentration in young (18-45 years) patients. Age does not have a clinically significant effect on the frequency of side effects.

In mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal failure, the pharmacokinetic parameters of sildenafil after a single oral dose of 50 mg do not change. In severe renal failure (creatinine clearance ≤30 ml/min), the clearance of sildenafil is reduced, leading to an approximately two-fold increase in AUC (100%) and C_max (88%) compared to those in patients with normal renal function of the same age group.

In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, leading to an increase in AUC (84%) and C_max (47%) compared to those in patients with normal liver function of the same age group. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh class C) has not been studied.

Indications

• Treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

Sildenafil is effective only with sexual stimulation.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. Orally disintegrating tablets can be taken with or without water. The tablet should be placed on the tongue, after which it will quickly dissolve and can be swallowed. The tablet should be taken immediately after opening the blister. For patients who are recommended a sildenafil dose of 100 mg, the second sildenafil 50 mg tablet should be taken after the first sildenafil 50 mg tablet has completely dissolved.

It should be taken into account that the absorption of sildenafil is significantly slowed down when used in combination with fatty foods.

For most patients, the recommended dose is 50 mg approximately 1 hour before sexual activity. Depending on efficacy and tolerability, the dose can be increased to 100 mg or reduced to 25 mg (only film-coated tablets of the corresponding dosage should be taken).

The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once a day. Patients who are recommended a sildenafil dose of 100 mg need to take two 50 mg orally disintegrating tablets one after the other.

In mild to moderate renal impairment (creatinine clearance 30-80 ml/min), dose adjustment is not required; in severe renal impairment (creatinine clearance <30 ml/min), the sildenafil dose should be reduced to 25 mg.

Since the elimination of sildenafil is impaired in patients with liver damage (e.g., cirrhosis), the dose of the drug should be reduced to 25 mg.

In elderly patients, no dose adjustment is required.

Concomitant use with other drugs

When used concomitantly with ritonavir, the maximum single dose of Viagra^® should not exceed 25 mg, and the frequency of use should be once every 48 hours.

When used concomitantly with inhibitors of the CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Viagra^® should be 25 mg.

To minimize the risk of postural hypotension in patients taking alpha-blockers, the use of Viagra^® should be started only after hemodynamic stabilization has been achieved in these patients. The advisability of reducing the initial dose of sildenafil should be considered.

Adverse Reactions

The most common side effects were headache and flushing.

Side effects are usually mild or moderate and transient.

In fixed-dose studies, it was found that the frequency of some adverse events increases with increasing dose.

The frequency of adverse reactions is defined as follows: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%), frequency unknown (cannot be estimated from the available data).

Immune system disorders uncommon – hypersensitivity reactions (including skin rash), allergic reactions.

Eye disorders common – blurred vision, visual impairment, cyanopsia; uncommon – eye pain, photophobia, photopsia, chromatopsia, eye redness/scleral injection, change in brightness perception, mydriasis, conjunctivitis, ocular tissue hemorrhage, cataract, lacrimal gland disorder; rare – eyelid and adjacent tissue edema, feeling of dryness in the eyes, presence of rainbow circles in the field of vision around a light source, increased eye fatigue, seeing objects in yellow (xanthopsia), seeing objects in red (erythropsia), conjunctival hyperemia, irritation of the eye mucosa, eye discomfort; frequency unknown – non-arteritic anterior ischemic optic neuropathy (NAION), retinal vein occlusion, visual field defect, diplopia*, temporary loss of vision or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreous traction.

Ear and labyrinth disorders uncommon – sudden decrease or loss of hearing, tinnitus, ear pain.

Cardiac disorders common – flushing; uncommon – tachycardia, palpitations, decreased blood pressure, increased heart rate, unstable angina, AV block, myocardial ischemia, cerebral vascular thrombosis, cardiac arrest, heart failure, ECG abnormalities, cardiomyopathy; rare – atrial fibrillation, sudden cardiac death*, ventricular arrhythmia*.

Blood and lymphatic system disorders uncommon – anemia, leukopenia.

Metabolism and nutrition disorders uncommon – feeling of thirst, edema, gout, uncontrolled diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Respiratory, thoracic and mediastinal disorders common – nasal congestion; uncommon – nosebleed, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum volume, increased cough; rare – feeling of tightness in the throat, dryness of the nasal mucosa, swelling of the nasal mucosa.

Gastrointestinal disorders common – nausea, dyspepsia; uncommon – gastroesophageal reflux disease, vomiting, abdominal pain, dry mouth, glossitis, gingivitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, abnormal liver function tests, rectal bleeding; rare – hypoesthesia of the oral mucosa.

Musculoskeletal and connective tissue disorders common – back pain; uncommon – myalgia, limb pain, arthritis, arthrosis, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Renal and urinary disorders uncommon – cystitis, nocturia, breast enlargement, urinary incontinence, hematuria, ejaculation disorder, genital edema, anorgasmia, hematospermia, penile tissue damage; rare – prolonged erection and/or priapism.

Nervous system disorders very common – headache; common – dizziness; uncommon – drowsiness, migraine, ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depressive symptoms, insomnia, unusual dreams, increased reflexes, hypoesthesia; rare – convulsions*, recurrent convulsions*, syncope.

Skin and subcutaneous tissue disorders uncommon – skin rash, urticaria, herpes simplex, skin itching, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions uncommon – feeling hot, facial edema, photosensitivity reactions, shock, asthenia, increased fatigue, pain of various localization, chills, accidental falls, chest pain, accidental injuries; rare – irritability.

* Side effects identified during post-marketing studies.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension, and hypotension) have been reported, which had a temporal relationship with the use of sildenafil. Most of these patients, but not all, had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the noted adverse events and the mentioned or other factors.

Visual disturbances

In rare cases, during post-registration use of all PDE5 inhibitors, including sildenafil, non-arteritic anterior ischemic optic neuropathy (NAION) has been reported – a rare disease and cause of decreased or loss of vision. Most of these patients had risk factors, in particular a reduced cup-to-disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of PDE5 inhibitor class drugs is associated with the acute onset of NAION. The results indicate an approximately two-fold increase in the risk of NAION within 5 half-lives after using a PDE5 inhibitor. According to published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. Patients should be advised to discontinue sildenafil therapy and consult a doctor immediately in case of sudden loss of vision. Individuals who have already had an episode of NAION have an increased risk of recurrence of NAION. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential chance of adverse effects of PDE5 inhibitors. PDE5 inhibitors, including Sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk.

When using the drug Viagra^® at doses exceeding the recommended ones, the adverse events were similar to those noted above but were usually observed more frequently.

Contraindications

• Severe hepatic impairment (Child-Pugh class C);
• Severe cardiovascular diseases (severe heart failure, unstable angina, stroke or myocardial infarction within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg));
• Episodes of non-arteritic anterior ischemic optic neuropathy with vision loss in one eye;
• Hereditary pigmentary retinitis;
• Use in patients receiving continuous or intermittent nitric oxide donors, organic nitrates or nitrites in any form, since Sildenafil potentiates the hypotensive effect of nitrates;
• Concomitant use of PDE5 inhibitors, including Sildenafil, with guanylate cyclase stimulators, such as riociguat, as this may lead to symptomatic hypotension;
• Concomitant use of the drug with other agents for the treatment of erectile dysfunction (the safety and efficacy of combination therapy have not been studied);
• Concomitant use of ritonavir;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children and adolescents under 18 years of age;
• Use in women;
• Hypersensitivity to sildenafil or to any other component of the drug.

With caution anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie’s disease); conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia); conditions accompanied by bleeding; peptic ulcer of the stomach and duodenum in the acute phase; impaired liver function; severe renal impairment (creatinine clearance less than 30 ml/min); history of an episode of non-arteritic anterior ischemic optic neuropathy; concomitant use of alpha-adrenergic blockers.

Use in Pregnancy and Lactation

According to the registered indication, the drug is not intended for use in women.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

The drug should be prescribed with caution in patients with impaired liver function.

Use in Renal Impairment

The drug should be prescribed with caution in severe renal impairment (creatinine clearance less than 30 ml/min).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

To diagnose erectile dysfunction, determine its possible causes, and select adequate treatment, a complete medical history should be taken and a thorough physical examination performed. Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia).

During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, the patient should seek immediate medical attention. If therapy for priapism is not administered immediately, it may lead to penile tissue damage and irreversible loss of potency.

Drugs intended for the treatment of erectile dysfunction should not be prescribed to men for whom sexual activity is not advisable.

Sexual activity poses a certain risk in the presence of heart disease; therefore, before initiating any therapy for erectile dysfunction, the physician should refer the patient for a cardiovascular assessment. Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg). The use of sildenafil in such patients is contraindicated. Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 person-years) or mortality from cardiovascular diseases (0.3 per 100 person-years) in patients receiving Viagra^® compared to patients receiving placebo.

Cardiovascular complications

During the post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, arterial hypertension and hypotension) have been reported, which were temporally associated with the use of sildenafil. Most, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events were observed shortly after sexual activity, and some were noted after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct causal relationship between the reported adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in blood pressure, which is not a clinically significant effect and does not lead to any consequences in most patients. However, before prescribing Viagra^®, the physician should carefully assess the risk of possible adverse manifestations of the vasodilatory effect in patients with relevant conditions, especially during sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe impairment of blood pressure regulation by the autonomic nervous system.

Since the concomitant use of sildenafil and alpha-adrenergic blockers may lead to symptomatic hypotension in some sensitive patients, Viagra^® should be prescribed with caution to patients taking alpha-adrenergic blockers. To minimize the risk of developing postural hypotension in patients taking alpha-adrenergic blockers, Viagra^® should be initiated only after hemodynamic stabilization has been achieved in these patients. The advisability of reducing the initial dose of Viagra^® should also be considered. Patients should be informed about what actions to take in case symptoms of postural hypotension appear.

Visual disturbances

In rare cases, during the post-registration use of all PDE5 inhibitors, including sildenafil, non-arteritic anterior ischemic optic neuropathy (NAION) has been reported – a rare disease and cause of vision decrease or loss. Most of these patients had risk factors, particularly a reduced cup-to-disc ratio (“crowded disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of PDE5 inhibitor class drugs was associated with the acute onset of NAION. The results indicate an approximately two-fold increase in the risk of NAION within 5 half-lives after using a PDE5 inhibitor. According to published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population. Patients should be advised to discontinue sildenafil therapy and consult a physician immediately in case of sudden vision loss. Individuals who have already experienced an episode of NAION have an increased risk of NAION recurrence. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential chance of adverse effects from PDE5 inhibitors. PDE5 inhibitors, including Sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk. In patients with episodes of NAION with vision loss in one eye, the use of sildenafil is contraindicated.

A small number of patients with hereditary pigmentary retinitis have genetically determined disorders of retinal phosphodiesterase functions. There is no information on the safety of using Viagra^® in patients with pigmentary retinitis, so Sildenafil should be used with caution.

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden hearing deterioration or loss associated with the use of all PDE5 inhibitors, including Sildenafil. Most of these patients had risk factors for sudden hearing deterioration or loss. A causal relationship between the use of PDE5 inhibitors and sudden hearing deterioration or hearing loss has not been established. In case of sudden hearing deterioration or hearing loss while taking sildenafil, the patient should consult a physician immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil use in patients with a tendency to bleeding or exacerbation of peptic ulcer of the stomach and duodenum, so Viagra^® should be used with caution in these patients. The frequency of epistaxis in patients with pulmonary hypertension associated with diffuse connective tissue diseases was higher (Sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (Sildenafil 3%, placebo 2.4%). In patients receiving Sildenafil in combination with a vitamin K antagonist, the frequency of epistaxis was higher (8.8%) than in patients not taking a vitamin K antagonist (1.7%).

Use with other agents for the treatment of erectile dysfunction

The safety and efficacy of Viagra^® in combination with other PDE5 inhibitors or other drugs for the treatment of pulmonary hypertension containing Sildenafil (for example, Revatio^®), or other agents for the treatment of erectile dysfunction have not been studied, so the use of such combinations is not recommended.

Effect on the ability to drive vehicles and operate machinery

No negative effect on the ability to drive a car or other technical means was observed while taking sildenafil. However, since dizziness, decreased blood pressure, chromatopsia, blurred vision and other side effects may develop while taking sildenafil, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Attention should also be paid to the individual effect of the drug in these situations, especially at the beginning of treatment and when changing the dosage regimen.

Overdose

With a single dose of Viagra^® up to 800 mg, the adverse events were comparable to those with lower doses of the drug but were observed more frequently.

The use of the drug at a dose of 200 mg did not lead to an increase in the efficacy of the drug, but the frequency of adverse reactions (headache, “flushing”, dizziness, dyspepsia, nasal congestion, visual impairment) increased.

Treatment symptomatic therapy. Hemodialysis does not accelerate the clearance of sildenafil, as the latter is actively bound to plasma proteins and is not excreted in the urine.

Drug Interactions

Effect of other drugs on the metabolism of sildenafil

The metabolism of sildenafil occurs mainly in the liver under the action of the isoenzymes CYP3A4 (the main pathway) and CYP2C9, so inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers, respectively, may increase the clearance of sildenafil.

When used concomitantly with CYP3A4 inhibitors (ketoconazole, erythromycin, cimetidine), a decrease in the clearance of sildenafil was noted.

Cimetidine (at a dose of 800 mg), a non-specific inhibitor of CYP3A4, when taken concomitantly with sildenafil (at a dose of 50 mg), causes an increase in the plasma concentration of sildenafil by 56%.

A single dose of sildenafil 100 mg simultaneously with erythromycin – a specific inhibitor of CYP3A4 (500 mg twice daily for 5 days) – against the background of achieving a steady-state concentration of erythromycin in the blood leads to an increase in the AUC of sildenafil by 182%.

When sildenafil (single dose of 100 mg) and saquinavir (at a dose of 1200 mg three times daily), which is both an HIV protease inhibitor and a CYP3A4 inhibitor, were used concomitantly against the background of achieving a steady-state concentration of saquinavir in the blood, the C_max of sildenafil in the blood increased by 140%, and the AUC increased by 210%. Sildenafil did not affect the pharmacokinetic parameters of saquinavir.

Stronger inhibitors of the CYP3A4 isoenzyme, such as ketoconazole or itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant use of sildenafil (single dose of 100 mg) and ritonavir (500 mg twice daily), which is an HIV protease inhibitor and a strong inhibitor of cytochrome P450 isoenzymes, against the background of achieving a steady-state concentration of ritonavir in the blood leads to an increase in the C_max of sildenafil by 300% (4 times), and the AUC by 1000% (11 times). After 24 hours, the plasma concentration of sildenafil was approximately 200 ng/ml (with a single use of sildenafil alone – 5 ng/ml). This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates. Sildenafil does not affect the pharmacokinetics of ritonavir. Given these data, concomitant use of ritonavir and sildenafil is not recommended. In any case, the maximum dose of sildenafil under no circumstances should exceed 25 mg within 48 hours.

If Sildenafil is taken at recommended doses by patients receiving strong CYP3A4 inhibitors concomitantly, the C_max of free sildenafil does not exceed 200 nM, and the drug is well tolerated.

A single dose of an antacid (magnesium hydroxide/aluminum hydroxide) does not affect the bioavailability of sildenafil.

In studies involving healthy volunteers, with the concomitant use of the endothelin receptor antagonist bosentan (an inducer of the CYP3A4 isoenzyme (moderate), CYP2C9 and possibly CYP2C19) at steady-state concentration (125 mg twice daily) and sildenafil at steady-state concentration (80 mg three times daily), a decrease in the AUC and C_max of sildenafil by 62.6% and 52.4%, respectively, was noted. Sildenafil increased the AUC and C_max of bosentan by 49.8% and 42%, respectively. It is assumed that the concomitant use of sildenafil with potent inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater decrease in the plasma concentration of sildenafil.

Inhibitors of the CYP2C9 isoenzyme (such as tolbutamide, warfarin), the CYP2D6 isoenzyme (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, ACE inhibitors and calcium antagonists do not affect the pharmacokinetics of sildenafil.

Concomitant use of azithromycin (500 mg/day for 3 days) does not affect the AUC, C_max, T_max, elimination rate constant and T_1/2 of sildenafil or its main circulating metabolite.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 system isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀>150 µmol). When sildenafil is used at recommended doses, its C_max is about 1 µmol, so it is unlikely that Sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil potentiates the hypotensive effect of nitrates, both during long-term use and during acute use. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

With the concomitant use of the alpha-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the mean additional decrease in systolic/diastolic blood pressure in the supine position was 7/7 mmHg, 9/5 mmHg and 8/4 mmHg, respectively, and in the standing position – 6/6 mmHg, 11/4 mmHg and 4/5 mmHg, respectively. Rare cases of symptomatic postural hypotension manifested as dizziness (without fainting) have been reported in such patients. In some sensitive patients receiving alpha-adrenergic blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

No signs of significant interaction between sildenafil and tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by CYP2C9, were found.

Sildenafil at a dose of 100 mg does not affect the pharmacokinetic parameters of the HIV protease inhibitor saquinavir, which is a substrate of CYP3A4, at its steady-state blood concentration.

Concomitant use of sildenafil at steady state (80 mg three times daily) leads to an increase in the AUC and C_max of bosentan (125 mg twice daily) by 49.8% and 42%, respectively.

Sildenafil at a dose of 50 mg does not cause additional prolongation of bleeding time when taking acetylsalicylic acid at a dose of 150 mg.

Sildenafil at a dose of 50 mg does not enhance the hypotensive effect of ethanol in healthy volunteers at a maximum blood ethanol level averaging 0.08% (80 mg/dL).

In patients with arterial hypertension, no signs of interaction between sildenafil (at a dose of 100 mg) and amlodipine were found. The mean additional decrease in blood pressure in the supine position was 8 mmHg (systolic) and 7 mmHg (diastolic).

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

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.