Sildenafil (Tablets) Instructions for Use

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of erectile dysfunction

Pharmacological Action

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

The physiological mechanism of erection involves 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: it is 10 times more selective for PDE5 than for PDE6; more than 80 times more selective than for PDE1; and more than 700 times more selective than for PDE2, PDE4, PDE7-PDE11. Sildenafil is 4000 times more selective for PDE5 compared to PDE3, which is of paramount importance since PDE3 is one of the key enzymes regulating myocardial contractility.

Sexual stimulation is a necessary condition for the effectiveness of sildenafil.

Pharmacokinetics

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

After oral administration, sildenafil is rapidly absorbed. The absolute bioavailability averages about 40% (range 25% to 63%). In vitro, sildenafil at a concentration of about 1.7 ng/mL (3.5 nM) inhibits human PDE5 activity by 50%. After a single oral dose of 100 mg of sildenafil, the mean C_max of free sildenafil in the plasma of healthy men is about 18 ng/mL (38 nM). The C_max of orally administered sildenafil under fasting conditions is achieved on average within 60 minutes (range 30 to 120 minutes). When taken with a high-fat meal, the rate of absorption is reduced: C_max decreases by an average of 29%, and T_max increases by 60 minutes, but the extent of absorption is not significantly altered (AUC decreases by 11%).

The mean steady-state volume of distribution (V_d) for sildenafil is 105 L. The binding of sildenafil and its primary circulating N-desmethyl metabolite to plasma proteins is approximately 96% and is independent of the total drug concentration. Less than 0.0002% of the sildenafil dose (average 188 ng) was found in the semen 90 minutes after drug intake.

Sildenafil is metabolized primarily in the liver by the cytochrome P450 isoform CYP3A4 (major pathway) and the cytochrome P450 isoform CYP2C9 (minor pathway). The primary circulating active metabolite results from N-desmethylation of sildenafil and undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its in vitro potency against PDE5 is about 50% of that of sildenafil. The plasma concentrations of this metabolite in healthy volunteers were approximately 40% of those of sildenafil. The N-desmethyl metabolite undergoes further metabolism; its terminal T_1/2 is about 4 hours.

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

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 in the presence of sexual stimulation.

ICD codes

Dosage Regimen

Take tablets orally.

The recommended starting dose for most adult patients is 50 mg.

Take the tablet approximately one hour before anticipated sexual activity.

Sexual stimulation is required for the drug to be effective.

Adjust the dose based on individual efficacy and tolerability.

Increase the dose to a maximum of 100 mg if the 50 mg dose is insufficient.

Reduce the dose to 25 mg if side effects are not well tolerated.

The maximum recommended frequency of administration is once per day.

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), a dose reduction is recommended.

In patients with hepatic impairment (particularly cirrhosis), a dose reduction is required due to impaired elimination.

For elderly patients, dose adjustment is not required.

Avoid concomitant use with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).

Do not use with any form of organic nitrates or nitric oxide donors.

Adverse Reactions

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

Blood and lymphatic system disorders Uncommon – anemia, leukopenia.

Metabolism and nutrition disorders Uncommon – thirst sensation, edema, gout, uncontrolled diabetes mellitus, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemia, hypernatremia.

Eye disorders Common – blurred vision, visual impairment, cyanopsia; Uncommon – eye pain, photophobia, photopsia, chromatopsia, eye redness/scleral injection, altered perception of light brightness, mydriasis, conjunctivitis, ocular hemorrhage, cataract, lacrimal disorder; Rare – eyelid and periorbital edema, dry eye sensation, seeing halos around lights, eye fatigue, xanthopsia (yellow vision), erythropsia (red vision), conjunctival hyperemia, eye irritation, eye discomfort; Frequency not known – non-arteritic anterior ischemic optic neuropathy, retinal vein occlusion, visual field defect, diplopia*, temporary vision loss or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, posterior vitreous detachment/vitreous traction.

Ear and labyrinth disorders Uncommon – sudden hearing decrease or loss, tinnitus, ringing in ears, ear pain.

Nervous system disorders Very common – headache; Common – dizziness; Uncommon – somnolence, migraine, ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depressive symptoms, insomnia, unusual dreams, hyperreflexia, hypoesthesia; Rare – convulsions, seizure recurrence, syncope, cerebrovascular accident, transient ischemic attack.

Cardiac disorders Common – flushing; Uncommon – tachycardia, palpitations, decreased or increased blood pressure, increased heart rate, unstable angina, atrioventricular block, myocardial infarction, cerebral thrombosis, cardiac arrest, heart failure, abnormal ECG findings, cardiomyopathy; Rare – atrial fibrillation, sudden cardiac death, ventricular arrhythmia.

Respiratory, thoracic and mediastinal disorders Common – nasal congestion; Uncommon – epistaxis, rhinitis, asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, increased sputum volume, increased cough; Rare – throat tightness, nasal dryness, nasal mucosal swelling.

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 – oral mucosa hypoesthesia.

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, urinary incontinence, hematuria.

Reproductive system and breast disorders Uncommon – breast enlargement, ejaculation disorder, genital edema, anorgasmia, hematospermia, penile tissue damage; Rare – prolonged erection and/or priapism, penile bleeding.

Skin and subcutaneous tissue disorders Uncommon – skin rash, urticaria, herpes simplex, pruritus, increased sweating, skin ulceration, contact dermatitis, exfoliative dermatitis; Frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions Uncommon – feeling hot, facial edema, photosensitivity reaction, shock, asthenia, increased fatigue, pain of various locations, chills, accidental falls, chest pain, accidental injuries; Rare – irritability.

Contraindications

Hypersensitivity to sildenafil; 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; children and adolescents under 18 years of age; according to the registered indication, sildenafil is not intended for use in women; concomitant use of sildenafil with ritonavir, or with other agents for the treatment of erectile dysfunction is not recommended.

With caution

Anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie’s disease); conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia); bleeding disorders; exacerbation of peptic ulcer disease; retinitis pigmentosa; heart failure, unstable angina, myocardial infarction, stroke, or life-threatening arrhythmias within the last 6 months, hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg); in patients with a history of non-arteritic anterior ischemic optic neuropathy.

Use in Pregnancy and Lactation

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

Use in Hepatic Impairment

Since the elimination of sildenafil is impaired in patients with liver damage (particularly cirrhosis), the dose of Sildenafil-SZ should be reduced.

Use in Renal Impairment

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 dose of sildenafil should be reduced.

Pediatric Use

According to the registered indication, sildenafil is not intended for use in children and adolescents under 18 years of age.

Geriatric Use

Dose adjustment of sildenafil in elderly patients is not required.

Special Precautions

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

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

Sexual activity carries a certain risk in patients with pre-existing cardiovascular diseases. Therefore, prior to initiating any treatment for erectile dysfunction, the physician should assess the patient’s cardiovascular status. Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg).

During post-marketing use of sildenafil for 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, with a temporal relationship to sildenafil intake. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many of these adverse events were observed shortly after sexual activity, and some were reported after taking sildenafil without subsequent sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient’s underlying cardiovascular disease, or to a combination of these or other factors.

Sildenafil has a systemic vasodilatory effect, leading to transient decreases in blood pressure, which is not a clinically significant event and has no consequences for most patients. However, prior to initiating treatment with sildenafil, physicians should carefully consider the potential risk of adverse vasodilatory effects in patients with underlying conditions, particularly in the context of sexual activity. Increased susceptibility to vasodilators is observed in patients with left ventricular outflow obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), and in patients with the rare syndrome of multiple system atrophy, which presents with severe autonomic nervous system dysregulation of blood pressure.

Concomitant administration of sildenafil and alpha-adrenergic blockers may lead to symptomatic hypotension in some susceptible individuals. Sildenafil should be used with caution in patients taking alpha-adrenergic blockers. To minimize the risk of postural hypotension in patients taking alpha-blockers, sildenafil should be initiated only after hemodynamic stabilization has been achieved in these patients. Consideration should also be given to a lower starting dose of sildenafil. The physician should advise patients what actions to take in the event of symptoms of postural hypotension.

Rare cases of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased or loss of vision, have been reported with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had underlying risk factors, such as optic disc cupping, age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. A causal relationship between PDE5 inhibitor use and NAION has not been established. Physicians should advise patients of the increased risk of NAION if they have already experienced this condition. In the event of sudden vision loss, patients should seek immediate medical attention. A small number of patients with hereditary retinitis pigmentosa have genetic disorders of retinal phosphodiesterase. There is no safety information on the use of sildenafil in patients with retinitis pigmentosa; therefore, sildenafil should be used with caution in these patients.

In case of sudden hearing deterioration or hearing loss while taking sildenafil, a physician should be consulted immediately.

Sildenafil potentiates the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil in patients with bleeding tendencies or active peptic ulceration; therefore, sildenafil should be used with caution in these patients. The incidence of epistaxis in patients with pulmonary hypertension associated with connective tissue diseases was higher than in patients with primary pulmonary hypertension (Sildenafil 3%, placebo 2.4%). In patients receiving sildenafil concomitantly with vitamin K antagonists, the incidence of epistaxis was higher (8.8%) than in patients not taking vitamin K antagonists (1.7%).

Effect on ability to drive and operate machinery

Since sildenafil may cause decreased blood pressure, chromatopsia, blurred vision, and other adverse reactions, individual response to the drug should be considered in these situations, especially at the start of treatment and when changing the dosage regimen.

Drug Interactions

Sildenafil is metabolized primarily by the CYP3A4 isoenzyme (major pathway) and CYP2C9, therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers may correspondingly increase the clearance of sildenafil. A reduction in sildenafil clearance has been observed with the concomitant use of CYP3A4 inhibitors (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-selective inhibitor of cytochrome P450 CYP3A4, when co-administered with sildenafil (50 mg), caused a 56% increase in plasma sildenafil concentrations. A single 100 mg dose of sildenafil co-administered with erythromycin (500 mg twice daily for 5 days), a specific CYP3A4 inhibitor, at steady-state erythromycin concentrations, resulted in a 182% increase in sildenafil AUC.

When sildenafil (single 100 mg dose) was co-administered with saquinavir (1200 mg three times daily), an HIV protease inhibitor and CYP3A4 inhibitor, at steady-state saquinavir concentrations, the C_max of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil did not affect the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome P450 CYP3A4 isoenzyme, such as ketoconazole and itraconazole, would be expected to have even greater effects on sildenafil pharmacokinetics.

Concomitant administration of sildenafil (single 100 mg dose) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a potent cytochrome P450 inhibitor, at steady-state ritonavir concentrations, resulted in a 300% (4-fold) increase in sildenafil C_max and a 1000% (11-fold) increase in sildenafil AUC. After 24 hours, the plasma concentration of sildenafil was about 200 ng/mL (compared to 5 ng/mL after sildenafil alone), which is consistent with ritonavir’s marked effect on the pharmacokinetics of various cytochrome P450 substrates. Sildenafil did not affect the pharmacokinetics of ritonavir. Concomitant use of sildenafil with ritonavir is not recommended.

If sildenafil is taken at recommended doses by patients concurrently receiving strong CYP3A4 inhibitors, 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.

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

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.

Sildenafil is a weak inhibitor of the cytochrome P450 isoenzymes -1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (IC₅₀>150 µmol). When sildenafil is taken 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 enhances the hypotensive effect of nitrates, both during their long-term use and when prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.