Silafil (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

A potent and selective inhibitor of cyclic guanosine monophosphate (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: 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 utmost importance since PDE3 is one of the key enzymes regulating myocardial contractility.

A necessary condition for the efficacy of sildenafil is sexual stimulation.

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 sildenafil, the mean C_max of free sildenafil in plasma of healthy male volunteers is about 18 ng/mL (38 nM). The C_max after oral administration of sildenafil on an empty stomach 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 is delayed by 60 minutes, but the extent of absorption is not significantly altered (AUC decreases by 11%).

The steady-state volume of distribution (V_d) for sildenafil averages 105 L. The plasma protein binding of sildenafil and its major circulating N-desmethyl metabolite 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 semen 90 minutes after drug administration.

Sildenafil is metabolized primarily in the liver by the cytochrome P450 isoform CYP3A4 (major pathway) and the cytochrome P450 isoform CYP2C9 (minor pathway). The major circulating active metabolite results from N-desmethylation of sildenafil and is further metabolized. 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 concentration of this metabolite in healthy volunteers was about 40% of the concentration 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 adult starting dose is 50 mg taken approximately one hour before sexual activity.

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.

Decrease the dose to 25 mg if the 50 mg dose is not well tolerated.

Do not exceed the maximum recommended single dose of 100 mg.

Do not take more than once per day.

For patients with severe hepatic impairment (e.g., cirrhosis) or severe renal impairment (creatinine clearance less than 30 mL/min), initiate therapy at 25 mg.

In elderly patients, dose adjustment is not typically required.

A high-fat meal may delay the onset of action.

The effect is dependent on sexual stimulation.

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, vitreous detachment/vitreous traction.

Ear and labyrinth disorders: Uncommon – sudden hearing decrease or loss, tinnitus, ringing in the 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 – seizures, recurrent seizures, 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 localization, 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 treatments for 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); diseases associated with bleeding; exacerbation of peptic ulcer of the stomach and duodenum; hereditary retinal pigmentary degeneration; heart failure, unstable angina, myocardial infarction, stroke, or life-threatening arrhythmias within the last 6 months, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg); 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 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

To diagnose erectile dysfunction, determine its possible causes, and select appropriate treatment, a complete medical history should be taken and a thorough physical examination performed. Erectile dysfunction treatments 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 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 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, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg).

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 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 reported after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct causal relationship between the reported adverse events and the aforementioned or other factors.

Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before starting sildenafil, 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 left ventricular outflow obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, which presents with severe autonomic nervous system dysregulation of blood pressure.

Concomitant use of sildenafil and alpha-adrenergic blockers may lead to symptomatic arterial hypotension in some sensitive patients. Sildenafil should be used with caution in patients taking alpha-adrenergic blockers. To minimize the risk of postural hypotension in patients taking alpha-adrenergic blockers, Sildenafil should be initiated only after hemodynamic stabilization has been achieved in these patients. Consideration should also be given to reducing the initial dose of sildenafil. The physician should inform patients about what actions to take in case of symptoms of postural hypotension.

Rare cases of non-arteritic anterior ischemic optic neuropathy, as 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 risk factors such as optic disc cupping, age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. A causal relationship between the use of PDE5 inhibitors and the development of non-arteritic anterior ischemic optic neuropathy has not been established. The physician should inform the patient about the increased risk of non-arteritic anterior ischemic optic neuropathy if this condition has been previously experienced. In case of sudden vision loss, patients should seek immediate medical attention. A small number of patients with hereditary retinal pigmentary degeneration have genetically determined retinal PDE dysfunction. There is no information on the safety of sildenafil use in patients with pigmentary retinopathy; therefore, Sildenafil should be used with caution.

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

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; therefore, Sildenafil 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 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%).

Effect on ability to drive vehicles and operate machinery

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

Drug Interactions

Sildenafil metabolism occurs primarily with the participation of the CYP3A4 isoenzyme (major pathway) and CYP2C9, therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil, and inducers, respectively, may increase the clearance of sildenafil. A decrease in the clearance of sildenafil has been observed with the concomitant use of cytochrome P450 CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome P450 CYP3A4 isoenzyme, when taken concomitantly with sildenafil (50 mg), causes a 56% increase in plasma sildenafil concentration. A single dose of sildenafil 100 mg co-administered with erythromycin (500 mg twice daily for 5 days), a specific inhibitor of the cytochrome P450 CYP3A4 isoenzyme, at steady-state erythromycin concentrations, leads to a 182% increase in sildenafil AUC.

When sildenafil (single dose 100 mg) was co-administered with saquinavir (1200 mg three times daily), an HIV protease inhibitor and cytochrome P450 CYP3A4 isoenzyme inhibitor, at steady-state saquinavir concentrations, the C_max of sildenafil increased by 140%, and the AUC increased by 210%. Sildenafil does not affect the pharmacokinetics of saquinavir.

Stronger inhibitors of the cytochrome P450 CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

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

If Sildenafil is taken at recommended doses by patients who are simultaneously receiving strong cytochrome P450 CYP3A4 isoenzyme 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), 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.

With the simultaneous administration of the alpha-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 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, manifested as dizziness (without fainting), have been reported in such patients. In certain sensitive patients receiving alpha-blockers, the concomitant 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.