Sildemax^® (Tablets) Instructions for Use

Marketing Authorization Holder

Zvezda Media, LLC (Russia)

Manufactured By

Severnaya Zvezda NAO (Russia)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Dosage Forms

	Sildemax®	Film-coated tablets, 25 mg: 4, 7, 10 or 20 pcs.
		Film-coated tablets, 50 mg: 4, 7, 10 or 20 pcs.
		Film-coated tablets, 100 mg: 4, 7, 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets are blue, round, biconvex; white or almost white in cross-section.

Excipients: microcrystalline cellulose 102 – 50 mg, croscarmellose sodium (primellose) – 7.5 mg, lactose monohydrate (milk sugar) – 51.4 mg, povidone K30 – 4.5 mg, magnesium stearate – 1.5 mg.

Shell composition hypromellose – 2.66 mg, polysorbate 80 (tween 80) – 1.05 mg; talc – 1.05 mg; titanium dioxide (E171) – 0.215 mg; aluminum lake based on brilliant blue dye E133 – 0.025 mg.

4 pcs. – contour cell blisters – cardboard packs.
7 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
20 pcs. – jars – cardboard packs.
20 pcs. – bottles – cardboard packs.

Film-coated tablets are blue, round, biconvex; white or almost white in cross-section.

Excipients: microcrystalline cellulose 102 – 54 mg, croscarmellose sodium (primellose) – 10 mg, lactose monohydrate (milk sugar) – 53.8 mg, povidone K30 – 10 mg, magnesium stearate – 2 mg.

Shell composition hypromellose – 3.2 mg, polysorbate 80 (tween 80) – 1.26 mg; talc – 1.26 mg; titanium dioxide (E171) – 0.25 mg; aluminum lake based on brilliant blue dye E133 – 0.03 mg.

4 pcs. – contour cell blisters – cardboard packs.
7 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
20 pcs. – jars – cardboard packs.
20 pcs. – bottles – cardboard packs.

Film-coated tablets are blue, round, biconvex; white or almost white in cross-section.

Excipients: microcrystalline cellulose 102 – 83.5 mg, croscarmellose sodium (primellose) – 15 mg, lactose monohydrate (milk sugar) – 43 mg, povidone K30 – 15 mg, magnesium stearate – 3 mg.

Shell composition hypromellose – 4.8 mg, polysorbate 80 (tween 80) – 1.9 mg; talc – 1.9 mg; titanium dioxide (E171) – 0.35 mg; aluminum lake based on brilliant blue dye E133 – 0.05 mg.

4 pcs. – contour cell blisters – cardboard packs.
7 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters – cardboard packs.
10 pcs. – contour cell blisters (2) – cardboard packs.
20 pcs. – jars – cardboard packs.
20 pcs. – bottles – cardboard packs.

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.

A prerequisite for the effectiveness 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 of sildenafil, the mean C_max of free sildenafil in plasma of healthy men is about 18 ng/mL (38 nM). C_max after oral administration on an empty stomach is reached 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 steady-state volume of distribution (V_d) of sildenafil averages 105 L. The binding of sildenafil and its main circulating N-desmethyl metabolite to plasma proteins is about 96% and is independent of the total drug concentration.

Less than 0.0002% of the sildenafil dose (average 188 ng) was detected in semen 90 minutes after drug administration.

Sildenafil is metabolized mainly in the liver by the cytochrome P450 isoform CYP3A4 (major pathway) and the cytochrome P450 isoform CYP2C9 (minor pathway).

The main circulating active metabolite, formed by N-desmethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its in vitro activity against PDE5 is about 50% of the activity of sildenafil.

The plasma concentration of the metabolite in healthy volunteers was about 40% of the sildenafil concentration. The N-desmethyl metabolite undergoes further metabolism; its half-life (T_1/2) is about 4 hours.

The total clearance of sildenafil is 41 L/h, and the terminal 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 with sexual stimulation.

ICD codes

Dosage Regimen

Take tablets orally with a glass of water.

Initiate therapy at the recommended adult dose of 50 mg.

Ingest the tablet approximately one hour before anticipated 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.

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

Do not exceed a single dose of 100 mg.

Limit administration to a maximum of once per 24-hour period.

For elderly patients, no initial dose adjustment is necessary.

For patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), initiate therapy at 25 mg.

For patients with severe hepatic impairment (Child-Pugh class C) and severe renal impairment (creatinine clearance less than 30 mL/min), initiate therapy at 25 mg.

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

If co-administration with a CYP3A4 inhibitor is necessary, a maximum single dose of 25 mg is recommended.

Concomitant administration with alpha-blockers may potentiate hypotensive effects; initiate sildenafil therapy only after the patient is hemodynamically stable on the alpha-blocker.

Consider a starting dose of 25 mg when used concomitantly with alpha-blockers.

The drug is effective only in the presence of sexual stimulation.

Taking the tablet with a high-fat meal may delay the onset of action.

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*, transient 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 loss or impairment, 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 – convulsions, 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 vascular 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 accompanied by bleeding; exacerbation of gastric and duodenal ulcer; hereditary pigmentary retinopathy; heart failure, unstable angina, myocardial infarction, stroke, or life-threatening arrhythmias within the last 6 months, arterial 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 should be reduced.

Use in Renal Impairment

In mild to moderate renal impairment (creatinine clearance 30-80 mL/min), no dose adjustment is required; in severe renal impairment (creatinine clearance <30 mL/min), the sildenafil dose 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

No dose adjustment of sildenafil is required in elderly patients.

Special Precautions

For the diagnosis of erectile dysfunction, determination of its possible causes, and selection of adequate treatment, a complete medical history should be taken and a thorough physical examination performed.

Drugs 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 undesirable.

Sexual activity poses a certain risk in the presence of heart disease, so before initiating any therapy for erectile dysfunction, the physician should refer the patient for cardiovascular assessment. Sexual activity is undesirable 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).

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. Nevertheless, 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, manifested by severe autonomic nervous system dysregulation of blood pressure.

Concomitant use of sildenafil and alpha-blockers may lead to symptomatic arterial hypotension in some sensitive patients. Sildenafil should be used with caution in patients receiving alpha-blockers. To minimize the risk of orthostatic 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 reducing the initial dose of sildenafil. The physician should inform patients about what actions to take in case of symptoms of orthostatic hypotension.

Rare cases of non-arteritic anterior ischemic optic neuropathy, as a cause of visual impairment or loss, have been observed 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. No causal relationship has been established between the use of PDE5 inhibitors and the development of non-arteritic anterior ischemic optic neuropathy. The physician should inform the patient about the increased risk of non-arteritic anterior ischemic optic neuropathy if he has previously experienced this condition. In case of sudden vision loss, patients should seek immediate medical attention. A small number of patients with hereditary retinitis pigmentosa have genetically determined retinal PDE dysfunction. There is no safety information on the use of sildenafil in patients with retinitis pigmentosa, so 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 gastric and duodenal ulcers, therefore Sildenafil should be used with caution in these patients. The frequency of epistaxis in patients with PAH 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 the Ability to Drive Vehicles and Operate Machinery

Since a decrease in BP, development of chromatopsia, blurred vision, and other adverse effects are possible when taking sildenafil, individual reaction to the drug in these situations should be carefully monitored, especially at the beginning of treatment and when changing the dosage regimen.

Drug Interactions

Sildenafil is metabolized mainly with the participation of the CYP3A4 isoenzyme (the main 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 sildenafil clearance has been observed with the simultaneous use of cytochrome CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a non-specific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken concomitantly with sildenafil (50 mg), causes a 56% increase in plasma concentration of sildenafil. A single dose of sildenafil 100 mg concomitantly with erythromycin (500 mg twice daily for 5 days), a specific inhibitor of the cytochrome CYP3A4 isoenzyme, against the background of achieving a steady-state concentration of erythromycin in the blood, leads to a 182% increase in the AUC of sildenafil.

When sildenafil (a single 100 mg dose) and saquinavir (1200 mg three times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme inhibitor, were taken concomitantly against the background of achieving a steady-state concentration of saquinavir in the blood, 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 CYP3A4 isoenzyme, such as ketoconazole and itraconazole, may cause more pronounced changes in the pharmacokinetics of sildenafil.

Concomitant use of sildenafil (a single 100 mg dose) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, against the background of achieving a steady-state concentration of ritonavir in the blood, leads to a 300% (4-fold) increase in the C_max of sildenafil, and a 1000% (11-fold) increase in AUC. After 24 hours, the plasma concentration of sildenafil is about 200 ng/ml (after a single dose of sildenafil alone – 5 ng/ml), which is consistent with information about the 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 CYP3A4 isoenzyme inhibitors, then 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 CYP2C9 isoenzyme (tolbutamide, warfarin), cytochrome CYP2D6 isoenzyme (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 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 they are 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 decrease in systolic/diastolic BP 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 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.