Maxigra (Tablets) Instructions for Use

Marketing Authorization Holder

Polpharma Pharmaceutical Works, Sa (Poland)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil (USAN)

Dosage Forms

	Maxigra	Film-coated tablets, 50 mg: 1 or 4 pcs.
		Film-coated tablets, 100 mg: 1 or 4 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets blue in color, round, biconvex.

Excipients : mannitol – 70.76 mg, crospovidone – 6 mg, povidone – 6 mg, corn starch – 10 mg, colloidal silicon dioxide – 2 mg, sodium lauryl sulfate – 2 mg, magnesium stearate – 3 mg.

Shell composition hypromellose – 4.13 mg, macrogol 6000 – 1.3 mg, titanium dioxide – 0.9 mg, talc – 0.43 mg, indigo carmine (E132) – 0.24 mg.

1 pc. – blisters (1) – cardboard packs.
4 pcs. – blisters (1) – cardboard packs.

Film-coated tablets blue in color, round, biconvex.

Excipients : mannitol – 141.52 mg, crospovidone – 12 mg, povidone – 12 mg, corn starch – 20 mg, colloidal silicon dioxide – 4 mg, sodium lauryl sulfate – 4 mg, magnesium stearate – 6 mg.

Shell composition hypromellose – 5.9 mg, macrogol 6000 – 1.85 mg, titanium dioxide – 1.3 mg, talc – 0.6 mg, indigo carmine (E132) – 0.35 mg.

1 pc. – blisters (1) – cardboard packs.
4 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

A drug for the treatment of erectile dysfunction. Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5).

During sexual stimulation, it restores impaired erectile function by enhancing blood flow to the penis. Sildenafil does not have a direct relaxing effect on the isolated corpus cavernosum but actively enhances the relaxing effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP in the corpus cavernosum. When the NO/cGMP pathway is activated, inhibition of PDE5 under the influence of sildenafil leads to an increase in cGMP levels in the corpus cavernosum, resulting in relaxation of smooth muscle tissue and increased blood flow to the corpus cavernosum. The activity of sildenafil against PDE5 is 10-10,000 times greater than its activity against other PDE isoenzymes (1-11).

The pharmacological effect is achieved only in the presence of sexual stimulation.

Clinical studies have shown that the average time to achieve an erection with 60% rigidity (sufficient for sexual intercourse) was 25 minutes (range from 12 to 37 minutes).

In some patients, 1 hour after taking the drug at a dose of 100 mg, a mild and transient impairment of the ability to distinguish colors (blue/green) was detected using the Farnsworth-Munsell 100 test; 2 hours after taking the drug, these changes were absent. It is believed that the impairment of color vision is caused by inhibition of PDE6, which is involved in the process of light transmission in the retina. Sildenafil does not affect visual acuity, contrast perception, electroretinogram, intraocular pressure, or pupil diameter.

In healthy volunteers, after a single dose of sildenafil at a dose of 100 mg, no effects on sperm motility or morphology were noted.

Pharmacokinetics

Absorption

After oral administration, Sildenafil is rapidly absorbed. The absolute bioavailability averages 41% (25-63%). After a single oral dose of 100 mg on an empty stomach, the C_max in plasma is 18 ng/mL (38 nM) and is achieved within 30-120 minutes (average 60 minutes).

When sildenafil is taken with a high-fat meal, C_max decreases by 20-40% and is achieved after 1.5-3 hours.

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 approximately 96% and does not depend on the total concentration of sildenafil.

In healthy volunteers taking Sildenafil (a single dose of 100 mg), less than 0.0002% (average 188 ng) of the administered dose was detected in semen 90 minutes after oral administration.

Metabolism

Sildenafil is metabolized primarily in the liver by the microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (minor pathway). The main circulating metabolite is formed from sildenafil by N-desmethylation. In terms of selectivity of action on PDE, the metabolite is comparable to sildenafil; its activity against PDE5 in vitro is approximately 50% of the activity of sildenafil. The concentration of the main metabolite in plasma is approximately 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism, with its T_1/2 being 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, Sildenafil is excreted as metabolites primarily through the intestines (approximately 80% of the dose) and to a lesser extent by the kidneys (approximately 13% of the dose).

Pharmacokinetics in special patient groups

In elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the concentration of free active substance in plasma is approximately 40% higher than in young (18-45 years) patients.

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

In patients with mild and moderate 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 with normal liver function in patients of the same age group. The pharmacokinetic parameters of sildenafil in patients with severe hepatic impairment have 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

The drug is taken orally, approximately 1 hour before planned sexual activity. When taken simultaneously with fatty food, the onset of action of the drug may be delayed compared to taking it on an empty stomach.

The recommended dose is 50 mg once a day. Depending on efficacy and tolerability, the dose can be increased to 100 mg or decreased to 25 mg.

The maximum single dose is 100 mg. The maximum recommended frequency of use is once a day.

In elderly patients, dose adjustment is not required.

In mild and moderate renal impairment (creatinine clearance 30-80 mL/min), dose adjustment is not required. In patients with severe renal impairment (creatinine clearance <30 mL/min), the dose should be reduced to 25 mg. Depending on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

In patients with impaired liver function, the dose of the drug should be reduced to 25 mg. Depending on efficacy and tolerability, the dose can be increased to 50 mg and 100 mg.

Concomitant use with other drugs

In patients receiving concomitant treatment with CYP3A4 inhibitors (except for ritonavir, with which simultaneous use of sildenafil is not recommended), the initial dose of sildenafil should be 25 mg.

To minimize the possibility of orthostatic hypotension in patients taking alpha-blockers, treatment with sildenafil should be started after hemodynamic stabilization. The advisability of prescribing sildenafil at an initial dose of 25 mg should be considered.

Adverse Reactions

The frequency of side effects is defined as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

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

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.

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 – cerebrovascular accident, transient ischemic attack, convulsions*, recurrent convulsions*, syncope.

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

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

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

Respiratory, thoracic and mediastinal disorders common – nasal congestion; uncommon – epistaxis, 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.

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.

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 – penile bleeding, priapism and/or prolonged erection.

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.

* 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 causal relationship between the reported 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 vision loss or decrease. Most of these patients had risk factors, particularly a small cup-to-disc ratio (‘crowded disc’), age over 50 years, diabetes, 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 twofold 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 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 an adverse effect 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.

When sildenafil was used in doses exceeding the recommended ones, the adverse events were similar to those noted above but usually occurred more frequently.

Contraindications

• Concomitant use of nitric oxide donors or organic nitrates or nitrites in any form;
• Concomitant use of PDE5 inhibitors, including Sildenafil, with guanylate cyclase stimulators, such as riociguat;
• Concomitant use with other treatments for erectile dysfunction;
• Concomitant use of ritonavir;
• 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, hypertension (BP >170/100 mm Hg) or arterial hypotension (BP <90/50 mm Hg));
• Patients with episodes of non-arteritic anterior ischemic optic neuropathy with vision loss in one eye;
• Hereditary retinal pigmentosa;
• Hypersensitivity to sildenafil or any of the components of the drug.

For the registered indication, Sildenafil is not intended for use in women, as well as in children and adolescents under 18 years of age.

With caution, the drug should be used in cases of anatomical deformation of the penis (including angulation, cavernous fibrosis, or Peyronie’s disease); diseases predisposing to priapism (such as sickle cell anemia, multiple myeloma, leukemia, thrombocytopenia); diseases accompanied by bleeding; exacerbation of gastric and duodenal ulcers; hereditary retinal pigmentosa; heart failure, unstable angina, myocardial infarction within the last 6 months, stroke, life-threatening arrhythmias, arterial hypertension (BP more than 170/100 mm Hg) or hypotension (BP less than 90/50 mm Hg); in patients with a history of episodes of non-inflammatory anterior ischemic optic neuropathy; with simultaneous use of alpha-blockers.

Use in Pregnancy and Lactation

According to the registered indication, Sildenafil 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).

Use in Renal Impairment

In mild to moderate renal impairment ( creatinine clearance 30-80 ml/min), no dose adjustment is required. In patients with severe renal impairment ( creatinine clearance <30 ml/min), the dose should be reduced.

Pediatric Use

Sildenafil is not intended for use in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Before prescribing the drug, it is necessary to collect a medical history and perform a physical examination to diagnose erectile dysfunction and determine its possible causes.

Medications 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). If an erection persists for more than 4 hours, the patient should seek immediate medical attention. If priapism therapy is not performed in a timely manner, it can 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.

Since sexual activity carries a certain risk in heart disease, 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).

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 Sildenafil compared with patients receiving placebo.

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 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 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 phenomenon and does not lead to any consequences in most patients. However, before prescribing 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 tract obstruction (e.g., aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare multiple system atrophy syndrome, manifested by severe impairment of blood pressure regulation by the autonomic nervous system.

Sildenafil should be prescribed with caution to patients taking alpha-blockers, as their concomitant use may lead to symptomatic hypotension in some sensitive patients. This effect is most likely to occur within 4 hours of taking sildenafil. To minimize the risk of postural hypotension in patients taking alpha-blockers, treatment with sildenafil should be initiated after hemodynamic parameters have stabilized in these patients. The advisability of reducing the initial dose of sildenafil should also be considered. The physician should inform patients what actions to take if symptoms of postural hypotension occur.

Visual disturbances

Rare cases of non-arteritic anterior ischemic optic neuropathy as a cause of visual impairment or loss have been reported with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as a small cup-to-disc ratio (“crowded disc”), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking.

In case of sudden visual impairment, the patient should be advised to discontinue sildenafil and consult a physician immediately.

A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase function. There is no information on the safety of sildenafil use in patients with retinitis pigmentosa.

Hearing impairment

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

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There is 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 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 treatments for erectile dysfunction

The safety and efficacy of the combined use of sildenafil with other PDE5 inhibitors or other drugs for the treatment of pulmonary hypertension containing Sildenafil, or other treatments for erectile dysfunction have not been studied, therefore the use of such combinations is not recommended.

Effect on ability to drive and operate machinery

The effect of sildenafil on the ability to drive a car and perform work requiring increased attention has not been studied. However, caution should be exercised when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions during the period of drug use, as dizziness and visual disturbances are possible.

Overdose

Symptoms In studies in healthy volunteers with a single dose of the drug up to 800 mg, adverse events were comparable to those with sildenafil at lower doses, but their frequency and severity increased. The use of the drug at a dose of 200 mg did not lead to an increase in efficacy, but increased the frequency of adverse events (headache, facial flushing, dizziness, dyspepsia, nasal congestion, visual impairment).

Treatment Symptomatic therapy should be administered. Sildenafil is not removed by hemodialysis.

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, therefore inhibitors of these isoenzymes may reduce the clearance of sildenafil.

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

A single dose of sildenafil 100 mg co-administered with erythromycin, a specific CYP3A4 inhibitor (with erythromycin taken 500 mg twice daily for 5 days), under conditions of achieving steady-state blood concentrations of erythromycin, leads to an increase in the AUC of sildenafil by 182%.

Cimetidine (at a dose of 800 mg), a non-specific CYP3A4 inhibitor, when co-administered with sildenafil (at a dose of 50 mg) in healthy volunteers, caused a 56% increase in plasma concentration of sildenafil.

Concomitant use of sildenafil (single dose of 100 mg) and the HIV protease inhibitor ritonavir (500 mg twice daily), a potent inhibitor of cytochrome P450 isoenzymes, against the background of achieving steady-state blood concentrations of ritonavir, led to an increase in the C_max of sildenafil by 300% (4-fold), and the AUC of sildenafil by 1000% (11-fold). After 24 hours, the plasma concentration of sildenafil was approximately 200 ng/ml (with sildenafil alone – approximately 5 ng/ml).

Concomitant use of sildenafil (single dose of 100 mg) and the HIV protease inhibitor saquinavir (at a dose of 1200 mg three times daily), an inhibitor of CYP3A4, against the background of achieving steady-state blood concentrations of saquinavir, led to an increase in the C_max of sildenafil by 140%, and the AUC of sildenafil by 210%. Sildenafil did not affect the pharmacokinetics of saquinavir.

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

Inhibitors of CYP2C9 (such as tolbutamide, warfarin, phenytoin), inhibitors of CYP2D6 (e.g., selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazides and thiazide-like diuretics, loop and potassium-sparing diuretics, ACE inhibitors, beta-blockers, calcium channel blockers do not affect the pharmacokinetics of sildenafil.

In studies involving healthy volunteers, concomitant use of the endothelin receptor antagonist bosentan (an inducer of isoenzyme CYP3A4 (moderate), CYP2C9 and possibly CYP2C19) at steady-state concentration (125 mg twice daily) and sildenafil at steady-state concentration (80 mg three times daily) resulted in a decrease in the AUC and C_max of sildenafil by 62.6% and 52.4%, respectively. Sildenafil increased the AUC and C_max of bosentan by 49.8% and 42%, respectively.

It is assumed that 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.

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

In healthy male volunteers, concomitant administration 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.

Grapefruit juice is a weak inhibitor of CYP3A4 and may cause a moderate increase in plasma levels of sildenafil.

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). It is unlikely that Sildenafil can affect the clearance of substrates of these isoenzymes.

Sildenafil enhances the hypotensive effect of nitrates, therefore its concomitant use with nitric oxide donors or nitrates in any form is contraindicated.

Preclinical studies have demonstrated an additional (additive) decrease in blood pressure with the combined use of PDE5 inhibitors and riociguat. Clinical trials have shown an enhancement of the hypotensive effect of PDE5 inhibitors when administered in combination with riociguat. No positive clinical effect was identified from the use of the combination of these drugs in the studied population. Concomitant use of riociguat and PDE5 inhibitors, including Sildenafil, is contraindicated.

In some sensitive patients receiving alpha-blockers, concomitant use of sildenafil may lead to symptomatic hypotension. With concomitant 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 supine systolic/diastolic blood pressure 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 orthostatic hypotension, manifested as dizziness (without fainting), have been reported in such patients.

No signs of significant interaction of sildenafil (50 mg) with 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 HIV protease inhibitors at their steady-state blood concentrations, such as saquinavir and ritonavir, which are also substrates of CYP3A4.

Sildenafil at a dose of 50 mg does not cause additional prolongation of bleeding time induced by 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 concentration averaging 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 reduction in supine blood pressure was 8 mm Hg (systolic) and 7 mm Hg (diastolic).

The use of sildenafil in combination with antihypertensive drugs does not lead to 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

The shelf life is 4 years. Do not use the drug after the expiration date.

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.