Gent^® (Spray) Instructions for Use

Marketing Authorization Holder

Pharmamed, LLC (Russia)

Manufactured By

PharmVILAR NPO, LLC (Russia)

Quality Control Release

PharmVILAR NPO, LLC (Russia)

Or

Pharmamed, LLC (Russia)

Contact Information

Pharmamed LLC (Russia)

ATC Code

G04BE03 (Sildenafil)

Active Substance

Sildenafil

Dosage Form

Gent®

Dosed oral spray 12.5 mg/1 dose: 5 ml (32 doses) or 10 ml (64 doses) bottle with dosing pump

Dosage Form, Packaging, and Composition

Dosed oral spray as a clear yellowish or greenish-yellow liquid with a characteristic odor.

Excipients: propylene glycol, ethanol, macrogol 400 (polyethylene glycol 400), purified water, hydrochloric acid, lemon oil, sucralose, racemic menthol.

5 ml (32 doses) – type I dark glass bottles (1) with an oral spray dispenser* – cardboard boxes.
10 ml (64 doses) – type I dark glass bottles (1) with an oral spray dispenser* – cardboard boxes.

* The oral spray dispenser may be supplied with a protective cap.
An emblem-sticker may be included in the cardboard box.
A self-adhesive sticker for opening control is applied to the cardboard box.

Clinical-Pharmacological Group

Erectile dysfunction treatment drug. PDE5 inhibitor

Pharmacotherapeutic Group

Erectile dysfunction treatment agent – PDE5 inhibitor

Pharmacological Action

Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), which causes the breakdown of cGMP in the corpus cavernosum of the penis.

Mechanism of action

Sildenafil restores impaired erectile function under conditions of sexual stimulation by increasing blood flow to the cavernous bodies of the penis. The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates the enzyme guanylate cyclase, leading to an increase in the concentration of cyclic guanosine monophosphate (cGMP). In turn, cGMP causes relaxation of vascular smooth muscles and, accordingly, blood flow into the corpus cavernosum of the penis. Sildenafil does not have a direct relaxing effect on the smooth muscles of the corpus cavernosum but enhances the relaxing effect of NO on this tissue and increases blood flow in the penis. A prerequisite for the effectiveness of sildenafil is sexual stimulation.

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

Preclinical safety data

Preclinical data obtained from standard repeated-dose toxicity studies, genotoxicity, carcinogenic potential, and reproductive and ontogenetic toxicity studies did not reveal any specific harm to humans.

Pharmacokinetics

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

Absorption

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 the plasma of men is about 18 ng/ml (38 nM). C_max when taking sildenafil orally on an empty stomach is reached on average within 60 minutes (range 30 minutes to 120 minutes). When taken with a high-fat meal, the rate of absorption decreases: C_max decreases by an average of 29%, and T_max increases by 60 minutes, but the extent of absorption does not change significantly (AUC decreases by 11%).

Distribution

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

Metabolism

Sildenafil is metabolized mainly in the liver by the cytochrome CYP3A4 isoenzyme (main pathway) and the cytochrome CYP2C9 isoenzyme (minor pathway). The main circulating active metabolite, formed as a result of N-desmethylation of sildenafil, undergoes further metabolism. The selectivity of this metabolite for PDE in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-desmethyl metabolite undergoes further metabolism; T_1/2 is about 4 hours.

Excretion

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

Pharmacokinetics in special patient groups

Elderly patients. In healthy elderly patients (over 65 years of age), the clearance of sildenafil is reduced, and the plasma concentration of free sildenafil is approximately 40% higher than in young patients (18-45 years). Age does not have a clinically significant effect on the incidence of adverse reactions.

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

Hepatic impairment. In patients with liver cirrhosis (Child-Pugh class A and B), the clearance of sildenafil is reduced, leading to an increase in AUC (84%) and C_max (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) 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.

During the first use or after a break in using the drug, press the sprayer sharply several times, directing the spray into the air, until a uniform spray cloud is formed.

When using, the bottle should be held vertically with the sprayer facing up. Bring the bottle close to the mouth and, with a short, sharp movement, press the sprayer to inject the solution (one dose contains 12.5 mg of sildenafil). Repeat the injection procedure until the recommended dose is reached and drink with water.

The solution should not be inhaled.

The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity (the effect of the drug begins approximately 30 minutes after administration). Depending on efficacy and tolerability, the dose can be increased to 100 mg or decreased to 25 mg.

The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Special patient groups

The recommended starting dose of Gent^® for patients aged 65 years and older is 25 mg. Considering the efficacy and tolerability of the starting dose, if necessary, a stepwise increase in the dose to 50 mg or 100 mg is possible.

For mild and moderate renal failure (CrCl 30-89 ml/min), no dose adjustment of sildenafil is required; for severe renal failure (CrCl <30 ml/min), the starting dose of Gent^® should be 25 mg.

Since the excretion of sildenafil is impaired in patients with liver damage (in particular, cirrhosis), the starting dose of Gent^® should be 25 mg.

The use of Gent^® is not indicated for children and adolescents under 18 years of age.

Concomitant use with other medicines

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

To minimize the risk of orthostatic hypotension in patients taking alpha-blockers, Gent^® should be initiated only after stable hemodynamics have been achieved in these patients. The advisability of reducing the starting dose of sildenafil should also be considered.

Concomitant use with ritonavir is not recommended. In any case, the maximum dose of Gent^® should not exceed 25 mg, and the frequency of use should not exceed once every 48 hours (see section “Drug Interactions”).

Adverse Reactions

The most frequent adverse reactions with sildenafil were headache and flushing. As a rule, adverse reactions are mild to moderate and transient. The frequency of some adverse reactions is dose-dependent.

Adverse reactions possible during the use of sildenafil are distributed by system-organ classes with an indication of the frequency of their occurrence according to WHO recommendations: very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders uncommon – anemia, leukopenia.

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

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, insomnia, hyperreflexia, hypoesthesia; rare – seizures, recurrent seizures, syncope, cerebrovascular disorders, transient ischemic attack.

Psychiatric disorders uncommon – depressive symptoms, unusual dreams.

Eye disorders common – blurred vision, visual impairment, cyanopsia; uncommon – eye pain, photophobia, chromatopsia, red eyes/injected sclera, change in brightness perception, mydriasis, conjunctivitis, eye hemorrhage, cataract, lacrimal gland dysfunction; rare – eyelid and periorbital edema, feeling of dryness in the eyes, presence of halos around lights, eye fatigue, yellow vision (xanthopsia), red vision (erythropsia), conjunctival hyperemia, eye mucosa irritation, eye discomfort; frequency unknown – non-arteritic anterior ischemic optic neuropathy (NAION), retinal vein occlusion, visual field defect, diplopia, temporary loss of vision or decreased visual acuity, increased intraocular pressure, retinal edema, retinal vascular disease, vitreous detachment/vitreous traction.

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

Cardiac disorders common – flushing; uncommon – tachycardia, palpitations, increased heart rate, unstable angina, AV block, myocardial infarction, decreased blood pressure, increased blood pressure, cerebral vascular thrombosis, cardiac arrest, heart failure, abnormal ECG readings, 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 – 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 (Lyell’s syndrome).

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 – gynecomastia (men), ejaculation disorder, genital edema, anorgasmia, hematospermia, penile tissue damage; rare – prolonged erection and/or priapism.

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.

Cardiovascular complications

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

Visual disturbances

In rare cases, during the post-registration use of all PDE5 inhibitors, including sildenafil, non-arteritic anterior ischemic optic neuropathy (NAION) has been reported – a rare disease and cause of vision loss or impairment. Most of these patients had risk factors, in particular, a small cup-to-disc ratio (“crowded disc”), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed the association of recent use of PDE5 inhibitor class drugs with the acute onset of NAION. The results indicate an approximately 2-fold increased 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 risk of adverse effects of PDE5 inhibitors. PDE5 inhibitors, including Sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the risk (see section “Special Instructions”).

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

If any of the side effects listed in the instructions get worse, or if any other side effects not listed in the instructions are noticed, the patient should inform the doctor.

Contraindications

• Hypersensitivity to sildenafil or to any other component of the drug;
• Use in patients receiving continuously or intermittently nitric oxide donors, organic nitrates or nitrites in any form, since Sildenafil enhances the hypotensive effect of nitrates (see section “Drug Interactions”);
• Concomitant use with guanylate cyclase stimulators, such as riociguat, as this may lead to symptomatic hypotension (see section “Drug Interactions”);
• Concomitant use with other means of treating erectile dysfunction has not been studied, therefore the use of such combinations is not recommended (see section “Special Instructions”);
• Severe hepatic failure (Child-Pugh class C);
• Concomitant use of ritonavir;
• 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 (NAION) with vision loss in one eye, regardless of whether these episodes were associated with previous use of a PDE5 inhibitor.
• Diagnosed hereditary degenerative retinal disorders, including hereditary retinitis pigmentosa (see section “Special Precautions”);
• Female gender;
• Age under 18 years (efficacy and safety not established).

With caution anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie’s disease) (see section “Special Precautions”); conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section “Special Precautions”); conditions accompanied by bleeding; impaired liver function (Child-Pugh class A and B); peptic ulcer of the stomach and duodenum in the acute phase; severe renal failure (CrCl <30 ml/min); patients with a history of episodes of anterior non-arteritic ischemic optic neuropathy (see section “Special Precautions”); concomitant use of alpha-adrenergic blockers.

Use in Pregnancy and Lactation

The drug is not intended for use in women.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (Child-Pugh class C).

The drug should be used with caution in impaired liver function (Child-Pugh class A and B).

Use in Renal Impairment

The drug should be used with caution in severe renal failure (CrCl <30 ml/min).

Pediatric Use

Contraindicated for use under 18 years of age.

Geriatric Use

The recommended initial dose of Gent^® for patients aged 65 years and older is 25 mg. Depending on the efficacy and tolerability of the initial dose, a stepwise dose increase to 50 mg or 100 mg is possible if necessary.

Special Precautions

A complete medical history and a thorough physical examination are necessary to diagnose erectile dysfunction, determine its possible causes, and select adequate treatment.

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) (see section “With caution”).

During post-marketing surveillance of sildenafil, cases of prolonged erection and priapism have been reported.

If an erection persists for more than 4 hours, the patient should seek immediate medical attention.

If priapism therapy is not administered promptly, it may lead to penile tissue damage and irreversible loss of potency.

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

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

Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke within the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mmHg) or hypotension (BP <90/50 mmHg).

The use of sildenafil in such patients is contraindicated (see section “Contraindications”).

There is 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 to patients receiving placebo.

Cardiovascular complications

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, 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 reactions 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.

Arterial hypotension

Sildenafil has a systemic vasodilatory effect, leading to a transient decrease in BP, which is not a clinically significant phenomenon and does not lead to any consequences in most patients.

Nevertheless, before prescribing sildenafil, the physician should assess the risk of possible undesirable manifestations of the vasodilatory effect of sildenafil in patients with relevant conditions, especially during sexual activity.

Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe impairment of blood pressure regulation by the autonomic nervous system.

Caution should be exercised when using sildenafil concomitantly with alpha-adrenergic blockers due to the risk of symptomatic hypotension in some sensitive patients (see section “Drug Interactions”).

To minimize the risk of postural hypotension in patients taking alpha-adrenergic blockers, sildenafil should be initiated only after hemodynamic stabilization has been achieved.

The advisability of reducing the initial dose of Gent^® should also be considered (see section “Dosage and Administration”).

The physician should inform the patient about what actions to take in case of symptoms of postural hypotension.

Visual disturbances

Rare cases of NAION – a rare condition and cause of decreased or loss of vision – have been reported during the post-marketing period with the use of PDE5 inhibitors, including sildenafil.

Most of these patients had risk factors such as a reduced cup-to-disc ratio (“crowded disc”), age over 50 years, diabetes mellitus, arterial hypertension, coronary artery disease, hyperlipidemia, and smoking.

An observational study assessed the association of recent use of PDE5 inhibitor class drugs with the acute onset of NAION.

The results indicate an approximately 2-fold increased risk of NAION within 5 half-lives after taking a PDE5 inhibitor.

According to published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 men aged ≥50 years in the general population.

Patients should be advised to discontinue sildenafil therapy and consult a physician immediately in case of sudden vision loss.

Individuals who have already experienced an episode of NAION have an increased risk of NAION recurrence.

Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential chance of adverse effects from PDE5 inhibitors.

PDE5 inhibitors, including Sildenafil, should be used with caution in these patients and only in situations where the expected benefit outweighs the risk (see section “Adverse Reactions”).

A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase function.

There is no safety information on the use of sildenafil in patients with retinitis pigmentosa; therefore, such patients should not use Sildenafil (see section “Contraindications”).

Hearing impairments

Cases of sudden hearing impairment or loss associated with the use of PDE5 inhibitors, including Sildenafil, have been reported.

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 hearing loss has not been established (see section “Adverse Reactions”).

In case of sudden hearing impairment or hearing loss while taking sildenafil, the patient should consult a physician immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro.

There is no safety data on the use of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers; therefore, Sildenafil should be used with caution in these patients (see section “With caution”).

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 3.0%, 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%).

Gastric and duodenal ulcer

There is no safety data on the use of sildenafil in patients with a tendency to bleeding; therefore, the drug should be used with caution in patients with exacerbation of gastric and duodenal ulcer.

Concomitant use with other treatments for erectile dysfunction

Concomitant use of Gent^® with other PDE5 inhibitors (avanafil, vardenafil, tadalafil, udenafil), other drugs for the treatment of pulmonary arterial hypertension containing Sildenafil, or other treatments for erectile dysfunction is not recommended, as the efficacy and safety of concomitant use have not been studied (see section “Contraindications”).

Excipients

The medicinal product Gent^® contains propylene glycol, which may cause symptoms similar to alcohol intake; a small amount of ethanol (alcohol), less than 100 mg per dose.

Effect on ability to drive and operate machinery

Sildenafil intake has a minor influence on the ability to drive and operate machinery.

However, since dizziness, decreased BP, chromatopsia, blurred vision, and other adverse reactions may develop while taking sildenafil (see section “Adverse Reactions”), caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Individual response to the drug in these situations should also be carefully considered, especially at the beginning of treatment and when changing the dosage regimen.

Overdose

With a single dose of sildenafil up to 800 mg, adverse reactions were comparable to those with lower doses of the drug but occurred more frequently.

Treatment is symptomatic. Hemodialysis does not accelerate the clearance of sildenafil, as the latter is highly bound to plasma proteins and is not excreted by the kidneys.

Drug Interactions

Effect of other drugs on the pharmacokinetics of sildenafil

Sildenafil is metabolized primarily by the cytochrome isoenzymes CYP3A4 (major pathway) and CYP2C9 (minor pathway); 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 concomitant 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 sildenafil plasma concentration.

A single dose of 100 mg sildenafil co-administered with erythromycin (500 mg twice daily for 5 days), a moderate inhibitor of the cytochrome CYP3A4 isoenzyme, at steady-state erythromycin concentration, leads to a 182% increase in sildenafil AUC.

When sildenafil (single dose 100 mg) and saquinavir (1200 mg three times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme inhibitor, were co-administered at steady-state saquinavir concentration, 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 (single dose 100 mg) and ritonavir (500 mg twice daily), an HIV protease inhibitor and a strong cytochrome P450 inhibitor, at steady-state ritonavir concentration, leads to an increase in sildenafil C_max by 300% (4-fold), and AUC by 1000% (11-fold).

After 24 hours, the plasma concentration of sildenafil is about 200 ng/ml (after a single dose of sildenafil alone – 5 ng/ml).

This is consistent with the effect of ritonavir on a wide range of cytochrome P450 substrates.

Sildenafil does not affect the pharmacokinetics of ritonavir.

Given these data, concomitant use of ritonavir and sildenafil is not recommended.

In any case, the maximum dose of sildenafil under no circumstances should exceed 25 mg within 48 hours.

If Sildenafil is taken at recommended doses by patients simultaneously receiving strong cytochrome 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.

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

Sildenafil increased the AUC and C_max of bosentan by 49.8% and 42%, respectively.

It is assumed that concomitant use of sildenafil with potent inducers of the CYP3A4 isoenzyme, such as rifampicin, may lead to a greater decrease in sildenafil plasma concentration.

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.

Effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 (inhibitory molar concentration 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 potentiates the hypotensive effect of nitrates, both during their long-term use and when prescribed for acute indications.

Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

With the concomitant use of the alpha-adrenergic blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) in patients with benign prostatic hyperplasia and stable hemodynamics, the mean additional decrease in systolic BP/diastolic BP in the supine position was 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, and in the standing position – 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively.

Rare cases of symptomatic postural hypotension, manifested as dizziness (without fainting), have been reported in such patients.

In some sensitive patients receiving alpha-adrenergic blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

No signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme, were found.

Sildenafil (100 mg) does not affect the pharmacokinetics of the HIV protease inhibitor saquinavir, which is a substrate of the cytochrome CYP3A4 isoenzyme, at its steady-state level.

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

Sildenafil (50 mg) does not cause additional prolongation of bleeding time when taking acetylsalicylic acid (150 mg).

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

In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were found.

The mean additional decrease in BP in the supine position was 8 mmHg (systolic) and 7 mmHg (diastolic).

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

Storage Conditions

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

Shelf Life

Shelf life – 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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