Sealex Sildenafil, 100 mg

Pharmacodynamics

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

The mechanism of action.

The realization of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the cavernous body during sexual stimulation. This in turn leads to an increase in cGMP levels, a subsequent relaxation of the smooth muscle tissue of the corpora cavernosa and an increase in blood flow.

Sildenafil does not have a direct relaxing effect on the isolated human cavernous body, but it enhances the effect of nitric oxide (NO) by inhibiting FDE5, which is responsible for the breakdown of cGMP.
Sildenafil is selective against FDE5 in vitro, its activity against FDE5 exceeds activity against other known phosphodiesterase isoenzymes: FDE6 – 10 times; FDE1 – more than 80 times; FDE2, FDE4, FDE7-FDE11 – more than 700 times.

Sildenafil is 4,000 times more selective for FDE5 compared to FDEZ, which is of critical importance because FDEZ 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 is linear.

Intake

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (25% to 63%). In vitro sildenafil at a concentration of about 1.7 ng/ml (3.5 nM) inhibits human FDE5 activity by 50%.

After a single dose of sildenafil at a dose of 100 mg, the average maximum plasma concentration (Cmax) of free sildenafil in men is about 18 ng/ml (38 nM). Cmax when sildenafil is taken orally on an empty stomach is reached on average within 90 min.

If fatty foods are taken in combination, the absorption rate is decreased: Cmax is decreased by 29% on average, and the time to maximum concentration (Tmax) is increased by 60 min, but absorption is not significantly changed (the area under the pharmacokinetic curve of concentration-time (AUC) is decreased by 11%).

Distribution

The volume of sildenafil distribution in equilibrium is on average 105 l. Binding to plasma proteins of sildenafil and its major circulating N-demethyl metabolite is approximately 96% and is independent of total drug concentration. Less than 0.0002% of the dose (188 ng on average) is detected in semen 90 min after sildenafil administration.

Metabolism

Sildenafil is metabolized primarily in the liver by the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite formed as a result of N-demethylation of sildenafil undergoes further metabolism.

The selectivity of this metabolite against FDE is comparable with that of sildenafil, and its activity against FDE5 in vitro is about 50% of the activity of sildenafil. Concentration of this metabolite in blood plasma of healthy volunteers was about 40% of sildenafil concentration. The N-demethyl metabolite undergoes further metabolism; its half-life (T1/2) is about 4 hours.

The total clearance of sildenafil is 41 l/hour and the final T1/2 is 3-5 hours. After oral administration as well as after intravenous administration sildenafil is excreted as metabolites mainly by the intestine (about 80% of the oral dose) and, to a lesser extent, by the kidneys (about 13% of the oral dose).

Pharmacokinetics in special patient groups:

Elderly patients

In the elderly (65 years and older), sildenafil clearance is decreased and free sildenafil plasma concentrations are about 40% higher than in younger patients (18-45 years). Age has no clinically significant effect on the incidence of side effects.

Renal dysfunction

In mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) renal impairment, the pharmacokinetics of sildenafil after a single oral dose of 50 mg is unchanged. In severe renal failure (creatinine clearance ≤30 ml/min) sildenafil clearance is decreased, resulting in approximately two-fold increase of the area under the pharmacokinetic curve of concentration-time (AUC by 100%) and Cmax (88%) compared to those in normal renal function in patients of the same age group.

Hepatic disorders

In patients with cirrhosis (Child-Pugh stages A and B), sildenafil clearance is decreased, resulting in increased AUC (84%) and Cmax (47%) compared to those in normal hepatic function in patients in the same age group. Pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh stage C) has not been studied.

Indications

The treatment of erectile dysfunction characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory intercourse.

Sildenafil is effective only in the presence of sexual stimulation.

Active ingredient

Composition

Active ingredient:

sildenafil citrate – 140.5 mg (in terms of sildenafil – 100.0 mg).

Auxiliary substances:

corn starch – 223.0 mg,

microcrystalline cellulose – 110.0 mg,

magnesium stearate – 8.0 mg,

talc — 5.0 mg,

Colloidal silicon dioxide – 3.0 mg,

sodium carboxymethyl starch – 10.0 mg.

Film coating blue – 12.0 mg:

Titanium dioxide – 1.3 mg, Brilliant Blue dye – 1.9 mg,

Hypromellose – 3.8 mg,

Macrogol – 4.5 mg,

Talc – 0.5 mg.

How to take, the dosage

Ingestion.

The recommended dose for most adult patients is 50 mg approximately | hour before sexual activity. Depending on efficacy and tolerability, the dose may be increased to 100 mg. The maximum recommended dose is 100 mg. The maximum recommended frequency of use is once daily.

Elderly patients

There is no need to adjust the dose of sildenafil.

Interaction

The effect of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the action of cytochrome CYP3A4 isoenzymes (main pathway) and CYP2C9, therefore inhibitors of these isoenzymes may decrease sildenafil clearance, and inducers, respectively, increase sildenafil clearance.

Cytochrome CYP3A4 isoenzyme inhibitors (ketoconazole, erythromycin, cimetidine) have been observed to decrease sildenafil clearance. Cimetidine (800 mg), a non-specific inhibitor of cytochrome CYP3A4 isoenzyme, when combined with sildenafil (50 mg) causes an increase in plasma concentration of sildenafil by 56%.

Single administration of sildenafil 100 mg together with erythromycin (500 mg/day 2 times daily for 5 days), a specific inhibitor of cytochrome CYP3A4 isoenzyme, on the background of achieving a constant concentration of erythromycin in blood, leads to an increase of sildenafil AUC by 182%.

When sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times daily), an HIV protease inhibitor and cytochrome CYP3A4 isoenzyme, were taken together with saquinavir at a constant concentration in the blood, sildenafil Cmax was increased by 140% and AUC was increased by 210%.

Sildenafil has no effect on the pharmacokinetics of saquinavir. Stronger inhibitors of CYP3A4 cytochrome isoenzyme, such as ketoconazole and itraconazole, may also cause greater changes in the pharmacokinetics of sildenafil.

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg twice daily), an HIV protease inhibitor and strong cytochrome P450 inhibitor, against reaching a steady blood concentration of ritonavir leads to an increase in Cmax of sildenafil by 300% (4 times) and AUC by 1000% (11 times). After 24 hours the plasma concentration of sildenafil is about 200 ng/ml (after a single use of sildenafil – 5 ng/ml).

If sildenafil is taken at the recommended doses in patients receiving concomitant strong CYP3A4 cytochrome isoenzyme inhibitors, the Cmax of free sildenafil does not exceed 200 nM and the drug is well tolerated.

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

CYP2C9 cytochrome isoenzyme inhibitors (tolbutamide, warfarin), CYP2D6 cytochrome isoenzyme inhibitors (selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and thiazide-like diuretics, ACE inhibitors and calcium antagonists, have no effect on sildenafil pharmacokinetics.

Asithromycin (500 mg/day for 3 days) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T1/2 of sildenafil or its major circulating metabolite.

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC5o >150 μmol). When sildenafil is taken at the recommended doses, its Cmax 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 with long-term use of the latter and when prescribed for acute indications. Therefore, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When the α-adrenoblocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, and 100 mg) were taken concomitantly 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 mmHg and 8/4 mmHg, respectively, and in the standing position were 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively.

Rare cases of symptomatic postural hypotension, manifested as dizziness (without syncope), have been reported in these patients. In some sensitive patients receiving α-adrenoblockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There are no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by cytochrome CYP2C9 isoenzyme. Sildenafil (100 mg) has no effect on the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, when their blood levels are constant.

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

Sildenafil (50 mg) does not increase the hypotensive effects of alcohol in healthy volunteers at a maximum blood alcohol concentration of 0.08% (80 mg/dL) on average.

In patients with arterial hypertension, there is no evidence of interaction of sildenafil (100 mg) with amlodipine. The mean additional reduction of BP in the supine position is 8 mm Hg (systolic) and 7 mm Hg (diastolic).

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

When using sildenafil concomitantly with bosentan (inducer of CYP3A4, CYP2C9 isoenzymes) there was a 62.6% and 52.4% decrease in AUC and Cmax of sildenafil, respectively. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively.

Special Instructions

To diagnose erectile dysfunction, determine its possible causes, and choose an appropriate treatment, a complete medical history and a thorough physical examination must be taken.

The erectile dysfunction therapy should be used with caution in patients with anatomic penile deformities (angulation, cavernous fibrosis, Peyronie’s disease), or in those with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

The drugs intended to treat erectile dysfunction should not be prescribed for men for whom sexual activity is undesirable.

If an erection persists for more than 4 hours, medical help should be sought. If priapism therapy is not administered in a timely manner, it can lead to damage to penile tissue and permanent loss of potency.

Sexual activity poses some risk if you have heart disease, so your doctor should refer you for a cardiovascular exam before starting any therapy for erectile dysfunction.

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

In clinical trials, there have been no differences in the incidence of myocardial infarction (1.1 per 100 people per year) or cardiovascular mortality rate (0.3 per 100 people per year) in patients receiving sildenafil compared to patients receiving placebo.

Cardiovascular Complications

In the postmarketing 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) that were temporarily associated with sildenafil use.

The majority, but not all, of these patients had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some occurred after sildenafil without subsequent sexual activity. A direct relationship between these adverse events and these or other factors cannot be established.

Hypotension

Sildenafil has a systemic vasodilatory effect resulting in a transient decrease in BP, which is not clinically significant and has no effect in most patients. However, before prescribing sildenafil, the physician should carefully evaluate the risk of possible adverse vasodilatory effects in patients with related conditions, especially with sexual activity.

The increased susceptibility to vasodilators is seen in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), and with the rare multiple systemic atrophy syndrome manifested by severe autonomic nervous system BP dysregulation.

Because co-administration of sildenafil and α-adrenoblockers may lead to symptomatic hypotension in some sensitive patients, caution should be exercised when prescribing the drug in patients taking α-adrenoblockers (see section “Interaction with other drugs”).

In order to minimize the risk of postural hypotension in patients taking α-adrenoblockers, sildenafil should be started only after hemodynamic stabilization has been achieved in these patients. It should also be considered whether it is reasonable to reduce the initial dose of sildenafil (see section “Dosage and administration”). The physician should inform patients about what actions should be taken if symptoms of postural hypotension occur.

Visual impairment

Rare cases of anterior nonarteritic ischemic optic neuropathy have been reported as a cause of visual impairment or loss with all FDE5 inhibitors, including sildenafil.

The majority of these patients had risk factors such as optic disc excavation (deepening), age over 50 years, diabetes mellitus, arterial hypertension, coronary heart disease, hyperlipidemia and smoking. A small number of patients with hereditary retinitis pigmentosa have genetically determined disorders of retinal phosphodiesterase function.

There is no information about the safety of sildenafil in patients with retinitis pigmentosa.

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden hearing impairment or loss associated with the use of all FDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or hearing loss.

There is no causal relationship between the use of FDE5 inhibitors and sudden hearing impairment or hearing loss. Consult a physician immediately if there is any sudden hearing loss or hearing loss with sildenafil.

Bleeding

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 in patients with a tendency to bleeding or exacerbation of peptic ulcer disease, so sildenafil should be used with caution in these patients (see section “Caution”).

The incidence of nasal bleeding in patients with LH associated with diffuse connective tissue disease was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). Patients who received sildenafil in combination with a vitamin K antagonist had a higher rate of nasal bleeding (8.8%) than patients who did not take a vitamin K antagonist (1.7%).
Use in combination with other treatments for erectile dysfunction.

The safety and effectiveness of sildenafil together with other erectile dysfunction treatment agents have not been studied, so the use of such combinations is not recommended (see section “Contraindications”).

Synopsis

Pills, blue film-coated, biconvex, diamond-shaped with cut and rounded edges, engraved “1005 SAO one.

On cross section the tablet core is white or almost white.

Pharmacotherapeutic group: erectile dysfunction treatment – FDE5 inhibitor.

Contraindications

1. Hypersensitivity to sildenafil or any other component of the drug. Use in patients receiving nitric oxide donators, organic nitrates or nitrites in any form continuously or intermittently, because sildenafil enhances the hypotensive effect of nitrates (see section “Interaction with other medicinal products”).

2. use in patients for whom sexual activity is undesirable (e.g., with severe cardiovascular disease, such as severe heart failure, unstable angina).

3. Arterial hypotension (blood pressure less than 90/50 mm Hg).

4. Severe chronic renal failure.

5. 5. Have had a cerebral circulation disorder or myocardial infarction within the past 6 months.

6. Severe liver dysfunction.

7. Hereditary degenerative retinal diseases, including retinitis pigmentosa. Concurrent use of ritonavir.

The safety and effectiveness of sildenafil when used in combination with other erectile dysfunction treatments have not been studied, so these combinations are not recommended (see section “Special Precautions”).

For the registered indication, sildenafil is not indicated for use in children

under 18 years of age. For the registered indication, sildenafil is not indicated for use in women.

With caution

1. Arterial hypertension (BP > 170/100 mm Hg).

2. Heart failure.

3. Life-threatening arrhythmias.

4. Anatomical deformity of the penis (angulation, cavernous fibrosis or Peyronie’s disease) (see section “Special Precautions”).

5. diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia) (see section “Special Precautions”). Patients with a history of episodes of anterior nonarteritic ischemic optic neuropathy.

6. diseases accompanied by bleeding.

7. Exacerbation of gastric and duodenal ulcers.

8. Simultaneous use of alpha-adrenoblockers.

The use in pregnancy and during breastfeeding

The drug is not intended for use in women according to the registered indication.

Side effects

Sildenafil side effects are usually mild to moderate

In fixed-dose studies, it has been shown that the frequency of some adverse events increases with increasing dose.

Disorders of the general condition: chest pain, general weakness, irritability, a feeling of fever, a feeling of fatigue.

Allergic reactions: hypersensitivity reactions (including skin rash), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Central and peripheral nervous system disorders: somnolence, stroke, syncope, hypoesthesia, transient ischemic attack, convulsions including recurrent ones.

Cardiovascular system disorders: tachycardia, increased or decreased BP, myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, “hot flashes” and palpitations, sudden death.

Respiratory disorders: nasal bleeding, stuffy sinuses, feeling of tightness in the throat, dry nasal mucosa, nasal mucosa edema.

Digestive system disorders: vomiting, nausea, dry oral mucosa, dyspepsia, abdominal pain, gastroesophageal reflux disease, oral mucosa hypoesthesia.

Visual disorders: Eye pain, eye redness/sclera injections, conjunctival lesions, tear production disorders, anterior ischemic optical neuropathy, retinal vascular occlusion, visual field defects, photophobia, photopsia, diplopia, glaucoma, decreased visual acuity, Myopia, asthenopia, retinal edema, retinal vascular disease, eye discomfort, mydriasis, blurred vision, visual disturbances, retinal hemorrhage, atherosclerotic retinopathy, eye irritation, eyelid edema, sclera discoloration.

Hearing disorders: vertigo, tinnitus, deafness, tinnitus.

Musculoskeletal disorders: myalgia, pain in the extremities.

Reproductive system disorders: prolonged erection and/or priapism, hematospermia and bleeding from the penis.

Urogenital system disorders: hematuria.

Overdose

Single doses of up to 800 mg had similar adverse events to those of lower doses, but were more frequent.

Similarities