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

Treatment of erectile dysfunction, characterized by the inability to achieve or maintain a penile erection sufficient for satisfactory sexual intercourse.

Sildenafil is effective only in the presence of sexual stimulation.

Pharmacological effect

Pharmacodynamics

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

Mechanism of action.

The implementation of the physiological mechanism of erection is associated with the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. This, in turn, leads to an increase in cGMP levels, subsequent relaxation of the smooth muscle tissue of the corpus cavernosum and increased blood flow.

Sildenafil does not have a direct relaxant effect on the isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting PDE5, which is responsible for the breakdown of cGMP.
Sildenafil is selective for PDE5 in vitro, its activity against PDE5 exceeds that of other known phosphodiesterase isoenzymes: PDE6 – 10 times; PDE1 – more than 80 times; PDE2, PDE4, PDE7-PDE11 – more than 700 times.

Sildenafil is 4000 times more selective for PDE5 compared to PDEZ, which is of utmost importance since PDEZ is one of the key enzymes in the regulation of myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Pharmacokinetics

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

Suction

After oral administration, sildenafil is rapidly absorbed. Absolute bioavailability averages about 40% (from 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 dose of sildenafil 100 mg, the average maximum concentration of free sildenafil in blood plasma (Cmax) in men is about 18 ng/ml (38 nM). Cmax when taking sildenafil orally on an empty stomach is achieved on average within 90 minutes.

When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and the time to reach maximum concentration (Tmax) increases by 60 minutes, but the degree of absorption does not significantly change (the area under the concentration-time pharmacokinetic curve (AUC) decreases by 11%).

Distribution

The volume of distribution of sildenafil at steady state averages 105 liters. The plasma protein binding of sildenafil and its main circulating N-demethyl metabolite is approximately 96% and is independent of the total drug concentration. Less than 0.0002% of the dose (average 188 ng) was found in semen 90 minutes after taking sildenafil.

Metabolism

Sildenafil is metabolized mainly in the liver under the influence of the cytochrome isoenzyme CYP3A4 (major pathway) and the cytochrome isoenzyme CYP2C9 (minor pathway). The main circulating active metabolite, resulting from N-demethylation of sildenafil, undergoes further metabolism.

The selectivity of this metabolite for PDE is comparable to that of sildenafil, and its activity against PDE5 in vitro is about 50% of the activity of sildenafil. The concentration of the metabolite in the blood plasma of healthy volunteers was about 40% of the concentration of sildenafil. The N-demethyl metabolite undergoes further metabolism; its half-life (T1/2) is about 4 hours.

Removal

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

Pharmacokinetics in special groups of patients:

Elderly patients

In the elderly (65 years and older), the clearance of sildenafil is reduced, and the concentration of free sildenafil in plasma is approximately 40% higher than in young people (18-45 years). Age does not have a clinically significant effect on the incidence of side effects.

Renal dysfunction

With mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-49 ml/min) degrees of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (creatinine clearance ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in the area under the pharmacokinetic concentration-time curve (AUC at 100%) and Cmax (88%) compared to those with normal renal function in patients of the same age group.

Liver dysfunction

In patients with liver cirrhosis (stages A and B according to the Child-Pugh classification), the clearance of sildenafil is reduced, which leads to an increase in AUC (84%) and Cmax (47%) compared to those with normal liver function in patients of the same age group. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.

Special instructions

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination.

Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie’s disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section “Caution”).

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

If an erection persists for more than 4 hours, you should seek medical help. If priapism therapy is not carried out in a timely manner, this can lead to damage to the tissue of the penis and irreversible loss of potency.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the condition of the cardiovascular system.

Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg).

Clinical studies showed no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular death (0.3 per 100 people per year) 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 events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) were reported, which were temporarily associated with the use of sildenafil.

Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating 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 undesirable manifestations of the vasodilating effect in patients with relevant diseases, especially against the background of 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 dysregulation of blood pressure from the autonomic nervous system.

Since the combined use of sildenafil and α-blockers can lead to symptomatic hypotension in some sensitive patients, the drug should be prescribed with caution to patients taking α-blockers (see section “Interaction with other drugs”).

To minimize the risk of postural hypotension in patients taking α-blockers, sildenafil should be started only after hemodynamic stability has been achieved in these patients. You should also consider the advisability of reducing the initial dose of sildenafil (see section “Dosage and Administration”). The physician should inform patients about what actions to take if symptoms of postural hypotension occur.

Visual impairment

Rare cases of anterior non-arteritic ischemic optic neuropathy as a cause of deterioration or loss of vision have been reported with the use of all PDE5 inhibitors, including sildenafil.

Most of these patients had risk factors such as optic disc excavation, age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases.

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

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing.

A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. If there is a sudden deterioration in hearing or hearing loss while taking sildenafil, you should consult your doctor immediately.

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 gastric and duodenal ulcers, so sildenafil should be used with caution in these patients (see section “With caution”).

The incidence of epistaxis in patients with PH 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%). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).
Use in conjunction with other means of treating erectile dysfunction.

The safety and effectiveness of sildenafil in combination with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section “Contraindications”).

Effect on the ability to drive a car and operate machinery

Active ingredient

Sildenafil

Composition

Active ingredient:

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

Excipients:

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, Diamond Blue dye – 1.9 mg,

hypromellose – 3.8 mg,

macrogol – 4.5 mg,

talc – 0.5 mg.

Contraindications

1. Hypersensitivity to sildenafil or any other component of the drug. Use in patients receiving continuous or intermittent nitric oxide donors, organic nitrates or nitrites in any form, since sildenafil enhances the hypotensive effect of nitrates (see section “Interaction with other drugs”).

2. Use in patients for whom sexual activity is undesirable (for example, with severe cardiovascular diseases such as severe heart failure, unstable angina).

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

4. Chronic renal failure of severe severity.

5. A history of cerebrovascular accident or myocardial infarction within the last six months.

6. Severe liver dysfunction.

7. Hereditary degenerative diseases of the retina, including retinitis pigmentosa. Concomitant use of ritonavir.

The safety and effectiveness of sildenafil when used in combination with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such

combinations are not recommended (see section “Special instructions”).

According to its registered indication, sildenafil is not intended for use in children

up to 18 years old. According to the registered indication, sildenafil is not intended for

use in women.

With caution

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

2. Heart failure.

3. Life-threatening arrhythmias.

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

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

6. Diseases accompanied by bleeding.

7. Exacerbation of peptic ulcer of the stomach and duodenum.

8. Simultaneous use of alpha-blockers.

Use during pregnancy and breastfeeding

According to its registered indication, the drug is not intended for use in women.

Side Effects

Usually the side effects of sildenafil are mild or moderate

Fixed-dose studies have shown that the incidence of some adverse events increases with increasing dose.

General condition disorders: chest pain, general weakness, irritability, feeling hot, feeling tired.

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

Disorders of the central and peripheral nervous system: drowsiness, stroke, fainting, hypoesthesia, transient ischemic attack, convulsions, incl. recurrent.

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

Respiratory disorders: nosebleeds, sinus congestion, tightness in the throat, dry nasal mucosa, swelling of the nasal mucosa.

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

Visual disorders: eye pain, eye redness/scleral injections, conjunctival damage, lacrimal dysfunction, anterior ischemic optic neuropathy, retinal vascular occlusion, visual field defects, photophobia, photopsia, diplopia, glaucoma, decreased visual acuity, myopia, asthenopia, retinal edema, retinal vascular disease, discomfort in eyes, mydriasis, blurred vision, blurred vision, retinal hemorrhage, atherosclerotic retinopathy, eye irritation, eyelid swelling, scleral discoloration.

Hearing disorders: vertigo, tinnitus, deafness, ringing in the ears.

Musculoskeletal disorders: myalgia, pain in the extremities.

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

Disorders of the genitourinary system: hematuria.

Interaction

The influence of other drugs on the pharmacokinetics of sildenafil

The metabolism of sildenafil occurs mainly under the influence of the cytochrome isoenzymes CYP3A4 (the main pathway) and CYP2C9, therefore inhibitors of these isoenzymes can reduce the clearance of sildenafil, and inducers, accordingly, increase the clearance of sildenafil.

A decrease in the clearance of sildenafil was noted with simultaneous use of inhibitors of the cytochrome CYP3A4 isoenzyme (ketoconazole, erythromycin, cimetidine). Cimetidine (800 mg), a nonspecific inhibitor of the cytochrome CYP3A4 isoenzyme, when taken together with sildenafil (50 mg), causes an increase in plasma sildenafil concentrations by 56%.

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

When co-administered with sildenafil (100 mg once) and saquinavir (1200 mg/day 3 times a day), an inhibitor of HIV protease and the cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, the Cmax of sildenafil increased by 140%, and the AUC increased by 210%.

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

The simultaneous use of sildenafil (100 mg once) and ritonavir (500 mg 2 times a day), an HIV protease inhibitor and a strong inhibitor of cytochrome P450, while achieving a constant concentration of ritonavir in the blood leads to an increase in Cmax of sildenafil by 300% (4 times), and AUC by 1000% (11 times). After 24 hours, the concentration of sildenafil in the blood plasma is about 200 ng/ml (after a single use of sildenafil alone – 5 ng/ml).

If sildenafil is taken in recommended doses by patients simultaneously receiving strong inhibitors of the cytochrome CYP3A4 isoenzyme, then the Cmax 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), the 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) has no effect on the AUC, Cmax, Tmax, elimination rate constant and T1/2 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 (IC5o >150 µmol). When sildenafil is taken at recommended doses, its Cmax is approximately 1 µmol, so it is unlikely that sildenafil could 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 they are prescribed for acute indications. In this regard, the use of sildenafil in combination with nitrates or nitric oxide donors is contraindicated.

When taking the α-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg and 100 mg) simultaneously in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional decrease in systolic/diastolic blood pressure in the supine position was 7/7 mm Hg. Art., 9/5 mm Hg. Art. and 8/4 mm Hg. Art., respectively, and in a standing position – 6/6 mm Hg. Art., 11/4 mm Hg. Art. and 4/5 mm Hg. Art., respectively.

Rare cases of symptomatic postural hypotension, manifested in the form of dizziness (without fainting), have been reported in such patients. In selected sensitive patients receiving α-blockers, concomitant use of sildenafil may lead to symptomatic hypotension.

There were no signs of significant interaction with tolbutamide (250 mg) or warfarin (40 mg), which are metabolized by the cytochrome CYP2C9 isoenzyme. Sildenafil (100 mg) does not affect the pharmacokinetics of HIV protease inhibitors, saquinavir and ritonavir, which are substrates of the cytochrome CYP3A4 isoenzyme, at their constant blood levels.

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

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

In patients with arterial hypertension, no signs of interaction between sildenafil (100 mg) and amlodipine were detected. The average additional decrease in blood pressure in the supine position is 8 mm Hg. Art. (systolic) and 7 mm Hg. Art. (diastolic).

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

With simultaneous use of sildenafil with bosentan (an inducer of CYP3A4 and CYP2C9 isoenzymes), a decrease in the AUC and Cmax of sildenafil by 62.6% and 52.4%, respectively, was observed. Sildenafil increased the AUC and Cmax of bosentan by 49.8% and 42%, respectively.

Overdose

With a single dose of the drug up to 800 mg, adverse events were

comparable to those when taking the drug in lower doses, but were more common.

Storage conditions

At a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

Shelf life: 3 years.

Do not use after expiration date.

Manufacturer

Oxford Laboratories Pvt. Ltd., India