Sildenafil 50 mg 10 pcs. film-coated tablets

Compound

Composition, release form

Female Sildenafil is an aphrodisiac drug. It is available in the form of film-coated tablets intended for oral administration. Tablets have different dosages: 25, 50 and 100 mg.

The main active ingredient is sildenafil citrate. As auxiliary components: lactose, magnesium stearate, titanium dioxide, polyvinylpyrrolidone.

Pharmacodynamics

Sildenafil is a powerful selective inhibitor of cGMP-specific PDE-5.

Mechanism of action

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 against PDE-5 in vitro, its activity against PDE-5 exceeds that against other known PDE isoenzymes: PDE-6 - 10 times; PDE-1 - more than 80 times; PDE-2, PDE-4, PDE-7 - PDE-11 - more than 700 times. Sildenafil is 4000 times more selective for PDE-5 compared to PDE-3, which is of utmost importance since PDE-3 is one of the key enzymes in the regulation of myocardial contractility.

A prerequisite for the effectiveness of sildenafil is sexual stimulation.

Clinical data

Cardiac research. The use of sildenafil in doses up to 100 mg did not lead to clinically significant ECG changes in healthy volunteers. The maximum decrease in SBP in the supine position after taking sildenafil at a dose of 100 mg was 8.3 mm Hg. Art., and DBP - 5.3 mm Hg. Art. A more pronounced, but also transient effect on blood pressure was observed in patients taking nitrates (see “Contraindications”, “Interaction”).

In a study of the hemodynamic effect of sildenafil at a single dose of 100 mg in 14 patients with severe coronary artery disease (more than 70% of patients had stenosis of at least one coronary artery), resting sBP and dBP decreased by 7 and 6%, respectively, and pulmonary sBP decreased by 9%. Sildenafil did not affect cardiac output or impair blood flow in stenotic coronary arteries, and also led to an increase (by approximately 13%) in adenosine-induced coronary flow in both stenotic and intact coronary arteries.

In a double-blind, placebo-controlled study, 144 patients with erectile dysfunction and stable angina taking antianginal drugs (except nitrates) exercised until their angina symptoms improved. The duration of the exercise was significantly longer (19.9 s; 0.9–38.9 s) in patients taking sildenafil in a single dose of 100 mg compared to patients receiving placebo.

A randomized, double-blind, placebo-controlled study examined the effect of varying the dose of sildenafil (up to 100 mg) in men (n=568) with erectile dysfunction and hypertension taking more than two antihypertensive medications. Sildenafil improved erections in 71% of men compared to 18% in the placebo group. The incidence of adverse effects was comparable to that in other patient groups, as well as in individuals taking more than three antihypertensive drugs.

Studies of visual impairments. In some patients, 1 hour after taking sildenafil at a dose of 100 mg, the Farnsworth-Munsell 100 test revealed a mild and transient impairment in the ability to distinguish shades of color (blue/green). 2 hours after taking the drug, these changes were absent. Color vision impairment is thought to be caused by inhibition of PDE6, which is involved in light transmission in the retina. Sildenafil had no effect on visual acuity, contrast perception, electroretinogram, IOP, or pupil diameter.

In a placebo-controlled crossover study of patients with proven early-onset macular degeneration (n=9), sildenafil in a single dose of 100 mg was well tolerated. There were no clinically significant changes in vision assessed by specific visual tests (visual acuity, Amsler grid, color perception, color transmission simulation, Humphrey perimeter and photostress).

Efficiency

The effectiveness and safety of sildenafil was assessed in 21 randomized, double-blind, placebo-controlled studies lasting up to 6 months in 3,000 patients aged 19 to 87 years with erectile dysfunction of various etiologies (organic, psychogenic or mixed). The effectiveness of the drug was assessed globally using an erection diary, the International Index of Erectile Function (a validated questionnaire about the state of sexual function) and a partner interview.

The effectiveness of sildenafil, defined as the ability to achieve and maintain an erection sufficient for satisfactory sexual intercourse, has been demonstrated in all studies conducted and confirmed in long-term studies lasting 1 year. In fixed-dose studies, the proportions of patients who reported that therapy improved their erections were: 62% (25 mg sildenafil dose), 74% (50 mg sildenafil dose), and 82% (100 mg sildenafil dose) versus 25 % in the placebo group). Analysis of the International Index of Erectile Function showed that in addition to improving erection, treatment with sildenafil also increased the quality of orgasm, achieved satisfaction from sexual intercourse and overall satisfaction.

According to the pooled data, among patients who reported improved erections with sildenafil treatment, 59% of patients with diabetes mellitus, 43% of patients who had undergone radical prostatectomy and 83% of patients with spinal cord injuries (versus 16, 15 and 12% in the placebo group, respectively) were included.

New in the treatment of erectile dysfunction

The problem of erectile dysfunction (ED), which has traditionally been dealt with almost exclusively by urologists and sex therapists, is now attracting the attention of doctors of other specialties due to the emergence of new possibilities for conservative treatment of this disorder.

First of all, it is necessary to determine the etiology of ED and, if possible, treat the disease itself, and not just eliminate its symptoms. It is known that ED can be caused by various factors. Some of these factors can be influenced: for example, changing the patient’s lifestyle, stopping some medications prescribed to him. In many cases, adjusting the therapy a patient receives for an internal disease can help overcome the negative sexual changes seen with some types of treatment. For example, with the development of ED in patients with arterial hypertension, thiazide diuretics and non-selective β-blockers are canceled and preference is given to calcium antagonists, angiotensin-converting enzyme inhibitors and α-blockers, which have a lesser effect on the sexual sphere (MA Khan et al., 2002; CM Ferrario, P. Levy, 2002); the use of angiotensin receptor inhibitors can even slightly increase sexual activity in men (R. Fogari, A. Zoppi, 2002).

Patients with androgen deficiency need to consult an endocrinologist to decide whether to prescribe hormone replacement therapy. Testosterone is usually prescribed in cases where other methods and agents are ineffective (primarily phosphodiesterase type 5 inhibitors - PDE-5). Testosterone hormone replacement therapy is contraindicated in patients with symptomatic prostate disease and a history of prostate cancer.

Treatment of ED itself includes non-invasive (drug therapy, use of vacuum constrictor devices) and invasive methods (intracavernous injections of vasoactive substances, surgical treatment). The advantages and disadvantages of various ED treatment methods are presented in Table 1.

Drug therapy for ED

The most effective and convenient method of treating both psychogenic and organic ED is the use of PDE-5 inhibitors. The appearance on the pharmaceutical market of the first drug from the group of PDE5 inhibitors - sildenafil citrate (Viagra) - marked a new era in the treatment of ED; relatively recently, it was “joined” by vardenafil (Levitra) and tadalafil (Cialis).

All these drugs have the same mechanism of action. During sexual stimulation, cyclic guanosine monophosphate (cGMP) accumulates in vascular smooth muscle cells due to activation of the nervous system and the release of nitric oxide. It is he who triggers a cascade of biochemical reactions leading to the occurrence and maintenance of an erection. Normally, the concentration of cGMP decreases when sexual stimulation ceases due to the destruction of PDE-5. With ED, there is a deficiency of cGMP due to various pathogenetic factors, and its destruction by PDE-5 leads to insufficient erection or its absence. PDE5 inhibitors do not have a direct relaxing effect on the corpora cavernosa, but enhance the relaxing effect of nitric oxide by inhibiting PDE5 and increasing cGMP concentrations during sexual arousal.

PDE-5 is localized primarily in cavernous tissue, although it is also found in the smooth muscles of blood vessels of other organs, lungs, kidneys, gastric cardia, and platelets. The distribution of PDE-5 in the body is quite individual, so some patients note certain undesirable effects that are common to drugs in this group and are associated with the blockade of this enzyme. Such undesirable effects include headache, hot flashes, dyspepsia (like reflux) and nasal congestion. Blockade of other PDE isoforms—a total of 11 of them are known (Table 2)—as a rule, is not clinically significant and is not accompanied by any serious undesirable effects, since all PDE-5 inhibitors are highly selective and their effect is reversible.

Compared to other drugs in this group, tadalafil blocks PDE-6 to a lesser extent (Table 3). Blockade of this PDE isoform causes transient color vision impairment; therefore, when used, there is a minimal risk of color vision impairment. On the other hand, tadalafil, compared to sildenafil and vardenafil, is less selective for PDE-11, but its blockade is not accompanied by any recorded clinical effects. This PDE isoenzyme is found in testicular tissue, however, as studies by WJ Hellstrom et al (2002) have shown, daily intake of tadalafil at a dose of 10 or 20 mg per day for 6 months does not have a negative effect on spermatogenesis.

The pharmacokinetics of sildenafil, tadalafil and vardenafil differ significantly (Table 4). All three drugs are rapidly absorbed from the gastrointestinal tract.

Bioavailability is the percentage of free drug in the blood plasma after enteral administration. Moreover, it is determined by the loss of the substance during its absorption from the digestive tract and during its first passage through the hepatic barrier. The bioavailability of sildenafil is 40%, vardenafil - 15%. The bioavailability of tadalafil (85%) is calculated indirectly, since the active substance is not soluble in water and cannot be administered intravenously.

Simultaneous intake of fatty foods reduces and delays the absorption of sildenafil. The speed and completeness of absorption of vardenafil also depend on the fat content of food: if the fat content exceeds 57%, these indicators decrease, and if it does not exceed 30%, they do not change. The rate and extent of absorption of tadalafil do not depend on food intake.

The time to reach the maximum concentration of a drug reflects the rate of its absorption and the onset of the therapeutic effect. The peak level of drug concentration in plasma is reached on average 1 hour after taking sildenafil and vardenafil. The maximum concentration of tadalafil in plasma is observed on average 2 hours after taking the drug. The clinical effect of drugs also depends on the minimum therapeutic concentration and begins to appear long before the maximum concentration is reached. A number of clinical studies have shown that in most patients the therapeutic effect of PDE-5 inhibitors appears within 30 minutes after taking them.

After a single oral dose of 100 mg of sildenafil, the maximum concentration of the drug in the blood plasma reaches 450 ng/ml; 20 mg of vardenafil - about 20.9 ng/ml; 20 mg tadalafil - 378 ng/ml. This parameter is important when comparing different forms of the same drug: for example, the maximum concentration may be lower than the minimum effective concentration at which a given substance has a therapeutic effect. Different drugs have different therapeutic concentrations, so in this case, comparison of this indicator is uninformative.

The half-life (T1/2) - the time during which the concentration of the drug in the blood decreases by half from its initial (maximum) value - is 4 hours for sildenafil and vardenafil, 17.5 hours for tadalafil. In practice, this means that in terms of duration The action of tadalafil is significantly superior to other PDE-5 inhibitors. The equilibrium concentration of tadalafil is reached on the 5th day when taken daily and exceeds the initial concentration by 1.6 times, so the drug does not have the ability to accumulate. The assumption about the possibility of accumulation of tadalafil with sufficiently frequent and regular use is not confirmed by clinical data, although there is evidence of good tolerability of the drug by men who took tadalafil for 2 years (F. Montorsi et al., 2004).

PDE5 inhibitors are metabolized via the cytochrome P450 system and are excreted primarily through the liver.

Direct comparative studies of the effectiveness and safety of PDE-5 inhibitors have not been conducted, however, due to the similarity of the mechanism of action of the above new drugs with sildenafil, comparison of their clinical effectiveness in the treatment of ED makes no sense at all. Potency is not relative from a clinical point of view, as it serves as a form of assessment of the effective concentration of the drug. Simply put, the clinical dose equivalent and the end result correspond to each other.

Results from different studies are difficult to compare due to differences in patient populations, inclusion criteria and statistical analysis methods.

In vitro, vardenafil demonstrated the greatest tropism for PDE-5 compared to sildenafil and tadalafil, i.e., its concentration required for effective blockade of PDE-5 was minimal. However, given its low bioavailability and the difference in doses used in clinical practice, the therapeutic effect of vardenafil in vivo is comparable to other PDE5 inhibitors. According to data obtained during the registration of drugs in Europe (Table 5), the proportion of successful attempts at sexual intercourse was 66% during therapy with sildenafil at a dose of 50–100 mg, 65% with vardenafil at a dose of 20 mg and 75% with tadalafil at a dose of 20 mg. In comparable studies, an improvement in the ability to achieve an erection during therapy with sildenafil was noted by 84% of patients (I. Goldstein et al., 1998), vardenafil - 80% (H. Porst et al., 2001), tadalafil - 81% (H. Padma- Nathan et al., 2001).

Fundamentally, PDE-5 inhibitors differ in the duration of the clinical effect: for sildenafil and vardenafil it is about 5 hours, for tadalafil - 36 hours. Some studies have shown that under certain conditions the duration of the clinical effect of sildenafil and vardenafil can exceed 4–5 hours, while While for tadalafil it is consistently long-lasting in the general population. Short-acting medications should be used shortly before sexual intercourse; the resulting dependence of intimacy on the time of action of the drug can lead to psychological discomfort. After taking tadalafil, patients can choose the most suitable moment for intimacy within 1.5 days. With sufficiently high sexual activity, the pharmacoeconomic effect also seems obvious: with approximately the same cost of the three drugs in terms of price/action time, the use of tadalafil turns out to be more profitable.

The in vitro activity of drugs varies significantly depending on the laboratory performing the analysis and whether the comparison used the original drug or whether it was synthesized (isolated) in the laboratory. Clinical efficacy is influenced by a number of parameters, such as bioavailability, elimination rate, binding to blood proteins, etc., so the therapeutic effect may not meet expectations based on high in vitro activity. In this regard, during clinical trials, the optimal dose from the point of view of effectiveness and safety is selected experimentally. Accepted drug dosage regimens are given in Table 6.

The safety profile of the three PDE5 inhibitors is also quite similar (Table 7). Sildenafil and vardenafil, compared to tadalafil, are slightly more likely to cause hot flashes and visual disturbances, but less often - dyspepsia (epigastric discomfort) and myalgia.

As noted above, most of the undesirable effects of these drugs, with the exception of visual impairment, are due to PDE5 blockade. The long half-life of tadalafil leads to a higher incidence of myalgia, which usually occurs at rest, in the evening or at night and is caused by the deposition of blood in the muscles. Similar effects have also been found in clinical studies of other PDE5 inhibitors when used in higher doses or with higher frequency. Adverse effects of all PDE5 inhibitors are usually short-lived and tend to resolve spontaneously. Their duration, as a rule, is shorter than the duration of the therapeutic effect of the drugs due to the lower concentration of PDE-5 in non-cavernous tissue and the body’s rapid adaptation to the secondary effect. The duration of side effects coincides with the duration of the therapeutic effect extremely rarely.

From a hemodynamic point of view, the action of PDE-5 inhibitors resembles nitrates (by the way, sildenafil was originally developed specifically for the treatment of angina pectoris). Since nitric oxide is involved in the regulation of blood pressure, PDE5 inhibitors have a slight hypotensive effect, which can be potentiated when taken simultaneously with nitrates and lead to a significant decrease in blood pressure. That is why the main contraindication to the use of PDE-5 inhibitors is the simultaneous use of organic nitrates: according to existing recommendations, they can be used no earlier than 24 hours after taking short-acting PDE-5 inhibitors, and no earlier than 48 hours after taking tadalafil . If the patient needs to periodically take nitrates, then there is no need to choose the safest of the three PDE-5 inhibitors, since an attack of angina can occur at any time after using these medications or directly during sexual intercourse. In general, it is believed that nitrates do not improve the prognosis in patients with coronary artery disease, therefore, in most cases, their use can be stopped or, if necessary, these drugs can be replaced with other drugs that have a similar mechanism of action. After stopping the use of nitrates, if no clinical complications have arisen, the patient can begin therapy with PDE-5 inhibitors without threat to health and life.

When using PDE-5 inhibitors, one should also take into account the potential risk of complications affecting sexual activity within 90 days after myocardial infarction, with unstable angina or angina that occurs during sexual intercourse, with heart failure that has developed within the last 6 months II functional class and higher according to NYHA, with uncontrolled heart rhythm disturbances, arterial hypotension (BP < 90/50 mm Hg) or uncontrolled arterial hypertension, as well as within 6 months after a stroke.

In addition, drugs in this group of drugs are used with caution in patients with a predisposition to priapism (for example, with sickle cell disease, multiple myeloma or leukemia), or in patients with anatomical deformation of the penis (for example, with angular curvature, cavernous fibrosis or disease Peyronie).

Thus, all three drugs are highly effective and safe drugs for the treatment of ED and have the same indications and contraindications for use. However, they have certain differences in terms of effectiveness and tolerability, the severity of which may vary between patients. In the absence of clear medical criteria for choosing a drug, it is quite difficult to assess the influence of one or another factor in each specific case.

Of interest are the first results of comparative studies of various PDE5 inhibitors, during which patient preferences were assessed. The study by H. Claes et al (2003) involved 91 patients with ED. Previously, all patients regularly took sildenafil citrate and each of them used tadalafil or vardenafil at least 4 times. The effectiveness of all three drugs was comparable, and 19 patients chose to switch to new drugs (tadalafil or vardenafil) mainly because they were better tolerated. An independent study conducted by H. Porst et al (2003) involved 150 patients with ED, including 24 (15%) who had not previously received treatment and 126 (85%) who were chronically taking sildenafil (Viagra). All patients were advised to take at least 6 tablets of each PDE5 inhibitor (sildenafil, tadalafil or vardenafil) sequentially. At the end of the study, 13% of patients preferred sildenafil to continue therapy, 30% preferred vardenafil, and 45% preferred tadalafil (in the vast majority of cases due to its long-lasting effect). In a double-blind study, P. Govier et al (2003) examined the preferences of primary patients who had not previously received therapy with PDE-5 inhibitors. Sildenafil and tadalafil were prescribed sequentially for 4 weeks. At the end of the study, 66% of patients preferred tadalafil and 34% preferred sildenafil to continue treatment.

The results of these studies, of course, cannot be considered final, especially taking into account the so-called expectancy effect of therapy - in clinical studies assessing the effectiveness of PDE-5 inhibitors, the placebo effect is consistently about 30%. In any case, the doctor should remember that he must convey to the patient balanced, reliable and objective information about the features of all three drugs, giving the patient the opportunity to choose the drug.

D. Yu. Pushkar , Doctor of Medical Sciences, Professor A. V. Vertkin , Doctor of Medical Sciences, Professor A. S. Segal, Doctor of Medical Sciences, Professor A. V. Topolyansky, Candidate of Medical Sciences, Associate Professor P. B. Nosovitsky, Candidate of Medical Sciences E. V. Krivtsova MGMSU, NNPOSMP, Moscow

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 nmol) inhibits human PDE-5 activity by 50%. After a single dose of sildenafil in a dose of 100 mg, the average Cmax of free sildenafil in the blood plasma of men is about 18 ng/ml (38 nmol) and is achieved when sildenafil is taken orally on an empty stomach for an average of 60 minutes (from 30 to 120 minutes). When taken in combination with fatty foods, the rate of absorption decreases: Cmax decreases by an average of 29%, and Tmax increases by 60 minutes, but the degree of absorption does not change significantly (AUC decreases by 11%).

Distribution. Vss of sildenafil averages 105 l. The binding of sildenafil and its main circulating N-demethyl 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 taking the drug.

Metabolism. Sildenafil is metabolized mainly in the liver under the influence of the cytochrome CYP3A4 isoenzyme (major pathway) and the cytochrome CYP2C9 isoenzyme (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 PDE-5 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; T1/2 is about 4 hours.

Excretion. The total clearance of sildenafil is 41 l/h, and the final T1/2 is 3–5 hours. After oral administration, as well 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).

Special patient groups

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

Renal dysfunction. With mild (Cl creatinine - 50-80 ml/min) and moderate (Cl creatinine - 30-49 ml/min) degree of renal failure, the pharmacokinetics of sildenafil after a single oral dose of 50 mg does not change. In severe renal failure (Cl creatinine ≤30 ml/min), the clearance of sildenafil is reduced, which leads to an approximately twofold increase in AUC (100%) and Cmax (88%) compared with 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 with those with normal liver function in patients of the same age groups. The pharmacokinetics of sildenafil in patients with severe liver dysfunction (Child-Pugh stage C) has not been studied.

Warnings for taking sildenafil during lactation

Little-known research data from the US Food and Drug Administration (FDA) suggests that women taking Revatio (sildenafil) while breastfeeding have low levels of it in breast milk.

Since there is virtually no data on the effects of sildenafil on newborns whose mothers used it while breastfeeding, if there is a need for its use, breastfeeding should be discontinued during the period of treatment with this drug.

Sources

• Sildenafil Pregnancy and Breastfeeding Warnings / Drugs.com (English)
• Sildenafil During Pregnancy: A Preclinical Meta-Analysis on Fetal Growth and Maternal Blood Pressure / PubMed (English)
• Sildenafil in Pregnancy: A Systematic Review of Maternal Tolerance and Obstetric and Perinatal Outcomes / NIH (English)
• Determination and quantitation of sildenafil and its major metabolite in the breast milk of a lactating woman / National Library of Medicine (English)

Contraindications

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 “Interaction”);

the safety and effectiveness of Sildenafil-SZ when used 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 “Special Instructions”);

Concomitant use of sildenafil with ritonavir is not recommended;

according to its registered indication, the drug Sildenafil-SZ is not intended for use in women;

lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

According to its registered indication, the drug Sildenafil-SZ is not intended for use in children under 18 years of age.

With caution: anatomical deformation of the penis (angulation, cavernous fibrosis or Peyronie's disease) (see "Special Instructions"); diseases predisposing to the development of priapism (sickle cell anemia, multiple myeloma, leukemia, thrombocythemia - see “Special Instructions”); diseases accompanied by bleeding; exacerbation of peptic ulcer of the stomach and duodenum; hereditary retinitis pigmentosa (see “Special Instructions”); heart failure, unstable angina, myocardial infarction in the last 6 months, stroke or life-threatening arrhythmias, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg) (see. "Special instructions"); patients with episodes of anterior non-arteritic ischemic optic neuropathy (history).

Efficiency

The drug Sildenafil for women was tested for a year. During studies, the ability to achieve and maintain sexual desire with increased sensitivity throughout sexual intercourse was noted. Women achieved sexual satisfaction faster, and the feeling itself was vivid.

After taking Sildenafil, the tablet quickly dissolves in the stomach and is absorbed into the blood. In less than an hour, it begins to have the necessary effect on the body, causing blood flow to the genitals.

Side effects

Typically, the side effects of Sildenafil-SZ are mild or moderate and transient.

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

When using the drug Sildenafil-SZ in doses exceeding the recommended ones, adverse events were similar to those noted above, but usually occurred more often.

General condition disorders: chest pain, general weakness.

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

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

From the cardiovascular system: tachycardia, increase or decrease in blood pressure, myocardial infarction, atrial fibrillation, ventricular arrhythmia, unstable angina, sudden death.

From the respiratory system: nosebleeds.

Gastrointestinal disorders: vomiting, nausea, dry oral mucosa.

From the organ of vision: pain in the eyes, redness of the eyes/scleral injections, damage to the conjunctiva, impaired lacrimation, anterior ischemic optic neuropathy, occlusion of retinal vessels, visual field defects.

On the part of the hearing organ: vertigo, tinnitus, deafness.

From the musculoskeletal system: myalgia.

From the reproductive system: prolonged erection and/or priapism, hematospermia and bleeding from the penis.

Action

The drug has a vasodilating effect on the vessels of the pelvic organs. As a result of taking the pathogen, the blood supply to the genital organs increases. After taking Sildenafil tablets, the woman notes:

1. Increased sensitivity during touch.
2. Enhanced impression of intimacy.
3. More vivid sensations.
4. Stimulation of secretion production by the gonads during arousal.
5. Reduced pain during penile insertion;
6. Increased sexual desire.

Immediately after the start of sexual intercourse, the woman notices the approaching orgasm. The sexual act itself may last longer than usual. The use of Sildenafil helps women during menopause and after surgery to remove the uterus to feel their partner and increase sexual desire.

The elements included in the composition have an antidepressant effect on the body. They help relieve fatigue, irritation, and reduce stress. Under the influence of the pathogen, the woman is completely sexually attracted and feels a vivid orgasm.

Sildenafil is available for women and men. It is recommended to take the drug specifically for the female body in order to get the desired effect. To do this, take the tablet an hour before sexual intercourse with a sufficient amount of water. During this time, the product dissolves, enters the bloodstream, and is distributed throughout the body.

Interaction

The influence of other drugs on the pharmacokinetics of sildenafil

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

A decrease in the clearance of sildenafil was noted with the 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, against the background of achieving a constant concentration of erythromycin in the blood, leads to an increase in the AUC of sildenafil by 182%.

When taking sildenafil (single 100 mg) and saquinavir (1200 mg/day 3 times a day), an inhibitor of HIV protease and cytochrome CYP3A4 isoenzyme, while achieving a constant concentration of saquinavir in the blood, Cmax of sildenafil increased by 140%, and 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 cytochrome P450 inhibitor, 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 dose of sildenafil alone - 5 ng/ml), which is consistent with information about the pronounced effect of ritonavir on the pharmacokinetics of various cytochrome P450 substrates.

Sildenafil has no effect on the pharmacokinetics of ritonavir. The combined use of sildenafil with ritonavir is not recommended.

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 nmol, 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 (SSRIs, 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.

The effect of sildenafil on other drugs

Sildenafil is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µmol). When sildenafil is taken at recommended doses, its 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.

With simultaneous administration of the α-blocker doxazosin (4 and 8 mg) and sildenafil (25, 50 and 100 mg) in patients with benign prostatic hyperplasia with stable hemodynamics, the average additional reduction in sBP/dBP in the supine position was 7/7, 9/ 5 and 8/4 mm Hg. Art. respectively, and in a standing position - 6/6 mm Hg, 11/4 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 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 blood alcohol Cmax 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. (sBP) and 7 mm Hg. Art. (dBP).

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

Sildenafil for women

03.01.2021 13:47

Author: Neurologist Oleg Olegovich Torsky

Sildenafil for women is a vasodilator drug used to increase sexual desire for a partner. It helps to enhance orgasm and get vivid emotions. The product does not affect sexual desire, but only enhances pleasure in moments of intimacy.

The components included in Sildenafil have a stimulating effect on the amount of lubrication produced during sexual arousal. If there are no deviations from the norm with sexual desire, orgasm, then the remedy is not taken, otherwise negative consequences may occur.

Directions for use and doses

Inside. The recommended dose for most adult patients is 50 mg approximately 1 hour before sexual activity. Taking into account effectiveness and tolerability, the dose can be increased to 100 mg or reduced to 25 mg.

The maximum recommended dose is 100 mg. The maximum recommended frequency of use is 1 time per day.

Renal dysfunction. In mild to moderate renal failure (creatinine clearance 30–80 ml/min), no dose adjustment is required; in severe renal failure (creatinine clearance <30 ml/min), the dose of sildenafil should be reduced to 25 mg.

Liver dysfunction. Since the elimination of sildenafil is impaired in patients with liver damage (particularly with cirrhosis), the dose of Sildenafil-SZ should be reduced to 25 mg.

Combined use with other drugs. When used together with ritonavir, the maximum single dose of Sildenafil-SZ should not exceed 25 mg, and the frequency of use should not exceed 1 time every 48 hours (see “Interaction”).

When used together with inhibitors of the cytochrome CYP3A4 isoenzyme (erythromycin, saquinavir, ketoconazole, itraconazole), the initial dose of Sildenafil-SZ should be 25 mg (see “Interactions”).

To minimize the risk of developing postural hypotension in patients taking α-blockers, Sildenafil-SZ should be started only after hemodynamic stabilization has been achieved in these patients. The advisability of reducing the initial dose of sildenafil should also be considered (see "Special Instructions" and "Interactions").

Elderly patients. No dose adjustment of Sildenafil-SZ is required.