Tadalafil

The active substance of the drug Cialis - tadalafil - is a reversible selective inhibitor of specific PDE type 5 (PDE-5) cGMP. When sexual stimulation causes local release of nitric oxide, PDE-5 inhibition by tadalafil results in an increase in cGMP levels in the corpus cavernosum of the penis. The consequence of this is the relaxation of the smooth muscles of the arteries and the flow of blood to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual stimulation.

In in vitro studies, it has been established that tadalafil is a selective PDE-5 inhibitor. PDE-5 is an enzyme found in the smooth muscles of the cavernous body and vessels of internal organs, in skeletal muscles, platelets, kidneys, lungs and cerebellum. The effect of tadalafil on PDE-5 is 10,000 times greater than its effect on other types of PDE (PDE-1, PDE-2, PDE-4 and PDE-7). Tadalafil is 10,000 times more active at blocking PDE-5 than PDE-3, an enzyme found in the heart and blood vessels. This selectivity for PDE-5 over PDE-3 is important because PDE-3 is an enzyme involved in cardiac muscle contraction. In addition, tadalafil is about 700 times more active against PDE-5 than against PDE-6, an enzyme found in the retina and responsible for phototransduction. Tadalafil is also 9000 times more potent against PDE-5 compared to its effect on PDE-8, PDE-9 and PDE-10, and 14 times more potent than PDE-11.

The distribution in tissues and the physiological effects of PDE-8 and PDE-11 have not been determined.

Tadalafil does not affect the perception of colors (blue / green), which is explained by its low affinity for PDE-6 compared to PDE-5. In addition, there was no effect of tadalafil on visual acuity, electroretinogram, intraocular pressure, and pupil size.

For 2.5 mg, 5 mg tablets: rare (<0.1%) reported in all studies about the change in color perception.

Three clinical studies were conducted with the participation of 1504 patients in order to determine the period of onset of the effect of Cialis, which demonstrated a statistically confirmed improvement in erectile function. Cialis acts for 36 hours. The effect appears already 16 minutes after taking the dose in the presence of sexual arousal.

Tadalafil in healthy individuals does not cause a significant change in systolic and diastolic blood pressure compared with placebo in the supine position (mean maximum the decrease is 1.6/0.8 mm Hg) and in the standing position (the average maximum decrease is 0.2/4.6 mm Hg). Tadalafil does not cause a significant change in heart rate. Significant changes were observed in patients who also took nitrates.

A placebo-controlled study of the effect on spermatogenesis of taking tadalafil for 6 months did not reveal a clinically significant effect of the drug on sperm characteristics (quantity, motility and structure of spermatozoa). For 2.5 mg, 5 mg tablets: Tadalafil had no effect on blood levels of testosterone, LH, and FSH.

Tadalafil 2.5 mg and 5 mg once daily have been evaluated in 3 clinical studies including 853 patients of different age (from 21 to 82 years old) and ethnic group, with erectile dysfunction of different severity (mild, moderate, severe) and different etiologies. Most patients have previously taken PDE-5 inhibitors as needed. In the 2 primary efficacy studies, the success rates were 57% and 67% for Cialis 5mg, 50% for Cialis 2.5mg compared to 31% and 37% for placebo. In studies in patients with secondary erectile dysfunction in relation to diabetes, the success rate was 41 and 46% for Cialis 5 mg and 2.5 mg, respectively, compared with 28% for placebo.

Pharmacokinetics. Absorption. After oral administration, tadalafil is rapidly absorbed. The average C_max in blood plasma is achieved on average 2 hours after ingestion.

The rate and degree of absorption of tadalafil do not depend on food intake, so the drug can be taken regardless of food. The time of administration (morning or evening) does not significantly affect the rate and extent of absorption.

Distribution. The average volume of distribution is about 63 liters. At therapeutic concentrations, 94% of tadalafil binds to plasma proteins.

In healthy individuals, <0.0005% of the administered dose is detected in semen.

Metabolism. Tadalafil is mainly metabolized with the participation of the CYP 3A4 isoenzyme of cytochrome P450. The main circulating metabolite is methylcatecholglucuronide. This metabolite is 13,000 times less active against PDE-5 than tadalafil. Therefore, it can be assumed that this metabolite is not clinically relevant at detectable concentrations.

Excretion. In healthy individuals, the average T_½ is 17.5 hours. Tadalafil is excreted mainly in the form of inactive metabolites, mainly with feces (about 61% of the dose) and to a lesser extent in the urine (about 36% of the dose) .

2.5 mg and 5 mg tablets

Oral clearance of tadalafil is 2.5 l/h.

The pharmacokinetics of tadalafil in healthy subjects is linearly proportional to time and dose. Increasing the dose from 2.5 mg to 20 mg, exposure (AUC) increases in proportion to the dose. A constant plasma concentration is achieved within 5 days after a single dose.

The pharmacokinetics of the drug is the same in patients with and without erectile dysfunction.

Separate groups of patients

In healthy elderly people (≥65 years), a lower clearance of tadalafil was noted when taking the drug orally, which was expressed in an increase in AUC by 25% compared with healthy individuals aged 19–45 years. This difference is not clinically significant and does not require dose adjustment.

Renal failure. For 2.5 mg and 5 mg tablets: In studies using a single dose of tadalafil (5-20 mg), tadalafil AUC exposure almost doubled in subjects with mild (creatinine clearance - from 51 to 80 ml / min) or moderate (creatinine clearance - 31 to 50 ml/min) in renal insufficiency, also in subjects with end-stage renal disease on dialysis.

For 20 mg tablets: in subjects with renal insufficiency, including patients on hemodialysis, exposure The AUC of tadalafil was higher than in healthy subjects.

Liver failure. The exposure of tadalafil (according to the AUC value) in patients with mild to moderate hepatic insufficiency is comparable to that in healthy individuals. There are no data on the pharmacokinetics of tadalafil in severe liver failure.

In patients with diabetes mellitus, while using tadalafil, its exposure (AUC) was approximately 19% less than the AUC value in healthy people persons. This difference in exposure does not require dose adjustment.

treatment for erectile dysfunction. The drug is effective in the presence of sexual stimulation.

Adults (men) should be taken by mouth, regardless of food intake.

2.5 mg and 5 mg tablets

The drug should be taken at least 30 minutes before the intended sexual activity.

The effectiveness of tadalafil can be maintained for 36 hours after taking the drug.

Adult men: The usual recommended dose is 10 mg. In patients in whom tadalafil at a dose of 10 mg does not give an adequate effect, it is advisable to use 20 mg. The maximum recommended frequency of administration is 1 time per day.

Tadalafil at a dose of 10 mg and 20 mg is prescribed for use before anticipated sexual activity and is not recommended for continuous daily use.

In patients those planning frequent use of Cialis (at least 2 times a week), it may be appropriate to take the drug daily at a low dose, based on the choice of the patient and the decision of the doctor.

For daily use, the recommended dose is 5 mg / day in approximately the same time. The dose may be reduced to 2.5 mg 1 time per day, depending on individual tolerance.

The feasibility of long-term daily use should be periodically reassessed.

Elderly patients. Dosage adjustment is not required.

Patients with impaired renal function. Patients with mild or moderate renal impairment do not require dosage adjustment. For patients with severe renal insufficiency, the maximum recommended dose is 10 mg, daily use is not recommended.

Patients with impaired liver function. The recommended dose of Cialis is 10 mg, which should be used before intended sexual activity regardless of food intake. Clinical data on the safety of Cialis in patients with severe hepatic insufficiency (Child-Pugh class C) are limited, so the physician must carefully and individually evaluate the benefits / risks of therapy. There are no data on the use of tadalafil at a dose higher than 10 mg in patients with liver damage. Once daily single dose administration has not been evaluated in patients with hepatic impairment, therefore the physician should carefully and individually assess the benefits/risks of this therapy.

Patients with diabetes mellitus: no dosage adjustment required.

20 mg tablets

The recommended dose is 20 mg before anticipated sexual activity. The drug can be taken 16 minutes before sexual activity. The effectiveness of tadalafil may be maintained for up to 36 hours after a dose.

The maximum recommended frequency of administration is 1 time per day.

Elderly patients. Dosage adjustment not required.

Patients with impaired renal function. Dosage adjustment is not required in patients with mild or moderate renal impairment. For patients with severe renal insufficiency, the maximum recommended dose is 10 mg, daily use is not recommended.

Patients with impaired liver function. The recommended dose of Cialis is 10 mg, which should be used before intended sexual activity regardless of food intake. Clinical data on the safety of Cialis in patients with severe hepatic insufficiency (Child-Pugh class C) are limited, so the physician must carefully and individually assess the benefits / risks of therapy. No data are available on the use of tadalafil at doses above 10 mg in patients with hepatic impairment.

hypersensitivity to tadalafil or other components of the drug; simultaneous use of organic nitrates in any dosage form.

The drug is not used in men with heart disease, for whom sexual activity is contraindicated. Physicians should be aware of the potential cardiac risk of sexual activity for patients with cardiovascular disease.

The following groups of patients with cardiovascular disease have not been included in clinical trials and therefore tadalafil is contraindicated in them:

• patients with myocardial infarction within the last 90 days;
• patients with unstable angina or angina that occurs during sexual intercourse;
• patients with heart failure that meets II NYHA class or higher in the last 6 months;
• patients with uncontrolled arrhythmias, arterial hypotension (<90/50 mm Hg) or uncontrolled hypertension;
• patients after a stroke that occurred within the last 6 months.

The drug is contraindicated in patients with loss of vision in one eye as a result of non-arterial anterior ischemic optic neuropathy (NAPION), regardless of whether this was due to previous exposure to PDE-5 inhibitors.

2.5 and 5 mg tablets

Undesirable effects, o reported most frequently were headache and dyspepsia. Adverse reactions were short-term, from mild to moderate.

Data on adverse reactions in patients over the age of 75 years are limited.

The following are data on adverse reactions recorded during clinical studies among patients who used tadalafil when needed and daily, as well as data obtained as a result of post-marketing surveillance among patients who used Cialis when necessary.

A slightly higher prevalence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil 1 once daily compared to placebo. Most of these ECG abnormalities were not associated with adverse reactions.

20 mg tablets

Reported adverse effects the most common are headache and dyspepsia (≥10%).

Below is a table that contains data on adverse reactions that were obtained during placebo-controlled clinical trials and post-marketing observations.

¹Most of the patients who reported these side effects had previous cardiovascular risk factors.

²About the sudden decline or hearing loss have been reported in a small number of cases, all associated with the use of PDE-5 inhibitors, including tadalafil.

³ Adverse reactions from post-marketing studies that were not detected in placebo controlled clinical trials.

Description of selected adverse reactions. A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with once-daily tadalafil compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

2.5 mg and 5 mg tablets

Erectile dysfunction assessment should include identification of potential underlying causes and identification of an appropriate course of treatment following appropriate medical definitions.

Before starting any treatment for erectile dysfunction, physicians should consider the cardiovascular status of patients, as there is a degree of cardiac risk associated with sexual activity. Tadalafil has an effect on vasodilatation, which can lead to a slight and transient decrease in blood pressure and thus enhance the hypotensive effect of nitrates.

In patients who simultaneously use antihypertensive drugs, tadalafil may cause a decrease in blood pressure. In the case of the start of daily use of tadalafil, measures should be taken regarding the possible correction of the dose of antihypertensive therapy.

Serious cardiovascular events including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, stroke, transient ischemic attacks, chest pain, irregular heartbeat, and tachycardia have been reported in post-marketing and/or clinical trials. research. The majority of patients with reported similar cases had previously noted cardiovascular risk factors. However, it is not possible to definitively determine whether these cases are directly related to risk factors, the use of Cialis, sexual activity, or a combination of those and other factors.

Visual defects and cases of NAPION have been associated with the use of tadalafil and other PDE-5 inhibitors. The doctor should warn the patient about the need to stop using tadalafil and seek medical attention in case of sudden loss of vision.

Due to increased tadalafil exposure (AUC), limited clinical experience, and lack of ability to influence dialysis clearance, daily use of tadalafil is not recommended in patients with severe renal impairment.

Given the lack data on the use of tadalafil in patients with severe hepatic impairment (Child-Pugh class C) in this group, tadalafil is prescribed with caution. The use of the drug daily has not been carefully studied in patients with hepatic insufficiency. Before prescribing Cialis, the physician should carefully assess the benefits/risks of this therapy individually.

Patients who experience erections lasting 4 hours or more should be advised to seek medical attention. If priapism is not treated immediately, this can lead to damage to the tissues of the penis and a prolonged loss of potency.

Tadalafil should be used with caution in patients with conditions that may cause a tendency to priapism (such as sickle cell anemia). , multiple myeloma, or leukemia), or patients with anatomical deformities of the penis (such as angular distortion, cavernous fibrosis, or Peyronie's disease).

Evaluation of erectile dysfunction should include identification of underlying potential causes and determination of appropriate therapy after appropriate medical evaluation . It is not known whether Cialis is effective in patients who have undergone pelvic surgery or radical nerve-sparing prostatectomy.

In some patients, the simultaneous use of tadalafil and α₁-adrenergic blockers can lead to symptomatic arterial hypotension. The combination of tadalafil and doxazosin is not recommended.

Tadalafil should be used with caution in patients using CYP 3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), since an increase in the AUC of tadalafil was noted with the simultaneous use of these drugs.

The safety and efficacy of the combination of tadalafil and other drugs for the treatment of erectile dysfunction have not been studied. Therefore, the use of this combination is not recommended.

The product contains lactose monohydrate, therefore patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactase malabsorption syndrome should not use the drug.

20mg Tablets

Assessing erectile dysfunction includes determining its underlying cause and the appropriateness of a course of treatment. Before starting any treatment for erectile dysfunction, the doctor should assess the patient's cardiovascular system, as there is a certain degree of risk associated with sexual activity.

It is not known whether Cialis is effective in patients who have undergone pelvic surgery or radical surgery. prostatectomy without nerve sparing.

There have been reports of visual impairment and NAPION during the use of Cialis and other PDE-5 inhibitors. The physician should warn the patient about the need to stop using tadalafil and seek medical help in case of sudden loss of vision.

The patient should also be warned about a significant increase in the risk of developing NAPION if he had a history of NAPION.< /p>

Patients who experience erections lasting 4 hours or more should be advised to seek immediate medical attention. Untimely treatment of priapism leads to damage to the tissues of the penis with the onset of prolonged impotence.

Cialis should be used with caution in patients with a predisposition to priapism (for example, sickle cell anemia, multiple myeloma or leukemia) or in individuals with deformity of the penis (for example, with angular curvature, cavernous fibrosis or Peyronie's disease).

Data on the safety of using a single dose of Cialis in patients with severe hepatic insufficiency (Child-Pugh class C) are limited. When prescribing Cialis to such patients, a thorough clinical assessment is required.

Caution should be exercised when prescribing Cialis to patients taking α₁-adrenergic receptor blockers, since in some cases, the simultaneous use of these drugs can lead to symptomatic hypotension. It is not recommended to combine the use with doxazosin.

Calis should be used with caution in patients receiving treatment with strong inhibitors of CYP 3A4 (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), since an increase in the concentration of tadalafil AUC was noted with the simultaneous use of these drugs .

The safety and efficacy of the combination of Cialis and other PDE-5 inhibitors or other drugs for the treatment of erectile dysfunction have not been studied. Therefore, it is necessary to inform patients that Cialis should not be taken in such combinations. Like other PDE-5 inhibitors, tadalafil is able to exert a systemic vasodilating effect, which can lead to a transient decrease in blood pressure. Therefore, before starting treatment, the doctor should assess the degree of the patient's tendency to adverse vasodilatory effects.

The drug should not be prescribed to patients with rare hereditary forms of galactose intolerance, glucose-galactase malabsorption syndrome and Lapp lactase deficiency due to the content of lactose monohydrate.

Use in pregnancy and breastfeeding

Cialis not indicated for use in women. Data from studies on the use of tadalafil in pregnant women are limited.

Children. The use of the drug is not recommended for persons under the age of 18.

Ability to influence reaction speed when driving a vehicle or operating other mechanisms

Tablets of 2.5 and 5 mg. No studies have been conducted on the ability of Cialis to influence the reaction rate when driving vehicles or working with other mechanisms.

Tablets of 20 mg. No studies have been conducted on the ability of Cialis to influence the reaction rate when driving vehicles or working with other mechanisms. Despite the fact that the incidence of dizziness during clinical studies with placebo and during clinical studies with tadalafil was similar, patients should know how tadalafil affects them before driving vehicles or working with other mechanisms.

Interactions

Overdose

Storage Conditions

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