Tadalafil

Cialis^® (Cialis^®)

TADALAFILUM G04B E08

Eli lilly

COMPOSITION AND FORM OF ISSUE:

tab. p / o 20 mg, No. 1, No. 2, No. 4, No. 8

Other ingredients: lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate, Opadri II yellow dye mixture, talc.

No. UA / 7881/01/01 from 10/08/2008 to 10/08/2013

tab. p / captive. 2.5 mg, No. 28

No. UA / 7881/01/02 from 07/26/2012 to 07/26/2017

tab. p / captive. 5 mg shell, No. 28

Other ingredients: tablet core: lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate;
tablet shell: lactose monohydrate, hypromellose, triacetin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) (only 2.5 mg tablets), talc.
20 mg tablets: Opadri II yellow dye mixture, talc.

No. UA / 7881/01/03 from 07/26/2012 to 07/26/2017

PHARMACOLOGICAL PROPERTIES:

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, inhibition of PDE-5 by tadalafil leads to an increase in the level of cGMP in the cavernous body of the penis. The consequence of this is relaxation of the smooth muscles of the arteries and blood flow to the tissues of the penis, which causes an erection. Tadalafil has no effect in the absence of sexual stimulation.
In studies in vitro Tadalafil is found to be a selective PDE-5 inhibitor. PDE-5 is an enzyme found in the smooth muscles of the cavernous body and blood 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 blocks PDE-5 10,000 times more actively than PDE-3, an enzyme that is detected in the heart and blood vessels. This selectivity for PDE-5 compared to PDE-3 is important because PDE-3 is an enzyme involved in the contraction of the heart muscle. In addition, tadalafil is about 700 times more active with respect to PDE-5 than with PDE-6, an enzyme found in the retina that is responsible for phototransduction. Tadalafil also exhibits 9,000 times more potent action against PDE-5, compared with its effect on PDE-8, PDE-9 and PDE-10, as well as 14 times compared to PDE-11.
Tissue distribution and physiological effects of PDE-8 and PDE-11 were not 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 tablets of 2.5 mg, 5 mg: in all studies, a change in color perception was rarely reported (<0.1%).
Three clinical trials were conducted with the participation of 1504 patients in order to identify the period of onset of the effect of Cialis, which showed a statistically confirmed improvement in erectile function. Cialis acts for 36 hours. The effect manifests itself 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 (average maximum decrease is 1.6 / 0.8 mm Hg) and in the standing position (average maximum decrease - 0.2 / 4.6 mmHg) 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 of tadalafil on spermatogenesis for 6 months did not reveal a clinically significant effect of the drug on sperm characteristics (sperm count, motility and structure). For tablets of 2.5 mg, 5 mg: tadalafil did not affect the level of testosterone, LH and FSH in the blood.
Tadalafil in doses of 2.5 mg and 5 mg at a dose of 1 time per day was evaluated in 3 clinical trials, which included 853 patients of different ages (from 21 years to 82 years) and an ethnic group, with erectile dysfunction of various degrees of severity (mild, moderate, severe) and of various etiologies.Most patients have previously taken PDE-5 inhibitors if necessary. In the 2 primary efficacy studies, the success rate was 57 and 67% for Cialis 5 mg, 50% for Cialis 2.5 mg compared to 31 and 37% for placebo. In studies in patients with secondary erectile dysfunction with respect to diabetes, the success rate was 41 and 46% for Cialis 5 mg and 2.5 mg, respectively, compared with 28% for placebo.
Pharmacokinetics Suction. After oral administration, tadalafil is rapidly absorbed. Average c_max in blood plasma is achieved on average 2 hours after ingestion.
The rate and extent of absorption of tadalafil are independent of food intake, so the drug can be taken without regard to food. The time of administration (morning or evening) does not significantly affect the rate and extent of absorption.
Distribution. The average distribution volume 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 isoenzyme CYP 3A4 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 significant at detectable concentrations.
Breeding. In healthy individuals, the average T_½ - 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 with urine (about 36% of the dose).
2.5 mg and 5 mg tablets
The clearance of oral 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 erectile dysfunction and without.
Individual patient groups. In healthy elderly people (≥65 years), a lower clearance of tadalafil was observed when taking the drug by mouth, which was expressed in an increase in AUC by 25% compared with that in healthy individuals aged 19–45 years. This difference is not clinically significant and does not require dose adjustment.
Renal failure. For tablets of 2.5 mg and 5 mg: in studies using a single dose of tadalafil (5–20 mg), the exposure to tadalafil AUC practically doubled in subjects with weak (creatinine clearance - from 51 to 80 ml / min) or moderate (creatinine clearance - from 31 to 50 ml / min) renal failure, also in subjects with the last stage of renal disease on dialysis.
For tablets of 20 mg: in subjects with renal failure, including patients undergoing hemodialysis, the exposure to tadalafil AUC was higher than in healthy ones.
Liver failure. Exposure to tadalafil (by AUC value) in patients with mild to moderate hepatic insufficiency is comparable to that in healthy individuals. There is no data on the pharmacokinetics of tadalafil in severe liver failure.
In patients with diabetes while tadalafil was used, its exposure (AUC) was approximately 19% less than the AUC value in healthy individuals. This difference in exposure does not require dose adjustment.

INDICATIONS:

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

APPLICATION:

take adults (men) inside, regardless of food intake.
2.5 mg and 5 mg tablets
The drug should be taken at least 30 minutes before the alleged sexual activity.
The effectiveness of tadalafil may persist 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 admission is 1 time per day.
Tadalafil at a dose of 10 mg and 20 mg is prescribed for use before the alleged sexual activity and is not recommended for continuous daily use.
In patients planning frequent use of Cialis (at least 2 times a week), it may be advisable to take a daily dose of the drug in 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 at approximately the same time. The dose may be reduced to 2.5 mg once a day, depending on individual tolerance.
The advisability of prolonged daily use should be periodically reevaluated.
Elderly patients. No dosage adjustment is required.
Patients with impaired renal function. In patients with mild or moderate renal impairment, dosage adjustment is not required. For patients with severe renal failure, 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 the alleged 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, therefore, the doctor must carefully and individually evaluate the benefits / risks of therapy. Data on the use of tadalafil in a dose above 10 mg in patients with liver damage are not available. Taking a single dose once a day has not been evaluated in patients with impaired liver function, so the doctor should carefully and individually evaluate the benefits / risks of this therapy.
Patients with diabetes: no dosage adjustment required.
20 mg tablets
The recommended dose is 20 mg before the alleged sexual activity. The drug can be taken 16 minutes before sexual activity. The effectiveness of tadalafil may persist for up to 36 hours after a dose.
The maximum recommended frequency of admission is 1 time per day.
Elderly patients. No dosage adjustment is required.
Patients with impaired renal function. In patients with mild or moderate renal impairment, dosage adjustment is not required. For patients with severe renal failure, 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 the alleged 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, therefore, the doctor must carefully and individually evaluate the benefits / risks of therapy. Data on the use of tadalafil in doses above 10 mg in patients with impaired liver function are not available.

CONTRAINDICATIONS:

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 which sexual activity is contraindicated. Doctors should consider the potential cardiac risk of sexual activity for patients with cardiovascular disease.
The following groups of patients with cardiovascular diseases were not included in clinical trials, therefore, the use of tadalafil in them is contraindicated:

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

The drug is contraindicated in patients with loss of vision of one eye as a result of non-arterial anterior ischemic optic neuropathy (NAPION), regardless of whether this was due to a previous effect of PDE-5 inhibitors.
20 mg tablets: Cialis should not be used in patients under the age of 18 years.

SIDE EFFECTS:

2.5 and 5 mg tablets
The most commonly reported adverse effects 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 is limited.
The following are data on adverse reactions recorded during clinical trials among patients who used tadalafil if necessary and daily, as well as data obtained after post-marketing observation among patients who used Cialis if necessary.

A somewhat higher prevalence of ECG disorders, primarily sinus bradycardia, has been reported in patients receiving tadalafil once a day, compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.
20 mg tablets
The most commonly reported adverse effects are headache and dyspepsia (≥10%).
The table below contains data on adverse reactions that were obtained during placebo-controlled clinical trials and post-marketing observations.

¹Most patients who reported such side effects previously had risk factors for the cardiovascular system.
²A sudden decrease or loss of hearing was 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 identified in placebo-controlled clinical trials.
Description of individual adverse reactions. A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, was reported in patients receiving tadalafil 1 time per day compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

SPECIAL INSTRUCTIONS:

2.5 and 5 mg tablets
Assessment of erectile dysfunction should include identification of potential root causes and identification of the appropriate course of treatment after an appropriate medical determination.
Before starting any treatment for erectile dysfunction, doctors should consider the condition of the cardiovascular system of patients, since there is a certain degree of cardiac risk associated with sexual activity. Tadalafil has an effect on vasodilation, which can lead to a slight and transient decrease in blood pressure and thus enhance the hypotensive effect of nitrates.
In patients simultaneously using antihypertensive drugs, tadalafil can cause a decrease in blood pressure. In 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 studies. Most patients with similar cases reported previously had cardiovascular risk factors. However, it is impossible to conclusively determine whether these cases are directly related to risk factors, the use of Cialis, sexual activity, or a combination of both.
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 help 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 of data on the use of tadalafil in patients with severely impaired liver function (Child-Pugh class C), tadalafil is prescribed to persons in this group with caution.The use of the drug daily has not been thoroughly studied in patients with liver failure. Before prescribing Cialis, the doctor must carefully individually assess the benefits / risks of this therapy.
Patients who have erections lasting 4 hours or more should be advised of the need to seek medical help. If priapism is not immediately treated, this can lead to damage to the tissues of the penis and prolonged loss of potency.
Caution is advised in administering tadalafil to patients with conditions that may cause a propensity to priapism (such as sickle cell anemia, myeloma or leukemia), or to patients with anatomical penile deformities (such as angular distortion, cavernous fibrosis, or Peyronies disease).
Evaluation of erectile dysfunction should include identification of the main potential causes and determination of appropriate therapy after an appropriate medical evaluation. It is not known whether Cialis is effective in patients undergoing pelvic surgery or radical, nerve-preserving prostatectomy.
In some patients, the simultaneous use of tadalafil and α blockers₁β-adrenoreceptors can lead to symptomatic arterial hypotension. The combination of tadalafil and doxazosin is not recommended.
Caution is advised to prescribe tadalafil to patients using CYP 3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), since an increase in AUC of tadalafil was noted with the simultaneous use of these drugs.
The safety and efficacy of a 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 drug contains lactose monohydrate, so patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactase malabsorption syndrome should not use the drug.
20 mg tablets
Assessing erectile dysfunction includes determining its root cause and the appropriateness of a course of treatment. Before starting any treatment for erectile dysfunction, the doctor must evaluate the patients cardiovascular system, since there is a certain degree of risk associated with sexual activity.
It is not known whether Cialis is effective in patients undergoing pelvic surgery or radical prostatectomy without preserving nerves.
Cases of visual impairment and NAPION have been reported during the use of Cialis and other PDE-5 inhibitors. The doctor should warn the patient about the need to stop using tadalafil and seek medical help in case of sudden loss of vision.
You should also warn the patient about a significant increase in the risk of developing NAPION, if in the history he had indications of the transferred NAPION.
Patients who have erections lasting 4 hours or more should be advised of the need to immediately seek medical help. 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, with sickle cell anemia, multiple myeloma or leukemia) or in people with penile deformity (for example, with angular curvature, cavernous fibrosis or Peyronies disease).
The safety data for a single dose of Cialis in patients with severe hepatic insufficiency (Child-Pugh class C) is limited. When prescribing Cialis to such patients, a thorough clinical evaluation is required.
Caution is advised to administer Cialis to patients taking α blockers.₁-adrenoreceptors, since in some cases the simultaneous use of these drugs can lead to symptomatic hypotension.Combination use with doxazosin is not recommended.
Cialis should be used with caution in patients receiving treatment with potent CYP 3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), since an increase in the concentration of AUC of tadalafil was noted with the simultaneous use of these drugs.
The safety and efficacy of a 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 vasodilator effect, which can lead to a transient decrease in blood pressure. Therefore, before starting treatment, the doctor should assess the degree of propensity of the patient to adverse vasodilator 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.
Application in pregnancy and breastfeeding
Cialis is not indicated for use in women. Research data on the use of tadalafil in pregnant women is limited.
Children. The use of the drug is not recommended for persons under the age of 18 years.
Ability to influence reaction rate at driving a vehicle or work with other mechanisms
2.5 and 5 mg tablets. No studies have been conducted regarding the ability of Cialis to influence the reaction rate when driving vehicles or working with other mechanisms.
20 mg tablets No studies have been conducted on the ability of Cialis to influence the reaction rate when driving vehicles or working with other mechanisms. Although the incidence of dizziness during clinical trials using placebo and during clinical trials using tadalafil was similar, patients should know how tadalafil affects them before driving or using other mechanisms.

INTERACTIONS:

tadalafil is not expected to exert a clinically significant inhibition or induction of clearance of drugs metabolized by the cytochrome P450 isoenzyme. The results of the study confirmed that tadalafil does not inhibit or induce the isoenzymes CYP 3A4, CYP 1A2, CYP 2D6, CYP 2C19, CYP 2E1 and CYP 2C9.
The effect of other substances on tadalafil
Tadalafil is mainly metabolized by the CYP 3A4 enzyme. Selective CYP 3A4 inhibitor ketoconazole when taken at a dose of 400 mg / day increases the AUC of tadalafil (20 mg) by 312%, increases C_max in plasma by 22%, and ketoconazole (200 mg daily) increases the AUC of a single dose of tadalafil (10 mg) by 107% and C_max 15% relative to AUC and C_max one tadalafil.
Ritonavir
For tablets of 2.5 and 5 mg: a CYP inhibitor 3A4, 2C9, 2C19 and 2D6 at a dose of 200 mg 2 times a day increases the AUC of tadalafil after a single dose by 124%, without changing C_max in blood. Although specific interactions have not been studied, it can be assumed that other HIV protease inhibitors, such as saquinavir and others, as well as CYP 3A4 inhibitors, such as erythromycin and itraconazole, increase the level of tadalafil in blood plasma.
For tablets of 20 mg: a CYP inhibitor 3A4, 2C9, 2C19 and 2D6 at a dose of 200 mg 2 times a day increases the AUC of tadalafil after a single dose by 124%, without changing C_max in blood. Although specific interactions have not been studied, it can be assumed that protease inhibitors such as saquinavir, as well as CYP 3A4 inhibitors such as erythromycin, clarithromycin, itraconazole and grapefruit juice, increase tadalafil levels in blood plasma.
For tablets of 2.5 and 5 mg: a reduced exposure to tadalafil is expected when combined with rifampicin, which reduces the effectiveness of the daily dose of tadalafil, the magnitude of the decrease is unknown.It is possible that the combined use of tadalafil with other CYP 3A4 inducers will also cause a decrease in the concentration of tadalafil in the blood plasma.
For tablets of 20 mg: a selective inducer of CYP 3A4 rifampicin (600 mg / day) reduces the AUC value with a single use of tadalafil by 88% and C_max - by 46% compared with the values ​​of AUC and C_max for only one tadalafil (10 mg). It can be expected that such a decrease in concentration will lead to a decrease in the effectiveness of tadalafil.
It can be expected that simultaneous application