Pharmacological properties: tadalafil (pirazinol [1 ', 2': 1,6] pyrido (3,4-b) indole-1 ,4-dione, 6 - (1,3-benzodioksol-5-yl) -2,3 , 6,7,12,12 a-hexahydro-2-methyl-, (6R, 12aR)) - Means, used for erectile dysfunction. Tadalafil is a reversible selective inhibitor of specific phosphodiesterase type 5 (PDE-5), cyclic guanosine monophosphate (cGMP). When sexual stimulation causes local release of nitric oxide, inhibition of PDE-5 tadalafilom leads to increased levels of cGMP in the cavernous body of penis. The result is relaxation of smooth muscles of arteries and blood flow to the tissues of the penis that causes an erection. Tadalafil has no effect without sexual stimulation.
In in vitro studies found that Tadalafil is a selective inhibitor of PDE-5. PDE-5 is an enzyme found in smooth muscles of cavernous bodies in the vascular smooth muscles of internal organs, skeletal muscle, platelets, kidney, lung and cerebellum. Effects of tadalafil for PDE-5 is more pronounced than on other types of phosphodiesterase. Tadalafil is 10 000 times more active against PDE-5 than for FDE1, FDE2 and FDE4, which are located in the heart, brain, blood vessels, liver and other organs. Tadalafil 10 000 times more active blocks PDE-5 than FDE3 - enzyme that is detected in the heart and blood vessels. This selectivity for PDE-5 compared with FDE3 is important, because FDE3 is an enzyme involved in the reduction of the heart muscle. In addition, tadalafil about 700 times more active against PDE-5 than for FDE6 found in the retina and is responsible for fotoperedachu. Tadalafil is also shown in 9,000 times more powerful effect on PDE-5 compared with its effect on FDE8, FDE9 and FDE10, as well as 14-fold compared with FDE11.
The drug acts within 36 hours The effect is manifested as little as 16 minutes after taking the drug in the presence of sexual stimulation.
Tadalafil in healthy individuals causes no significant change in systolic and diastolic blood pressure compared to placebo in supine position (mean maximum decrease of 1,6 / 0,8 mmHg. Cent.) And standing (mean maximum decrease of 0.2 / 4.6 mmHg. cent.). Tadalafil does not cause significant change in heart rate.
Tadalafil does not affect the perception of colors (blue / green), due to its low affinity to FDE6 compared with PDE-5. In addition, there is no influence of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.
Investigation of the effect on spermatogenesis receiving tadalafil for 6 months revealed no clinically significant effect of the drug on the number, mobility and structure of sperm. Receiving tadalafil had no effect on testosterone levels, LH and FSH in the blood.
After oral tadalafil is rapidly absorbed. The average maximum plasma concentration achieved after an average of 2 hours after ingestion.
The speed and extent of absorption of tadalafil is not dependent on food intake, so the drug can be taken irrespective of food intake. Hours (morning or evening) has no significant effect on the rate and extent of absorption.
The average volume of distribution is about 63 liters. At therapeutic concentrations, 94% of tadalafil is associated with plasma proteins.
In healthy persons less than 0.0005% of the administered dose is found in semen.
Tadalafil is mainly metabolized with the participation of isoenzyme (CYP) 3A4 cytochrome P450. The main circulating metabolite is metilkateholglyukuronid. This metabolite of at least 13,000 times less active against PDE-5 than tadalafil. Therefore, one can hardly assume that this metabolite at such concentrations is clinically significant.
In healthy individuals the average half-life - 17,5 hours Tadalafil appears 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).
In healthy elderly (65 years and older) were found lower clearance tadalafil while taking the drug by mouth, which was reflected in increased AUC by 25% compared with that in healthy individuals aged 19 to 45 years. This distinction is not clinically significant and does not require dose adjustment.
In individuals with renal failure (including patients on hemodialysis), tadalafil exposure (on the value of AUC) was greater than in healthy individuals.
Exposure tadalafil (by value AUC) in patients with mild and moderate hepatic insufficiency comparable to that in healthy individuals. Data on pharmacokinetics tadalafil with severe hepatic insufficiency is not.
Patients with diabetes mellitus during treatment with tadalafil AUC value was approximately 19% lower than in healthy individuals. This difference in exposure does not require dose adjustment.
INDICATIONS: Erectile dysfunction.
APPLICATION: The recommended dose is 20 mg. Cialis are inside before the alleged sexual activity regardless of the meal. The drug should be taken at least 16 minutes before the anticipated sexual activity.
The effectiveness of tadalafil may persist for 36 hours after taking the drug. The maximum recommended frequency of admission - once a day.
CONTRAINDICATIONS: Hypersensitivity to tadalafilu or other components of the preparation, the simultaneous application of organic nitrates.
SIDE EFFECTS: The most frequently noted headache (≥ 10% of cases). Other typical side effects (frequency ≥ 1% but <10%) are back pain, dyspepsia, dizziness, flushing, myalgia, nasal congestion. With a frequency of ≥ 0,1%, but <1% of the observed swelling of eyelids, pain in the eyes, hyperemia of the conjunctiva.
In postmarketing studies rarely observed such side effects:
hypersensitivity reactions: skin rash, hives and swelling of the person syndrome Stevens - Johnson, exfoliative dermatitis;
of the cardiovascular system: describes cases of serious reactions to the cardiovascular system, such as myocardial infarction, sudden cardiac death, stroke, angina, tachycardia, however, most patients had a history of guidance on the risk factors of the cardiovascular system . It is impossible to establish statistically significant association of these leaching reactions with cardiac risk factors, the reception tadalafil, sexual activity or with a combination of all these factors. It was also reported on the development of arterial hypotension (usually in the case of simultaneous reception of tadalafil with antihypertensive drugs), hypertension, collapse;
from the digestive system: abdominal pain, gastroesophageal reflux;
of the skin: hyperhidrosis;
from the organ of vision: blurring of vision, nearterialnaya anterior ischemic optic neuropathy, retinal vein occlusion, visual disturbances;
of the genitourinary system: a long erection priapism.
Cautions: sexual activity represents a potential risk for patients with diseases of the cardiovascular system. Therefore, treatment of erectile dysfunction, including the use of Cialis, you should not hold for men with heart disease, in which sexual activity is not recommended.
Keep in mind the potential risk of complications during sexual activity in patients with cardiovascular diseases such as myocardial infarction within the last 90 days, unstable angina or angina occurring during sexual intercourse, heart failure functional class II and higher NYHA, which developed in During the past 6 months, uncontrolled arrhythmias, hypotension (BP <90/50 mmHg. cent.) or hypertension, stroke, transferred within the last 6 months.
Safety and efficacy of a combination of Cialis with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.
There are reports of occurrence of priapism when using PDE-5 inhibitors, including tadalafil. Patients should be alert for immediate access to medical care in case of erection continuing for 4 h or more. Delayed treatment leads to priapism damage the tissues of the penis with the onset of long-term impotence. Cialis should be used with caution in patients with predisposition to priapism (eg sickle cell anemia, multiple myeloma, or leukemia) or in patients with deformity of the penis (eg, angulation, cavernous fibrosis or Peyronie's disease).
Given the lack of data on the use of Cialis in patients with severely impaired liver function (class C according to Child-Pugh), patients of this group appoint Cialis with caution.
Like other inhibitors of PDE 5, tadalafil is able to provide a systemic vasodilator action, which can lead to a transient decrease in BP. Therefore, before the appointment Sialis physician should evaluate the likelihood of such an effect in patients with cardio-vascular system.
Cialis is not indicated for use in women.
Cialis does not affect or have little effect on the ability to drive vehicles and operate machinery.
INTERACTION: Cialis has no clinically significant effect on clearance of drugs, the metabolism of which proceeds with the participation of isoenzyme cytochrome P450. The study confirmed that tadalafil does not inhibit or induce CYP isoenzymes 3A4, CYP 1A2, CYP 2D6, CYP 2E1 and CYP 2C9.
Tadalafil is mainly metabolized with the participation of the enzyme CYP 3A4. The selective inhibitor of CYP 3A4 ketoconazole when receiving a dose of 400 mg / day increases the AUC tadalafil after a single administration of 312%, increases the maximum concentration in blood plasma by 107% and 200 mg / day - at 107 and 15% respectively.
Ritonavir (an inhibitor of CYP3A4, 2C9, 2S19, and 2D6) in a dose of 200 mg 2 times a day increases the AUC after a single dose of tadalafil in 124%, without changing the maximum concentration in the blood.
Although specific interactions have not been studied, it is likely that protease inhibitors such as saquinavir, as well as inhibitors of CYP 3A4 such as erythromycin and intrakonazol, raise the level of tadalafil in plasma.
Selective CYP3A4 inducer rifampicin 600 mg / day reduces the AUC after a single receiving tadalafil, 88%, and its maximum concentration in blood plasma increased by 46%. One can expect that the simultaneous use of other CYP3A4 inducers will also help to reduce the concentration of tadalafil in the blood plasma.
Tadalafil has no clinically significant effect on the pharmacokinetics of S-warfarin or R-warfarin and does not alter the effect of warfarin on prothrombin time.
Tadalafil does not increase the duration of bleeding in the intake of acetylsalicylic acid.
Tadalafil has a systemic vasodilating action, which may potentiate the hypotensive effect of antihypertensive drugs. In patients receiving multiple antihypertensive drugs may be a significant reduction in blood pressure. In most patients blood pressure reduction is not accompanied by symptoms of hypotension.
There were no significant BP reduction in patients taking both tadalafil and selective blocker of a 1-adrenoceptor tamsulosin.
In appointing tadalafil healthy volunteers who took a 1-blocker doxazosin adrenoceptor in a dose of 8 mg / day, marked enhancement of the hypotensive action. Some patients reported dizziness.
Tadalafil did not affect the concentration of ethanol, and ethanol did not affect the concentration of tadalafil. During the course of high doses of ethanol (0.7 g / kg), simultaneous reception of tadalafil did not cause a statistically significant decrease in blood pressure. Observed in some patients postural dizziness and orthostatic hypotension. Receiving tadalafil on the background of lower doses of ethanol (0.6 g / kg) did not cause the development of arterial hypotension, and dizziness was observed with the same frequency as the reception of only one alcohol.
Simultaneous reception of antacids (magnesium hydroxide / aluminum hydroxide) reduces the rate of absorption of tadalafil without altering AUC.
Raising the pH in the stomach as a result of receiving H 2-blocker receptor nizatidina had no effect on the pharmacokinetics of tadalafil.
OVERDOSE: If a single appointment healthy persons tadalafil at a dose of 500 mg and patients with erectile dysfunction - many times up to 100 mg / day - adverse effects were the same as in the appointment of lower doses. In case of overdose should be carried out standard symptomatic treatment.
Storage: Store in original container at temperatures below 30 ° C.
In in vitro studies found that Tadalafil is a selective inhibitor of PDE-5. PDE-5 is an enzyme found in smooth muscles of cavernous bodies in the vascular smooth muscles of internal organs, skeletal muscle, platelets, kidney, lung and cerebellum. Effects of tadalafil for PDE-5 is more pronounced than on other types of phosphodiesterase. Tadalafil is 10 000 times more active against PDE-5 than for FDE1, FDE2 and FDE4, which are located in the heart, brain, blood vessels, liver and other organs. Tadalafil 10 000 times more active blocks PDE-5 than FDE3 - enzyme that is detected in the heart and blood vessels. This selectivity for PDE-5 compared with FDE3 is important, because FDE3 is an enzyme involved in the reduction of the heart muscle. In addition, tadalafil about 700 times more active against PDE-5 than for FDE6 found in the retina and is responsible for fotoperedachu. Tadalafil is also shown in 9,000 times more powerful effect on PDE-5 compared with its effect on FDE8, FDE9 and FDE10, as well as 14-fold compared with FDE11.
The drug acts within 36 hours The effect is manifested as little as 16 minutes after taking the drug in the presence of sexual stimulation.
Tadalafil in healthy individuals causes no significant change in systolic and diastolic blood pressure compared to placebo in supine position (mean maximum decrease of 1,6 / 0,8 mmHg. Cent.) And standing (mean maximum decrease of 0.2 / 4.6 mmHg. cent.). Tadalafil does not cause significant change in heart rate.
Tadalafil does not affect the perception of colors (blue / green), due to its low affinity to FDE6 compared with PDE-5. In addition, there is no influence of tadalafil on visual acuity, electroretinogram, intraocular pressure and pupil size.
Investigation of the effect on spermatogenesis receiving tadalafil for 6 months revealed no clinically significant effect of the drug on the number, mobility and structure of sperm. Receiving tadalafil had no effect on testosterone levels, LH and FSH in the blood.
After oral tadalafil is rapidly absorbed. The average maximum plasma concentration achieved after an average of 2 hours after ingestion.
The speed and extent of absorption of tadalafil is not dependent on food intake, so the drug can be taken irrespective of food intake. Hours (morning or evening) has no significant effect on the rate and extent of absorption.
The average volume of distribution is about 63 liters. At therapeutic concentrations, 94% of tadalafil is associated with plasma proteins.
In healthy persons less than 0.0005% of the administered dose is found in semen.
Tadalafil is mainly metabolized with the participation of isoenzyme (CYP) 3A4 cytochrome P450. The main circulating metabolite is metilkateholglyukuronid. This metabolite of at least 13,000 times less active against PDE-5 than tadalafil. Therefore, one can hardly assume that this metabolite at such concentrations is clinically significant.
In healthy individuals the average half-life - 17,5 hours Tadalafil appears 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).
In healthy elderly (65 years and older) were found lower clearance tadalafil while taking the drug by mouth, which was reflected in increased AUC by 25% compared with that in healthy individuals aged 19 to 45 years. This distinction is not clinically significant and does not require dose adjustment.
In individuals with renal failure (including patients on hemodialysis), tadalafil exposure (on the value of AUC) was greater than in healthy individuals.
Exposure tadalafil (by value AUC) in patients with mild and moderate hepatic insufficiency comparable to that in healthy individuals. Data on pharmacokinetics tadalafil with severe hepatic insufficiency is not.
Patients with diabetes mellitus during treatment with tadalafil AUC value was approximately 19% lower than in healthy individuals. This difference in exposure does not require dose adjustment.
INDICATIONS: Erectile dysfunction.
APPLICATION: The recommended dose is 20 mg. Cialis are inside before the alleged sexual activity regardless of the meal. The drug should be taken at least 16 minutes before the anticipated sexual activity.
The effectiveness of tadalafil may persist for 36 hours after taking the drug. The maximum recommended frequency of admission - once a day.
CONTRAINDICATIONS: Hypersensitivity to tadalafilu or other components of the preparation, the simultaneous application of organic nitrates.
SIDE EFFECTS: The most frequently noted headache (≥ 10% of cases). Other typical side effects (frequency ≥ 1% but <10%) are back pain, dyspepsia, dizziness, flushing, myalgia, nasal congestion. With a frequency of ≥ 0,1%, but <1% of the observed swelling of eyelids, pain in the eyes, hyperemia of the conjunctiva.
In postmarketing studies rarely observed such side effects:
hypersensitivity reactions: skin rash, hives and swelling of the person syndrome Stevens - Johnson, exfoliative dermatitis;
of the cardiovascular system: describes cases of serious reactions to the cardiovascular system, such as myocardial infarction, sudden cardiac death, stroke, angina, tachycardia, however, most patients had a history of guidance on the risk factors of the cardiovascular system . It is impossible to establish statistically significant association of these leaching reactions with cardiac risk factors, the reception tadalafil, sexual activity or with a combination of all these factors. It was also reported on the development of arterial hypotension (usually in the case of simultaneous reception of tadalafil with antihypertensive drugs), hypertension, collapse;
from the digestive system: abdominal pain, gastroesophageal reflux;
of the skin: hyperhidrosis;
from the organ of vision: blurring of vision, nearterialnaya anterior ischemic optic neuropathy, retinal vein occlusion, visual disturbances;
of the genitourinary system: a long erection priapism.
Cautions: sexual activity represents a potential risk for patients with diseases of the cardiovascular system. Therefore, treatment of erectile dysfunction, including the use of Cialis, you should not hold for men with heart disease, in which sexual activity is not recommended.
Keep in mind the potential risk of complications during sexual activity in patients with cardiovascular diseases such as myocardial infarction within the last 90 days, unstable angina or angina occurring during sexual intercourse, heart failure functional class II and higher NYHA, which developed in During the past 6 months, uncontrolled arrhythmias, hypotension (BP <90/50 mmHg. cent.) or hypertension, stroke, transferred within the last 6 months.
Safety and efficacy of a combination of Cialis with other treatments for erectile dysfunction have not been studied, so the use of such combinations is not recommended.
There are reports of occurrence of priapism when using PDE-5 inhibitors, including tadalafil. Patients should be alert for immediate access to medical care in case of erection continuing for 4 h or more. Delayed treatment leads to priapism damage the tissues of the penis with the onset of long-term impotence. Cialis should be used with caution in patients with predisposition to priapism (eg sickle cell anemia, multiple myeloma, or leukemia) or in patients with deformity of the penis (eg, angulation, cavernous fibrosis or Peyronie's disease).
Given the lack of data on the use of Cialis in patients with severely impaired liver function (class C according to Child-Pugh), patients of this group appoint Cialis with caution.
Like other inhibitors of PDE 5, tadalafil is able to provide a systemic vasodilator action, which can lead to a transient decrease in BP. Therefore, before the appointment Sialis physician should evaluate the likelihood of such an effect in patients with cardio-vascular system.
Cialis is not indicated for use in women.
Cialis does not affect or have little effect on the ability to drive vehicles and operate machinery.
INTERACTION: Cialis has no clinically significant effect on clearance of drugs, the metabolism of which proceeds with the participation of isoenzyme cytochrome P450. The study confirmed that tadalafil does not inhibit or induce CYP isoenzymes 3A4, CYP 1A2, CYP 2D6, CYP 2E1 and CYP 2C9.
Tadalafil is mainly metabolized with the participation of the enzyme CYP 3A4. The selective inhibitor of CYP 3A4 ketoconazole when receiving a dose of 400 mg / day increases the AUC tadalafil after a single administration of 312%, increases the maximum concentration in blood plasma by 107% and 200 mg / day - at 107 and 15% respectively.
Ritonavir (an inhibitor of CYP3A4, 2C9, 2S19, and 2D6) in a dose of 200 mg 2 times a day increases the AUC after a single dose of tadalafil in 124%, without changing the maximum concentration in the blood.
Although specific interactions have not been studied, it is likely that protease inhibitors such as saquinavir, as well as inhibitors of CYP 3A4 such as erythromycin and intrakonazol, raise the level of tadalafil in plasma.
Selective CYP3A4 inducer rifampicin 600 mg / day reduces the AUC after a single receiving tadalafil, 88%, and its maximum concentration in blood plasma increased by 46%. One can expect that the simultaneous use of other CYP3A4 inducers will also help to reduce the concentration of tadalafil in the blood plasma.
Tadalafil has no clinically significant effect on the pharmacokinetics of S-warfarin or R-warfarin and does not alter the effect of warfarin on prothrombin time.
Tadalafil does not increase the duration of bleeding in the intake of acetylsalicylic acid.
Tadalafil has a systemic vasodilating action, which may potentiate the hypotensive effect of antihypertensive drugs. In patients receiving multiple antihypertensive drugs may be a significant reduction in blood pressure. In most patients blood pressure reduction is not accompanied by symptoms of hypotension.
There were no significant BP reduction in patients taking both tadalafil and selective blocker of a 1-adrenoceptor tamsulosin.
In appointing tadalafil healthy volunteers who took a 1-blocker doxazosin adrenoceptor in a dose of 8 mg / day, marked enhancement of the hypotensive action. Some patients reported dizziness.
Tadalafil did not affect the concentration of ethanol, and ethanol did not affect the concentration of tadalafil. During the course of high doses of ethanol (0.7 g / kg), simultaneous reception of tadalafil did not cause a statistically significant decrease in blood pressure. Observed in some patients postural dizziness and orthostatic hypotension. Receiving tadalafil on the background of lower doses of ethanol (0.6 g / kg) did not cause the development of arterial hypotension, and dizziness was observed with the same frequency as the reception of only one alcohol.
Simultaneous reception of antacids (magnesium hydroxide / aluminum hydroxide) reduces the rate of absorption of tadalafil without altering AUC.
Raising the pH in the stomach as a result of receiving H 2-blocker receptor nizatidina had no effect on the pharmacokinetics of tadalafil.
OVERDOSE: If a single appointment healthy persons tadalafil at a dose of 500 mg and patients with erectile dysfunction - many times up to 100 mg / day - adverse effects were the same as in the appointment of lower doses. In case of overdose should be carried out standard symptomatic treatment.
Storage: Store in original container at temperatures below 30 ° C.
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