Instructions for Cialis film-coated tablets 20 mg blister No. 4
Composition
active ingredient: tadalafil;
1 tablet contains 20 mg of tadalafil;
excipients: lactose monohydrate, hydroxypropylmethylcellulose, croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, magnesium stearate: tablet shell: yellow dye mixture 32K12884 (lactose monohydrate, hypromellose HPMC 2910, titanium dioxide (E 171), triacetin, yellow iron oxide (E 172)); talc.
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, yellow in color and almond-shaped, embossed with "C20".
Pharmacotherapeutic group
Drugs for the treatment of erectile dysfunction. Tadalafil. ATX code G04B E08.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP) - a specific phosphodiesterase type 5 (PDE 5). When sexual stimulation causes local release of nitric oxide, inhibition of PDE 5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This leads to relaxation of smooth muscle and blood flow to the penile tissues, resulting in an erection. Tadalafil does not work without sexual stimulation.
The inhibitory effect on the concentration of cGMP in the corpus cavernosum is also observed in the smooth muscles of the prostate, the urinary bladder and their vessels that carry blood to the above organs. The vascular relaxation that occurs in this case leads to an increase in blood perfusion and may be the reason for the reduction of symptoms of benign prostatic hyperplasia. These vascular effects may be supplemented by inhibition of the activity of the bladder afferent nerves and relaxation of the smooth muscles of the prostate and bladder.
Pharmacodynamic effects
In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. PDE5 is an enzyme found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung and cerebellum. Tadalafil has a stronger effect on PDE5 than on other phosphodiesterases. Tadalafil's effect on PDE5 is 10,000 times greater than its effect on PDE1, PDE2, PDE4 and PDE7, which are present in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil is 10,000 times more potent on PDE5 than on PDE3, an enzyme present in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme that plays a role in cardiac muscle contraction. In addition, tadalafil is approximately 700 times more potent for PDE5 than for PDE6, an enzyme found in the retina and responsible for phototransduction. Tadalafil is also 10,000 times more potent for PDE5 than for PDE7, PDE8, PDE9, and PDE10.
Clinical efficacy and safety
Three clinical studies were conducted in 1,504 patients to determine the onset of effect of tadalafil, which demonstrated a statistically significant improvement in erectile function, as well as efficacy for 36 hours and onset of effect as early as 16 minutes after dosing compared to placebo.
In healthy volunteers, tadalafil did not show any significant difference compared to placebo in terms of systolic and diastolic blood pressure in the supine position (mean maximum decrease 1.6/0.8 mm Hg, respectively), systolic and diastolic blood pressure in the standing position (mean maximum decrease 0.2/4.6 mm Hg, respectively), and significant change in heart rate.
In a study of the effects of tadalafil on vision using the Famsworth-Munsell 100 Hue color perception test, tadalafil did not impair color perception (blue/green). Clinical study data support the low affinity of tadalafil for PDE6 compared to PDE5. In clinical studies, changes in color perception were rarely (< 0.1%) reported.
Tadalafil in doses from 2 mg to 100 mg was evaluated in 16 clinical studies involving 3250 patients, including patients with erectile dysfunction of varying severity (mild, moderate, severe), various etiologies, patients of various ages (21 to 86 years) and different ethnic groups. In the majority of patients, erectile dysfunction was observed for at least one year. In the primary efficacy studies, the improvement rate was 81% in the Cialis® group compared to 35% in the placebo group. In addition, patients with erectile dysfunction of varying severity reported improvement while taking Cialis® (the success rate was 86%. 83% and 72% in patients with moderate, moderate and severe erectile dysfunction, respectively, compared to 45%, 42% and 19% in the placebo group). In the primary efficacy studies, the success rate was 75% in the Cialis® group compared to 32% in the placebo group.
In a 12-week study of 186 patients (142 patients on tadalafil, 44 patients on placebo) with erectile dysfunction secondary to spinal cord injury, tadalafil significantly improved erectile function, and the average success rate with Cialis® 10 mg or 20 mg (dose titration, as needed) was 48% in the Cialis® group compared to 17% in the placebo group.
Children
One study was conducted in children with Duchenne muscular dystrophy (DMD) in which no conclusive evidence of efficacy was demonstrated. This efficacy study of tadalafil was a randomized, double-blind, placebo-controlled, three-arm, parallel-group study in 331 male children aged 7 to 14 years with DMD who were receiving concomitant corticosteroid therapy. The study included a 48-week double-blind period during which patients were randomized to receive tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily. Tadalafil did not demonstrate efficacy in the primary endpoint of slowing the decline in walking speed as measured by the change in distance in the 6-minute walk test (6MWT). The mean LS mean distance in TLC at week 48 was 51.0 m in the placebo group compared with 64.7 m in the tadalafil 0.3 mg/kg group (p-0.307) and 59.1 m in the tadalafil 0.6 mg/kg group (p=0.538). No evidence of efficacy was found in the re-analysis of the results of this study. The overall safety results obtained in this study were generally consistent with the known safety profile of tadalafil and the adverse events expected in the pediatric DMD population when treated with corticosteroids.
Pharmacokinetics
Absorption: Tadalafil is well absorbed after oral administration. The mean maximum plasma concentration (Cmax) is reached on average 2 hours after administration.
The absolute bioavailability of tadalafil after oral administration has not been established.
The rate and extent of absorption of tadalafil are independent of food intake, so Cialis® can be taken with or without food. The time of administration (morning or evening) had no clinically significant effect on the rate and extent of absorption.
Distribution. The mean volume of distribution is approximately 63 L, indicating that Cialis® is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is protein bound. Protein binding is not affected by renal impairment.
Less than 0.0005% of the administered dose was detected in semen from healthy volunteers.
Metabolism: Tadalafil is primarily metabolized by the cytochrome P450 (CYP) 3A4 isoform. The major circulating metabolite is methylcatechol glucuronide, which has a PDE5 activity 13,000-fold lower than that of tadalafil. Therefore, the metabolite is not expected to be clinically active at the concentrations observed.
Elimination: Oral tadalafil clearance is 2.5 L/hour and the mean half-life is 17.5 hours in healthy volunteers. Tadalafil is excreted primarily as inactive metabolites, primarily in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Linearity/non-linearity of pharmacokinetics. The pharmacokinetics of tadalafil in healthy volunteers are linearly proportional to time and dose. In the dose range from 2.5 mg to 20 mg, exposure (AUC) increases proportionally to dose. Steady-state plasma concentrations are achieved within 5 days of once-daily dosing.
The pharmacokinetics of the drug are the same in patients with and without erectile dysfunction.
Certain patient groups
Renal impairment. In clinical pharmacology studies with single doses of tadalafil (5-20 mg), tadalafil exposure (AUC) was approximately doubled in patients with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment, as well as in patients with end-stage renal disease on dialysis. In patients on hemodialysis, the maximum plasma concentration (Cmax) was 41% higher than in healthy volunteers. The effect of hemodialysis on the elimination of tadalafil is negligible.
Hepatic impairment. Tadalafil exposure (AUC) in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) is comparable to that in healthy volunteers given a 10 mg dose. There is limited safety data for Cialis® in patients with severe hepatic impairment (Child-Pugh Class C). When prescribing Cialis, the physician should carefully assess the individual benefit/risk. There are no data on doses above 10 mg in patients with hepatic impairment.
Diabetic patients: Tadalafil exposure (AUC) in diabetic patients was approximately 19% lower than in healthy volunteers. This difference in exposure does not require dose adjustment.
Indication
Treatment of erectile dysfunction in adult men.
The drug is effective in the presence of sexual stimulation.
Cialis® is not indicated for use in women.
Contraindication
Hypersensitivity to tadalafil or any other component of the drug.
In clinical studies, tadalafil has been shown to potentiate the hypotensive effect of nitrates. This is thought to be a result of the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, tadalafil is contraindicated in patients taking organic nitrates in any dosage form.
Cialis® should not be used in men with heart disease for whom sexual activity is undesirable. Physicians should consider the potential cardiac risk associated with sexual activity in patients with pre-existing cardiovascular disease. The following groups of patients with cardiovascular disease were not 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 occurring during sexual intercourse; Patients with heart failure corresponding to class 2 or higher according to the New York Heart Association classification within the last 6 months; Patients with controlled arrhythmias, arterial hypotension (<90/50 mm Hg) or uncontrolled hypertension; Patients after a stroke occurring within the last 6 months.
Cialis® is contraindicated in patients with loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy (NAPION), whether or not this was related to previous exposure to PDE5 inhibitors.
Concomitant use of PDE5 inhibitors, including tadalafil, with guanylate cyclase stimulators such as riociguat is contraindicated as it could potentially lead to symptomatic hypotension.
Interaction with other medicinal products and other types of interactions
Interaction studies were conducted at 10 mg and 20 mg doses, and the data are presented below. A clinically significant interaction at higher doses cannot be excluded if it has been observed at lower doses of Cialis® (10 mg).
Effects of other drugs on tadalafil
Cytochrome CYP450 inhibitors
Tadalafil is primarily metabolized by CYP3A4. Ketoconazole (200 mg daily), a selective CYP3A4 inhibitor, increased tadalafil (10 mg) exposure (AUC) by 2-fold and Cmax by 15% relative to the AUC and Cmax of tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) by 2-fold without changing Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be administered with caution as they are expected to increase tadalafil plasma concentrations when co-administered. As a result, the incidence of adverse reactions may increase.
Conveyors
The effect of transporters, such as p-glycoproteins, on the disposition of tadalafil is unknown. Thus, there is a possibility of drug interactions mediated by transporter inhibition.
Cytochrome CYP450 inducers
The CYP3A4 inducer rifampicin reduced the AUC of tadalafil by 88% compared to the AUC of tadalafil alone (10 mg). It can be assumed that this decrease in concentration will lead to a decrease in the efficacy of tadalafil. Concomitant use of other CYP3A4 inducers, such as phenobarbital, phenytoin and carbamazepine, may also reduce the plasma concentration of tadalafil.
Nitrates. In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) has been shown to potentiate the hypotensive effects of nitrates. Therefore, the use of Cialis® in patients receiving treatment with organic nitrates in any form is contraindicated. If, for a patient who is prescribed Cialis® in any dose (2.5-20 mg), the use of nitrates is medically necessary in a life-threatening condition, then at least 48 hours should elapse after the last dose of Cialis before the use of nitrates. In such cases, the use of nitrates should be under medical supervision with appropriate monitoring of hemodynamic parameters.
Antihypertensive drugs (including calcium channel blockers)
During the co-administration of tadalafil (at a dosage of 5 mg once a day or as a single dose of 20 mg) with the α-adrenoceptor blocker doxazosin (4-8 mg per day), a significant increase in the hypotensive effect of the latter was observed. This effect lasts up to 12 hours and may manifest itself in individual symptoms, including dizziness. This combination of drugs is not recommended for use.
In interaction studies involving a limited number of healthy volunteers, no such effects were reported when co-administered with alfuzosin or tamsulosin. Tadalafil should be administered with caution to patients receiving treatment with α-adrenergic blockers, especially in the elderly. Treatment should be initiated at a low dose and titrated gradually.
Clinical pharmacodynamic studies have investigated the potential of tadalafil to enhance the hypotensive effects of major antihypertensive drugs. The major classes of drugs studied were: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), β-adrenoceptor blockers (metoprolol), thiazide diuretics (bendrofluazide) and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenoceptor blockers and/or α-adrenoceptor blockers). Tadalafil (at a dose of 10 mg, except for interaction studies with angiotensin II receptor blockers and amlodipine, where the effect of a dose of 20 mg was studied) did not show significant interactions with the above-mentioned classes of drugs. Another clinical pharmacology study investigated the concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four). In patients receiving multiple antihypertensive agents, changes in blood pressure were dependent on the level of blood pressure control. Thus, in patients with well-controlled hypertension, the reduction in blood pressure was small and consistent with that in healthy volunteers. In patients with poorly controlled hypertension, a greater reduction in blood pressure was observed, although in most patients the reduction in blood pressure was not accompanied by hypotensive symptoms. In patients receiving concomitant antihypertensive agents, the use of tadalafil at a dose of 20 mg may lead to a decrease in blood pressure, which (except in the case of concomitant use with α-adrenergic blockers) is small and clinically insignificant. Analysis of data from the third phase of the clinical trial did not reveal any differences in adverse reactions occurring in patients treated with tadalafil with concomitant antihypertensive agents and those treated with tadalafil alone. Nevertheless, appropriate advice should be given to patients treated with antihypertensive agents and Cialis® regarding the possible lowering of blood pressure.
Riociguat
In preclinical studies, an additive hypotensive effect was observed when PDE5 inhibitors were co-administered with riociguat. In clinical studies, riociguat was shown to potentiate the hypotensive effect of PDE5 inhibitors. There was no evidence of a beneficial clinical effect of this combination in the study population. The concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated.
5-alpha-reductase inhibitors
In a clinical trial comparing tadalafil 5 mg and finasteride 5 mg to placebo and finasteride 5 mg for the treatment of symptoms of benign prostatic hyperplasia, no new adverse reactions were identified. However, since a drug-drug interaction study to evaluate the effects of tadalafil and 5-alpha-reductase inhibitors has not been conducted, caution should be exercised when prescribing tadalafil to patients receiving 5-alpha-reductase inhibitors.
CYP1A2 substrates (e.g. theophylline)
In a clinical pharmacology study, no pharmacokinetic interaction was observed when tadalafil (10 mg) was administered with theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate. The possibility of this effect occurring with the concomitant use of tadalafil and theophylline should be considered, although it is not clinically significant.
Ethinylestradiol and terbutaline
Tadalafil increased the bioavailability of oral ethinylestradiol formulations. This increase in bioavailability can be expected when co-administered with terbutaline, although the clinical consequences of this combination are unknown.
Alcohol (mean maximum concentration 0.08%) had no effect on the concomitant use of tadalafil (at a dose of 10 or 20 mg). There were also no changes in tadalafil concentrations during the next three hours after simultaneous intake of alcohol with tadalafil. Alcohol was administered in such a way as to achieve the maximum level of alcohol absorption (rapid intake without food within 2 hours after administration). Tadalafil (at a dose of 20 mg) did not lead to a statistically significant decrease in blood pressure against the background of alcohol intake (0.7 g/kg), but some patients experienced postural dizziness and orthostatic hypotension. Tadalafil intake with lower doses of alcohol (0.6 g/kg) did not cause arterial hypotension, and dizziness was observed with the same frequency as when alcohol was taken alone. The effect of alcohol on cognitive function was not enhanced by concomitant use of tadalafil (10 mg).
Medicinal products metabolized by cytochrome P-150
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP450 isoforms. In clinical studies, tadalafil has been shown not to inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.
CYP2C9 substrates (e.g. R-warfarin)
Tadalafil (10 mg and 20 mg) had no clinically significant effect on the exposure (AUC) of S-warfarin or R-warfarin (CYP2C9 substrates) and had no effect on warfarin-induced prothrombin time.
Aspirin
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Antidiabetic drugs
Specific studies of the interaction of tadalafil with antidiabetic drugs have not been conducted.
Interaction with other medicinal products and other types of interactions
Interaction studies were conducted at 10 mg and 20 mg doses, and the data are presented below. A clinically significant interaction at higher doses cannot be excluded if it has been observed at lower doses of Cialis® (10 mg).
Effects of other drugs on tadalafil
Cytochrome CYP450 inhibitors
Tadalafil is primarily metabolized by CYP3A4. Ketoconazole (200 mg daily), a selective CYP3A4 inhibitor, increased tadalafil (10 mg) exposure (AUC) by 2-fold and Cmax by 15% relative to the AUC and Cmax of tadalafil alone. Ketoconazole (400 mg daily) increased tadalafil (20 mg) exposure (AUC) by 4-fold and Cmax by 22%. Ritonavir, a protease inhibitor (200 mg twice daily) that inhibits CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil (20 mg) exposure (AUC) by 2-fold without changing Cmax. Although specific interactions have not been studied, other protease inhibitors such as saquinavir and other CYP3A4 inhibitors such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be administered with caution as they are expected to increase tadalafil plasma concentrations when co-administered. As a result, the incidence of adverse reactions may increase.
Conveyors
The effect of transporters, such as p-glycoproteins, on the disposition of tadalafil is unknown. Thus, there is a possibility of drug interactions mediated by transporter inhibition.
Cytochrome CYP450 inducers
The CYP3A4 inducer rifampicin reduced the AUC of tadalafil by 88% compared to the AUC of tadalafil alone (10 mg). It can be assumed that this decrease in concentration will lead to a decrease in the efficacy of tadalafil. Concomitant use of other CYP3A4 inducers, such as phenobarbital, phenytoin and carbamazepine, may also reduce the plasma concentration of tadalafil.
The effect of tadalafil on other drugs
Nitrates. In clinical studies, tadalafil (5 mg, 10 mg, 20 mg) has been shown to potentiate the hypotensive effects of nitrates. Therefore, the use of Cialis® in patients receiving treatment with organic nitrates in any form is contraindicated. If, for a patient who is prescribed Cialis® in any dose (2.5-20 mg), the use of nitrates is medically necessary in a life-threatening condition, then at least 48 hours should elapse after the last dose of Cialis before the use of nitrates. In such cases, the use of nitrates should be under medical supervision with appropriate monitoring of hemodynamic parameters.
Antihypertensive drugs (including calcium channel blockers)
During the co-administration of tadalafil (at a dosage of 5 mg once a day or as a single dose of 20 mg) with the α-adrenoceptor blocker doxazosin (4-8 mg per day), a significant increase in the hypotensive effect of the latter was observed. This effect lasts up to 12 hours and may manifest itself in individual symptoms, including dizziness. This combination of drugs is not recommended for use.
Clinical pharmacodynamic studies have investigated the potential of tadalafil to enhance the hypotensive effects of major antihypertensive drugs. The major classes of drugs studied were: calcium channel blockers (amlodipine), ACE inhibitors (enalapril), β-adrenoceptor blockers (metoprolol), thiazide diuretics (bendrofluazide) and angiotensin II receptor blockers (alone and in combination with thiazide diuretics, calcium channel blockers, β-adrenoceptor blockers and/or α-adrenoceptor blockers). Tadalafil (at a dose of 10 mg, except for interaction studies with angiotensin II receptor blockers and amlodipine, where the effect of a dose of 20 mg was studied) did not show significant interactions with the above-mentioned classes of drugs. Another clinical pharmacology study investigated the concomitant use of tadalafil (20 mg) with multiple antihypertensive agents (up to four). In patients receiving multiple antihypertensive agents, changes in blood pressure were dependent on the level of blood pressure control. Thus, in patients with well-controlled hypertension, the reduction in blood pressure was small and consistent with that in healthy volunteers. In patients with poorly controlled hypertension, a greater reduction in blood pressure was observed, although in most patients the reduction in blood pressure was not accompanied by hypotensive symptoms. In patients receiving concomitant antihypertensive agents, the use of tadalafil at a dose of 20 mg may lead to a decrease in blood pressure, which (except in the case of concomitant use with α-adrenergic blockers) is small and clinically insignificant. Analysis of data from the third phase of the clinical trial did not reveal any differences in adverse reactions occurring in patients treated with tadalafil with concomitant antihypertensive agents and those treated with tadalafil alone. Nevertheless, appropriate advice should be given to patients treated with antihypertensive agents and Cialis® regarding the possible lowering of blood pressure.
Riociguat
In preclinical studies, an additive hypotensive effect was observed when PDE5 inhibitors were co-administered with riociguat. In clinical studies, riociguat was shown to potentiate the hypotensive effect of PDE5 inhibitors. There was no evidence of a beneficial clinical effect of this combination in the study population. The concomitant use of riociguat with PDE5 inhibitors, including tadalafil, is contraindicated.
5-alpha-reductase inhibitors
In a clinical trial comparing tadalafil 5 mg and finasteride 5 mg to placebo and finasteride 5 mg for the treatment of symptoms of benign prostatic hyperplasia, no new adverse reactions were identified. However, since a drug-drug interaction study to evaluate the effects of tadalafil and 5-alpha-reductase inhibitors has not been conducted, caution should be exercised when prescribing tadalafil to patients receiving 5-alpha-reductase inhibitors.
CYP1A2 substrates (e.g. theophylline)
In a clinical pharmacology study, no pharmacokinetic interaction was observed when tadalafil (10 mg) was administered with theophylline (a non-selective phosphodiesterase inhibitor). The only pharmacodynamic effect was a slight increase in heart rate. The possibility of this effect occurring with the concomitant use of tadalafil and theophylline should be considered, although it is not clinically significant.
Ethinylestradiol and terbutaline
Tadalafil increased the bioavailability of oral ethinylestradiol formulations. This increase in bioavailability can be expected when co-administered with terbutaline, although the clinical consequences of this combination are unknown.
Alcohol
Alcohol (mean maximum concentration 0.08%) had no effect on the concomitant use of tadalafil (at a dose of 10 or 20 mg). There were also no changes in tadalafil concentrations during the next three hours after simultaneous intake of alcohol with tadalafil. Alcohol was administered in such a way as to achieve the maximum level of alcohol absorption (rapid intake without food within 2 hours after administration). Tadalafil (at a dose of 20 mg) did not lead to a statistically significant decrease in blood pressure against the background of alcohol intake (0.7 g/kg), but some patients experienced postural dizziness and orthostatic hypotension. Tadalafil intake with lower doses of alcohol (0.6 g/kg) did not cause arterial hypotension, and dizziness was observed with the same frequency as when alcohol was taken alone. The effect of alcohol on cognitive function was not enhanced by concomitant use of tadalafil (10 mg).
Medicinal products metabolized by cytochrome P-150
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP450 isoforms. In clinical studies, tadalafil has been shown not to inhibit or induce CYP450 isoforms, including CYP3A4, CYP1A2, CYP2D6, CYP2E1, CYP2C9, and CYP2C19.
CYP2C9 substrates (e.g. R-warfarin)
Tadalafil (10 mg and 20 mg) had no clinically significant effect on the exposure (AUC) of S-warfarin or R-warfarin (CYP2C9 substrates) and had no effect on warfarin-induced prothrombin time.
Tadalafil (10 mg and 20 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid.
Antidiabetic drugs
Specific studies of the interaction of tadalafil with antidiabetic drugs have not been conducted.
Application features
Before starting treatment with Cialis
Before using the drug, the doctor should determine the root causes of erectile dysfunction and prescribe an appropriate course of treatment.
Before initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of patients, as there is some degree of cardiac risk associated with sexual activity. Tadalafil has a vasodilatory effect, which may lead to a slight and transient decrease in blood pressure and potentiate the hypotensive effect of nitrates.
It is not known whether Cialis® is effective in patients who have undergone pelvic surgery or radical prostatectomy without nerve sparing.
Cardiovascular system
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, unstable angina, ventricular arrhythmia, cerebrovascular accident, transient ischemic attack, chest pain, palpitations, and tachycardia, have been reported from postmarketing sources and/or in clinical trials. The majority of patients who experienced these adverse reactions had cardiovascular risk factors. However, it is currently not possible to determine with certainty whether these events are related to the risk factors, the use of Cialis®, the sexual activity of the patients, or a combination of these or other factors.
Cialis® should be prescribed with caution to patients taking alpha-1 blockers, as in some patients concomitant administration of these drugs may lead to symptomatic hypotension. The combined use of tadalafil and doxazosin is not recommended.
Organs of vision
Cases of visual impairment and non-arteritic anterior ischemic optic neuropathy (NAPION) have been reported with the use of Cialis® and other PDE5 inhibitors. Analysis of observational data has shown an increased risk of developing acute NAPION in men with erectile dysfunction after the use of tadalafil or other PDE5 inhibitors. Since this increased risk can occur in all patients taking tadalafil, the physician should warn the patient about the need to stop taking tadalafil and seek medical attention in case of sudden vision loss (see section "Contraindications").
Deterioration or sudden loss of hearing
Cases of sudden hearing loss have been reported following the use of tadalafil. Regardless of the presence of other risk factors (such as age, diabetes, hypertension, and history of hearing loss), patients should be advised to discontinue tadalafil and seek medical attention in the event of sudden hearing loss or deterioration.
Liver failure
Clinical data on the safety of a single dose of Cialis® in patients with severe hepatic impairment (Child-Pugh Class C) are limited. When prescribing Cialis® to such patients, the physician should carefully assess the individual benefits/risks of therapy.
Priapism and anatomical deformation of the penis
Patients who experience erections lasting 4 hours or more should be advised to seek immediate medical attention. If priapism is not treated promptly, it can lead to penile tissue damage and long-term loss of potency.
Cialis should be prescribed with caution to patients with anatomical deformities of the penis (such as angular curvature, cavernous fibrosis or Peyronie's disease) or to patients with conditions that may lead to priapism (such as sickle cell anemia, myeloma or leukemia).
Concomitant use with CYP3A4 inhibitors
Cialis® should be prescribed with caution to patients taking CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin), since co-administration with tadalafil has been associated with an increase in tadalafil exposure (AUC).
Concomitant use with other drugs for the treatment of erectile dysfunction
The safety and efficacy of Cialis® in combination with other PDE5 inhibitors or other agents for the treatment of erectile dysfunction have not been studied, therefore patients should be advised not to take Cialis® in such combinations.
Lactose
Cialis contains lactose. Cialis® should not be administered to patients with rare hereditary forms of galactose intolerance, glucose-galactose malabsorption syndrome or the Lapp lactase deficiency.
Able
