Tadalafil tablets, a Western medicine name. It is used to treat male erectile dysfunction and the symptoms and signs of erectile dysfunction combined with benign prostatic hyperplasia.
Element
The main ingredient of this product is tadalafil.
Characteristics
This product is a yellow tablet.
Indications
This product is used to treat male erectile dysfunction and the symptoms and signs of erectile dysfunction combined with benign prostatic hyperplasia.
Specification
5mg, 10mg and 20mg.
Dosage
Erectile dysfunction
1. Take tadalafil tablets as needed
(1) For most patients, the recommended starting dose of tadalafil tablets for use as needed is 10 mg, taken before sexual intercourse.
(2) Depending on individual efficacy and tolerability, the dose can be increased to 20 mg or reduced to 5 mg. The maximum recommended frequency of administration for most patients is once a day.
(3) Compared with placebo, taking tadalafil tablets as needed can improve erectile function for up to 36 hours. Therefore, this factor should be considered when recommending the best way for patients to take tadalafil tablets.
(4) Creatinine clearance is 30-50 mL/min: The recommended starting dose is 5 mg, not more than once a day, and the maximum dose is 10 mg, not more than once every 48 hours. Creatinine clearance <30 mL/min or hemodialysis: The maximum dose is 5 mg, not more than once every 72 hours (see [Precautions]).
(5) Mild or moderate (Child Pugh grade A or B): The dose of tadalafil tablets should not exceed 10 mg once daily. Once-daily use of tadalafil tablets has not been extensively evaluated in patients with hepatic impairment and should therefore be used with caution.
(6) Severe (Child Pugh grade C): Tadalafil tablets are not recommended (see [Precautions]).
2. Take tadalafil tablets once a day
(1) The recommended starting dose of tadalafil tablets is 2.5 mg once daily, taken at approximately the same time each day, regardless of when sexual intercourse occurs.
(2) Depending on individual efficacy and tolerability, the dose of tadalafil tablets taken once daily can be increased to 5 mg.
(3) The risks and benefits should be weighed according to the patient’s specific situation and an appropriate treatment plan should be selected.
(4) Creatinine clearance <30 mL/min or hemodialysis: It is not recommended to take tadalafil tablets once daily (see [Precautions]).
(5) Mild or moderate (Child Pugh grade A or B): Once-daily tadalafil tablets have not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if once-daily tadalafil tablets are prescribed to these patients.
(6) Severe (Child Pugh grade C): Tadalafil tablets are not recommended (see [Precautions]).
Erectile dysfunction combined with benign prostatic hyperplasia
1. Take tadalafil tablets once a day. The recommended dose is 5 mg. Take it at about the same time every day without considering when you have sexual intercourse.
2. Creatinine clearance <30 mL/min or hemodialysis: It is not recommended to take tadalafil tablets once a day (see [Precautions]).
Elderly
No dose adjustment is required for patients aged >65 years.
Adverse Reactions
The following adverse reactions were found after tadalafil tablets were approved for marketing. Because these adverse reactions were reported spontaneously in a population of uncertain size, it is not possible to reliably estimate their incidence or establish a causal relationship with drug exposure levels. The reasons for selecting these events include severity, reporting frequency, lack of clear other causes, or all of the above.
1. Cardiovascular and cerebrovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported to be related to the use of tadalafil after marketing. Most of these patients (but not all patients) already had cardiovascular risk factors. According to reports, many events occurred during or shortly after sexual intercourse, and rarely occurred after taking the drug but without sexual intercourse. Others were reported several hours to days after taking tadalafil tablets and having sexual intercourse. It is not certain whether these events are directly related to the combined effects of tadalafil tablets, sexual intercourse, the patient’s existing cardiovascular disease, or other factors (see [Precautions]).
2. Systemic: Hypersensitivity reactions, including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis.
3. Neurology: migraine, epilepsy, seizures, transient amnesia
4. Eyes: visual field loss, retinal vein occlusion, retinal artery occlusion
5. Non-arteritic anterior ischemic optic neuropathy (NAION) is a cause of vision loss, including permanent blindness. There are rare reports of a temporal relationship with phosphodiesterase 5 (PDE 5) inhibitors, including tadalafil tablets, after the market launch. Most (but not all) of these patients already have anatomical or vascular risk factors for NAION, including but not limited to: small cup and disc (“optic disc crowding”), age over 50 years old, diabetes, hypertension, coronary heart disease, hyperlipidemia and smoking (see [Precautions]).
6. Ears: Cases of sudden hearing loss or loss have been reported post-marketing, which are temporally related to the use of PDE5 inhibitors, including tadalafil tablets. In some cases, medical conditions or other factors have been reported that may cause adverse events in the ears. In most cases, medical follow-up information is limited. It is not possible to determine whether these events are directly related to the use of tadalafil tablets, the patient’s existing risk factors for hearing loss, the combined effects of these factors, or other factors (see [Precautions]).
7. Urogenital: persistent erection (see [Precautions]).
Taboo
1. People who are allergic to any ingredient in this product are prohibited from using.
2. Patients who are taking any form of nitrate drugs, whether regularly and/or intermittently, are strictly prohibited from taking tadalafil tablets. Clinical pharmacology studies have shown that tadalafil tablets can enhance the antihypertensive effect of nitrate drugs (see [Drug Interactions]).
3. Patients with known severe allergy to tadalafil should not take tadalafil tablets. There have been reports of hypersensitivity reactions, including Stevens-Johnson syndrome and exfoliative dermatitis (see [Adverse Reactions]).
4. Patients who are currently taking GC stimulants (such as riociguat) should not take tadalafil tablets. PDE5 inhibitors, including tadalafil tablets, may enhance the antihypertensive effect of GC stimulants.
Precautions
1. The evaluation of erectile dysfunction and benign prostatic hyperplasia should include appropriate medical assessment to determine possible unknown causes and treatment options.
2. Because cardiac risk is somewhat related to sexual activity, doctors should consider the patient’s cardiovascular health status. Therefore, treatments for erectile dysfunction, including tadalafil tablets, should not be used in men who are not recommended to have sexual intercourse due to their existing cardiovascular conditions. Patients who experience symptoms at the beginning of sexual intercourse should be advised to abstain from sexual intercourse and seek medical treatment immediately.
3. Physicians should note that once-daily administration of tadalafil tablets can produce sustained plasma tadalafil concentrations, which should be taken into account when evaluating possible interactions with drugs (such as nitrates, α-blockers, antihypertensive drugs, and strong CYP3A4 inhibitors) or with heavy drinking.
4. This type of drug rarely causes prolonged erections of more than 4 hours and priapism (painful erections lasting more than 6 hours). If priapism is not treated in time, it may cause irreversible damage to the erectile tissue. Patients with erections lasting more than 4 hours, whether painful or not, should go to the emergency department for medical treatment.
5. Tadalafil tablets should be used with caution in patients with factors that predispose to persistent erections (such as sickle cell anemia, multiple myeloma, or leukemia) or anatomical defects of the penis (such as abnormal curvature, cavernous fibrosis, or Peyronie’s disease).
6. Doctors should advise patients that if sudden loss of vision in one or both eyes occurs, they should immediately stop taking all phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil tablets, and seek medical attention.
7. If hearing loss or hearing loss occurs suddenly, the doctor should advise the patient to stop taking PDE5 inhibitors, including tadalafil tablets, and seek medical attention immediately. These events may be accompanied by tinnitus and dizziness, which are related to the time of taking PDE5 inhibitors, including tadalafil tablets. It is not certain whether these events are directly related to the use of PDE5 inhibitors or other factors (see [Adverse Reactions]).
8. Physicians should discuss with patients the possibility that tadalafil tablets may enhance the blood pressure-lowering effects of alpha-blockers and antihypertensive drugs (see [Drug Interactions]).
9. In vitro studies have confirmed that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When tadalafil 20 mg is administered in combination with aspirin, it does not delay bleeding time relative to aspirin alone. There is no experience of taking tadalafil tablets in patients with bleeding abnormalities or significant active peptic ulcers. Although tadalafil tablets do not prolong the bleeding time of healthy subjects, patients with bleeding abnormalities or significant active peptic ulcers should use the drug with caution and conduct a careful risk-benefit assessment.
10. Tadalafil tablets do not protect against sexually transmitted diseases. Advise patients to take protective measures against sexually transmitted diseases, including human immunodeficiency virus (HIV).
11. Before starting tadalafil tablets to treat BPH, other urinary system diseases that may cause similar symptoms should be considered. In addition, prostate cancer and BPH may exist at the same time.
12. Tadalafil is not for use in women. There is currently no data on the use of tadalafil in pregnant women, and no information is available on any drug-related risk of adverse developmental outcomes.
13. Tadalafil tablets should not be used in women. There is no information on the secretion of tadalafil and/or its metabolites in human milk, the effects on breastfed children, or the effects on breast milk production.
14. According to data from three studies on adult men, tadalafil reduced sperm concentration in a study of 10 mg tadalafil for 6 months and a study of 20 mg tadalafil for 9 months. This effect was not observed in another study of 20 mg tadalafil for 6 months. Neither 10 mg nor 20 mg tadalafil had adverse effects on the mean concentrations of testosterone, luteinizing hormone, or follicle-stimulating hormone. The clinical significance of the reduction in sperm concentration in the first two studies is unclear, and no studies have evaluated the effect of tadalafil on male fertility.
15. Tadalafil tablets are not for use in children. Safety and effectiveness have not been established in patients under 18 years of age.
16. Of the total number of subjects in tadalafil clinical studies, approximately 19% were patients 65 years of age and older, and 2% were patients 75 years of age and older. Of the total number of subjects in tadalafil clinical studies for the treatment of BPH (including ED with BPH), approximately 40% were patients 65 years of age and older, and 10% were patients 75 years of age and older. In these clinical trials, no overall differences in efficacy or safety were observed between older subjects (>65 and ≥75 years of age) and younger subjects (≤65 years of age). However, in all placebo-controlled clinical studies of on-demand use of tadalafil tablets for the treatment of ED, patients aged 65 years and older experienced diarrhea more frequently when taking tadalafil tablets (2.5% of patients) (see [Adverse Reactions]). No dose adjustment is required based on age. However, it should be considered that some older individuals are more sensitive to the drug (see [Pharmacokinetics]).
Drug interactions
1. Nitrates: Clinical pharmacology studies have shown that tadalafil tablets can enhance the antihypertensive effect of nitrates. Therefore, patients who are taking any form of organic nitrates are strictly prohibited from taking tadalafil tablets. For patients taking tadalafil tablets, nitrates should only be considered for the treatment of life-threatening conditions, otherwise they should be considered at least 48 hours after the last dose of tadalafil tablets. Even in this case, nitrates can only be given under close medical monitoring and appropriate hemodynamic testing (see [Contraindications] and [Dosage and Administration] ) .
One study evaluated the extent of interaction between nitroglycerin and tadalafil, which may be necessary in an emergency situation after taking tadalafil. This was a double-blind, placebo-controlled, crossover study in 150 male subjects (including patients with diabetes and/or controlled hypertension) who received either 20 mg of tadalafil or matching placebo once daily for 7 days. Subjects were given a single dose of 0.4 mg of sublingual nitroglycerin (NTG) at prespecified time points (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil administration) after the last dose of tadalafil. The study was designed to determine when there was no significant blood pressure interaction after tadalafil administration. This study observed significant interactions between tadalafil and NTG at each time point during the first 24 hours after dosing. No interaction between tadalafil and NTG was observed at 48 hours on most hemodynamic measures, but more subjects on tadalafil had greater reductions in blood pressure at this time point compared with placebo.
Therefore, tadalafil tablets should not be administered simultaneously with nitrates. For patients taking tadalafil tablets, nitrates should only be considered for the treatment of life-threatening conditions, otherwise they should be considered at least 48 hours after the last dose of tadalafil tablets. Even in this case, nitrates should only be administered under close medical supervision and appropriate hemodynamic monitoring (see [Contraindications]).
Alpha-blockers – Caution should be used when PDE5 inhibitors are used in combination with alpha-blockers. PDE5 inhibitors, including tadalafil tablets, and alpha-adrenergic receptor blockers are vasodilators with blood pressure-lowering effects. When vasodilators are used together, there may be an additive effect on blood pressure. The clinical pharmacology of tadalafil used in combination with doxazosin, tamsulosin, or alfuzosin has been studied (see [Precautions] and [Dosage and Administration]).
2. Effects on blood pressure when co-administered with α-blockers: Six randomized, double-blind, crossover clinical pharmacology trials studied the possible drug interactions between tadalafil and α-blockers in healthy male subjects (see [Dosage and Administration] and [Precautions]). Four of these studies administered a single dose of tadalafil to healthy male subjects who were taking α-blockers daily (for at least 7 days). The other two studies administered daily oral α-blockers to male subjects who were repeatedly taking tadalafil daily (for at least 7 days).
3. Antihypertensive drugs: PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. A clinical pharmacology study was conducted to evaluate the effect of tadalafil on the hypotensive effect of specific antihypertensive drugs (amiodarone, angiotensin II receptor blockers, bendrofluazide, enalapril and metoprolol). When tadalafil is used in combination with these drugs, blood pressure is slightly reduced compared to placebo (see [Precautions]).
4. Alcohol: Alcohol and the PDE5 inhibitor tadalafil are both mild vasodilators. When mild vasodilators are used together, their respective hypotensive effects may increase. Drinking large amounts of alcohol (such as 5 units or more) combined with tadalafil tablets may increase the likelihood of orthostatic signs and symptoms, including increased heart rate, decreased orthostatic blood pressure, dizziness and headache. Tadalafil does not affect the plasma concentration of alcohol, and alcohol does not affect the plasma concentration of tadalafil (see [Precautions]).
Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of tadalafil with alcohol was evaluated in three clinical pharmacology studies. In two of the studies, the alcohol dose was 0.7 g/kg, equivalent to 6 ounces of 80-proof (US proof) vodka (equivalent to 180 ml of 40-proof liquor) in an 80-kg male, and the tadalafil dose was 10 mg in one study and 20 mg in the other. In both studies, all patients consumed the entire dose of alcohol within 10 minutes of initiation. One of the studies demonstrated a blood alcohol concentration of 0.08%. In both studies, more patients experienced clinically significant decreases in blood pressure with the combination of tadalafil and alcohol than with alcohol alone. Orthostatic dizziness occurred in some subjects, and orthostatic hypotension was observed in some patients. When tadalafil 20 mg was taken in combination with lower doses of alcohol (0.6 g/kg, equivalent to 4 ounces of 80-proof (US proof) vodka (equivalent to 120 ml of 40-proof liquor) consumed within 10 minutes by a male weighing 80 kg), orthostatic hypotension was not observed, the incidence of dizziness was similar to that of alcohol alone, and the hypotensive effect of alcohol was not enhanced.
5. Antacids: Antacids (magnesium hydroxide/aluminum hydroxide) will reduce the apparent absorption rate of tadalafil when administered simultaneously with tadalafil, but have no effect on the AUC of tadalafil.
6. H2 antagonists (such as nizatidine): After co-administration with nizatidine, gastric pH increased significantly, but had no significant effect on pharmacokinetics.
7. Cytochrome P450 inhibitors: Tadalafil tablets are substrates of CYP3A4 and are mainly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 increase the exposure level of tadalafil.
8. CYP3A4 (such as ketoconazole): Compared with 20 mg of tadalafil administered alone, ketoconazole (400 mg/day), a potent selective inhibitor of CYP3A4, can increase the AUC of 20 mg of tadalafil by 312% and C max (maximum observed plasma concentration) by 22% after a single dose. Compared with 10 mg of tadalafil administered alone, ketoconazole (200 mg/day) can increase the AUC of 10 mg of tadalafil administered alone by 107% and C max by 15% (see [Dosage and Administration]).
9. HIV protease inhibitors: Ritonavir (500 mg or 600 mg, twice daily to reach steady state) is an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6. Relative to a single dose of 20 mg tadalafil, it can increase the AUC of a single dose of 20 mg tadalafil by 32% and reduce Cmax by 30%. Ritonavir (200 mg twice daily) can increase the AUC of a single dose of 20 mg tadalafil by 124% and Cmax remains unchanged relative to a single dose of 20 mg tadalafil . Although specific interactions have not been studied, other HIV protease inhibitors are also likely to increase the exposure level of tadalafil (see [Dosage and Administration]).
10. Cytochrome P450 inducers: Studies have shown that drugs that can induce CYP3A4 can reduce the exposure level of tadalafil.
11. Aspirin: Tadalafil does not enhance the prolonged bleeding time caused by aspirin.
12. Cytochrome P450 substrates: Tadalafil tablets are not expected to have clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoenzymes. Studies have shown that tadalafil does not inhibit or induce P450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
12. CYP1A2 (such as theophylline): Tadalafil has no significant effect on the pharmacokinetics of theophylline. When tadalafil is co-administered with theophylline, it will slightly increase the heart rate increase caused by theophylline (3 times/minute).
13. CYP2C9 (such as warfarin): Tadalafil has no significant effect on the AUC of S-warfarin or R-warfarin, and has no effect on the changes in prothrombin time caused by warfarin.
14. CYP3A4 (such as midazolam or lovastatin): Tadalafil has no significant effect on the AUC of midazolam or lovastatin.
15. P-glycoprotein (eg, digoxin): Coadministration of tadalafil (40 mg once daily) for 10 days had no significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.
Overdose
In healthy subjects, single doses of up to 500 mg and patients taking multiple doses daily totaling up to 100 mg resulted in adverse events similar to those seen at lower doses. If overdose occurs, standard supportive care should be used. Hemodialysis does not significantly improve the elimination of tadalafil.
Pharmacological Action
During sexual stimulation, the penis becomes erect due to the relaxation of the penile arteries and corpus cavernosum smooth muscles, which increases the blood flow to the penis. This reaction is mediated by nitric oxide (NO) released by nerve endings and endothelial cells. NO stimulates smooth muscle cells to synthesize cyclic guanosine monophosphate (cGMP), which causes smooth muscle relaxation and increases blood flow to the corpus cavernosum. Phosphodiesterase 5 (PDE5) is inhibited, and erectile function is enhanced by increasing cGMP.
PDE5 is present in the smooth muscle of the corpus cavernosum, vascular and visceral smooth muscle, skeletal muscle, platelets, kidneys, lungs, cerebellum and pancreas. In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. Since sexual stimulation is required to stimulate the local release of NO, the inhibition of PDE5 by tadalafil is meaningless without sexual stimulation.
PDE5 inhibition can affect the cGMP concentration in the corpus cavernosum and pulmonary artery. The same phenomenon is also observed in the smooth muscle and blood vessels of the prostate and bladder. The mechanism of action in alleviating BPH symptoms is still unclear.
In vitro studies have shown that tadalafil has a stronger effect on PDE5 than on other phosphodiesterases. These studies showed that tadalafil’s effect on PDE5 is more than 10,000 times stronger than on PDE1, PDE2, PDE4, and PDE7 in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs; more than 10,000 times stronger than on PDE3 in the heart and blood vessels; about 700 times stronger than on PDE6 involved in phototransduction in the retina; more than 9,000 times stronger than on PDE8, PDE9, and PDE10; 14 times stronger than on PDE11A1, and 40 times stronger than on PDE11A4. PDE11 is found in the human prostate, testes, skeletal muscle, and other tissues. In vitro, tadalafil inhibits recombinant PDE11A1, and at therapeutic concentrations, inhibits the activity of PDE11A4 to a lesser extent. The physiological effects and clinical implications of PDE11 inhibition in humans are not yet clear.
Toxicological effects
1. General toxicity:
Vasculitis was observed in mice, rats, and dogs when tadalafil was administered. When the exposure to free tadalafil reached 2-33 times the exposure (AUC) at the maximum recommended human dose (MRHD) of 20 mg, lymphatic necrosis and hemorrhage were observed in the spleen, thymus, and mesenteric lymph nodes of mice and rats. When the exposure reached 1-54 times, the incidence of diffuse arteritis in dogs increased; in the 12-month dog toxicity study, when the exposure reached 14-18 times, no diffuse arteritis was observed, and two dogs showed a significant decrease in white blood cells (neutrophils) and thrombocytopenia and inflammatory symptoms, which recovered after 2 weeks of drug withdrawal.
2. Genotoxicity:
The results of the Ames test, mouse lymphocyte forward mutation test, human lymphocyte chromosome aberration test, and rat micronucleus test for tadalafil were all negative.
3. Reproductive toxicity:
Oral administration of tadalafil at 400 mg/kg/day (equivalent to 14 or 26 times the MRHD in terms of free tadalafil exposure) to male or female rats did not affect fertility, reproductive behavior, or reproductive organ morphology. In dogs given tadalafil for 3-12 months, 20%-100% of the animals experienced irreversible degeneration and atrophy of the seminiferous tubule epithelial cells related to administration, and 40%-75% of the animals in the ≥10 mg/kg/day dose group experienced a decrease in sperm production. The systemic exposure of free tadalafil at the no observed toxic effect dose (NOAEL) was similar to that at the MRHD dose. Rats or mice were given tadalafil at 400 mg/kg/day for 2 years, and no testicular changes related to administration were observed.
Administration of tadalafil during the period of organogenesis in pregnant rats or mice at exposures (AUC) up to 11 times the MRHD did not result in teratogenicity, embryotoxicity, or fetotoxicity.
In a perinatal developmental toxicity study in rats, when the mother was given tadalafil at an exposure level (AUC) higher than 10 times the MRHD, the survival rate of the pups after birth was reduced; at exposure levels higher than 16 times the MRHD, maternal toxicity occurred, but the growth and development of the surviving pups were not affected.
In a perinatal developmental toxicity study in rats, reduced survival of pups was observed at 60, 200, and 1000 mg/kg of tadalafil. The maternal no observed toxicity level (NOEL) was 200 mg/kg/day (approximately 16 times the AUC of the MRHD), and the developmental toxicity NOEL was 30 mg/kg/day (approximately 10 times the AUC of the MRHD). Tadalafil and/or its metabolites can cross the placenta.
4. Carcinogenicity:
In a 2-year carcinogenicity study in rats or mice, tadalafil was administered at doses up to 400 mg/kg/day, and no carcinogenicity was observed. Based on the AUC of free tadalafil, the exposure in mice was approximately 10 times the exposure in male humans taking 20 mg MRHD, and approximately 14 and 26 times in male and female rats, respectively.
Pharmacokinetics
1. Absorption: After a single oral dose, tadalafil reaches the average maximum observed plasma concentration (C max ) in 30 minutes to 6 hours (median time 2 hours). The absolute bioavailability of tadalafil tablets after oral administration has not yet been determined. The absorption rate and extent of tadalafil are not affected by food, so tadalafil tablets can be taken with or without food.
2. Distribution: The average apparent distribution volume after oral administration is about 63 liters, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. In healthy subjects, less than 0.0005% of the dose appears in semen.
3. Metabolism: Tadalafil is mainly metabolized by CYP3A4 to catechol metabolites. Catechol undergoes extensive methylation and glucuronidation to form methylcatechol and methylcatechol glucuronic acid conjugates, respectively. The main circulating metabolite is methylcatechol glucuronic acid. The concentration of methylcatechol is less than 10% of the concentration of glucuronic acid. In vitro data indicate that the observed concentration of metabolites does not produce pharmacological activity.
4. Elimination: The average clearance of tadalafil after oral administration in healthy subjects is 2.5L/hour, and the average half-life is 17.5 hours. Tadalafil is mainly excreted in the form of inactive metabolites, mainly in the feces (about 61% of the dose), and a small amount is excreted in the urine (about 36% of the dose).
5. Elderly: The oral clearance of tadalafil in healthy elderly subjects (65 years or older) is low, making the AUC 25% higher than that of healthy subjects aged 19-45 years, with no effect on C max . There is no need to adjust the dose based on age. However, it should be taken into account that some older individuals are more sensitive to the drug (see [Usage and Dosage]).
6. Children: Tadalafil has not been evaluated in individuals under 18 years of age (see [Dosage and Administration]).
7. Diabetic patients: After male patients with diabetes were given 10 mg of tadalafil, the AUC was reduced by about 19% and the C max was reduced by about 5% compared with healthy subjects. No dose adjustment is required.
8. Liver damage: In clinical pharmacology studies, the dose of tadalafil was 10 mg, and the AUC in subjects with mild and moderate liver damage (Child-Pugh A or B) was similar to that in healthy subjects. There is currently no information on the daily use of more than 10 mg of tadalafil in patients with liver damage. There is limited data on patients with severe liver damage (Child-Pugh grade C). (See [Dosage and Administration] and [Precautions]).
9. Renal impairment: In a single-dose tadalafil (5-10 mg) clinical pharmacology study, the AUC of tadalafil doubled in patients with mild (creatinine clearance 51-80 ml/min) or moderate (creatinine clearance 31-50 ml/min) renal impairment. In subjects with end-stage renal disease undergoing hemodialysis, C max increased by 2 times and AUC increased by 2.7-4.1 times after a single dose of 10 or 20 mg tadalafil. In subjects with impaired renal function, the exposure level of total methyl catechol (free + glucuronidated) was 2-4 times that of subjects with normal renal function. Dialysis (performed 24-30 hours after administration) had no effect on tadalafil or metabolic elimination. In a clinical study (N=28) at a dose of 10 mg, back pain occurred as a limiting adverse event in male patients with moderate renal impairment. At a dose of 5 mg, the incidence and severity of back pain were not significantly different from those in the general population. No cases of back pain have been reported in patients undergoing dialysis taking 10-20 mg of tadalafil (see Dosage and Administration and Precautions).
10. Effect on blood pressure: Compared with placebo, after taking 20 mg of tadalafil, there was no significant difference in supine systolic and diastolic blood pressure (average maximum decrease of 1.6/0.8 mmHg, respectively) and standing systolic and diastolic blood pressure (average maximum decrease of 0.2/4.6 mmHg, respectively). In addition, there was no significant change in heart rate.
11. Effect on exercise stress test: A separate clinical pharmacology trial studied the effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance. This blinded crossover trial included 23 patients with stable coronary heart disease and confirmed exercise-induced cardiac ischemia. The primary endpoint was the time of cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which was not clinically significant. Further statistical analysis demonstrated that tadalafil was not inferior to placebo in terms of the time of ischemia. It should be noted that in this study, subjects in the tadalafil group took nitroglycerin sublingually after exercise, and clinically significant blood pressure reductions were observed, which is consistent with the nature of tadalafil’s ability to enhance the antihypertensive effect of nitrates.
12. Effects on vision: The Farnsworth-Munsell 100-hue color test confirmed that a single oral dose of phosphodiesterase inhibitors can cause transient dose-related damage to color discrimination ability (blue/green), reaching the maximum effect near the peak plasma concentration. This result is consistent with the effect of inhibiting PDE6, which is related to retinal phototransduction. In a study evaluating the effect of a single dose of 40 mg of tadalafil on vision (N=59), no effects on visual acuity, intraocular pressure, or pupil measurement were observed. In all clinical studies of tadalafil tablets, reports of changes in color vision were rare (<0.1% of patients).
13. Effects on sperm characteristics: Three trials were conducted in men taking 10 mg (6 consecutive months) and 20 mg (6 consecutive months and 9 consecutive months) of tadalafil daily to study the effects of tadalafil on sperm characteristics. In these three studies, no adverse effects on sperm morphology or sperm motility were observed. In the 6-month study of 10 mg tadalafil and the 9-month study of 20 mg tadalafil, the results showed that the mean sperm concentration was reduced relative to placebo, but these differences were not clinically significant. This effect was not observed in the study of 20 mg tadalafil for 6 months. In addition, compared with the placebo group, 10 or 20 mg tadalafil had no adverse effects on reproductive hormones, testosterone, luteinizing hormone, or follicle-stimulating hormone.
14. Effects on cardiac electrophysiology: A randomized, double-blind, placebo- and active drug (intravenous ibutilide)-controlled crossover study was conducted in 90 healthy male subjects aged 18-53 years to evaluate the effect of a single dose of 100 mg tadalafil on the QT interval when reaching peak plasma concentration. The mean QT c (Fridericia QT correction) change of tadalafil relative to placebo was 3.5 milliseconds (bilateral 90% CI = 1.9, 5.1). The mean QT c (individual QT correction) change of tadalafil relative to placebo was 2.8 milliseconds (bilateral 90% CI = 1.2, 4.4). The 100 mg dose of tadalafil (5 times the recommended maximum dose) was selected because the exposure level produced by this dose covers the exposure levels observed in patients with co-administration of tadalafil with strong CYP3A4 inhibitors or in patients with renal impairment. In this study, 100 mg tadalafil increased the heart rate by an average of 3.1 beats/minute compared with the placebo group.
Storage method
Store at room temperature (10-30℃).
Validity
24 months
Implementation Standards
National Food and Drug Administration National Drug Standard YBH06132022.