Date of approval.
Date of revision.
Tadalafil Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings.
1. This product is available in 5mg and 20mg sizes and is not suitable for patients using a dose of 2.5mg.
2. This product should not be taken by breaking.
Drug Name
Generic name: Tadalafil Tablets
English name: Tadalafil Tablets
Hanyu Pinyin: Tadalafei Pian
Ingredients
The main ingredient of this product is tadalafil.
Chemical name: (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]-pyrido[3,4-b]indole-1,4-dione
Chemical structure formula.
Molecular formula: C22H19N3O4
Molecular weight: 389.41
Properties
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Treatment of erectile dysfunction (ED, Erectile Dysfunction).
Treatment of erectile dysfunction (ED) combined with benign prostatic hyperplasia (BPH) signs and symptoms.
Specification】（1）5mg （2）20mg
Dosage]
Taking tadalafil tablets is not affected by eating.
Do not break open tadalafil tablets, this product should be taken whole.
Erectile dysfunction
Take Tadalafil Tablets as needed
For most patients, the recommended starting dose of tadalafil tablets on demand is 10 mg, taken prior to sexual intercourse.
The maximum recommended dosing frequency for most patients is once daily.
Tadalafil tablets taken as needed improved erectile function for up to 36 hours compared to placebo. Therefore, this factor should be considered when recommending that patients take tadalafil tablets in the optimal manner.
Once-daily tadalafil tablets
The recommended starting dose of once-daily tadalafil tablets is 2.5 mg, taken at approximately the same time each day, regardless of when sexual intercourse occurs.
The dose of once-daily tadalafil tablets may be increased to 5 mg depending on individual efficacy and tolerability.
The risks and benefits should be weighed on a patient-by-patient basis to select the appropriate treatment regimen.
Erectile dysfunction combined with benign prostatic hyperplasia
The recommended dose of tadalafil tablets is 5 mg taken once daily at approximately the same time each day without regard to when sexual intercourse occurs.
Medication for Special Populations
Renal impairment
Take tadalafil tablets as needed
Creatinine clearance of 30-50mL/min: the recommended starting dose is 5mg no more than once a day and the maximum dose is 10mg no more than once every 48 hours. Creatinine clearance<30mL/min or hemodialysis: the maximum dose is 5mg no more than once every 72 hours (see [Precautions]).
Once daily dose of tadalafil tablets
Erectile dysfunction
Creatinine clearance<30mL/min or hemodialysis: once-daily dosing of tadalafil tablets is not recommended (see [Precautions]).
Erectile dysfunction combined with benign prostatic hyperplasia
Creatinine clearance 30-50mL/min: no data available for Chinese population.
Creatinine clearance <30mL/min or hemodialysis: once-daily tadalafil tablets are not recommended (see [Precautions]).
Liver damage
Take tadalafil tablets as needed
Mild or moderate (Child Pugh classification A or B): Tadalafil tablets should not be dosed above 10 mg once daily. Once-daily dosing of tadalafil tablets has not been extensively evaluated in patients with hepatic impairment; therefore, it should be used with caution.
Severe (Child Pugh Classification C): Tadalafil Tablets are not recommended (see [Precautions]).
Once-daily dosing of tadalafil tablets
Mild or Moderate (Child Pugh Classification 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 for these patients.
Severe (Child Pugh Classification C): Tadalafil tablets are not recommended (see [Precautions]).
Elderly
For patients aged >65 years, no dose adjustment is required.
Concomitant Medications
Nitrates
Combination dosing with any form of nitrates is strictly prohibited (see [Contraindications]).
Alpha-blockers
ED-When tadalafil tablets are combined with alpha-blockers, patients treated with alpha-blockers should be stabilized before starting tadalafil tablets at the lowest recommended dose (see [Precautions], [Drug Interactions], and [Pharmacology and Toxicology]).
BPH – Tadalafil Tablets are not recommended in combination with alpha-blockers for the treatment of BPH. (See [Precautions], [Drug Interactions], and [Pharmacology and Toxicology]).
CYP3A4 (Cytochrome P450 3A4) Inhibitors
Take tadalafil tablets as needed
The maximum recommended dose of tadalafil tablets is 10 mg no more than once every 72 hours for patients who are using a combination of strong CYP3A4 inhibitors such as ketoconazole or ritonavir (see [Precautions] and [Drug Interactions]).
Once daily dosing of tadalafil tablets
For patients who are using a combination of strong CYP3A4 inhibitors such as ketoconazole or ritonavir, the recommended dose is no more than 2.5 mg (see [Precautions] and [Drug Interactions]).
[Adverse Reactions].
Clinical study experience
Because of the wide variation in conditions under which clinical trials are conducted, the rate of adverse reactions observed in clinical trials of one drug cannot be directly compared to the incidence in clinical trials of another drug, and may not reflect the incidence observed in practice.
In total, more than 9,000 men have taken tadalafil in clinical trials worldwide. In trials with once-daily tadalafil tablets, 1,434, 905 and 115 patients received treatment for at least 6 months, 1 year and 2 years, respectively. For on-demand tadalafil tablets, more than 1,300 and 1,000 subjects, respectively, received treatment for at least 6 months and 1 year.
On-demand tadalafil tablets for ED
In eight major placebo-controlled phase 3 studies lasting 12 weeks, the mean age was 59 years (range 22 to 88) and the rate of discontinuation due to adverse events was 3.1% in patients treated with tadalafil 10 mg or 20 mg, compared with 1.4% in patients treated with placebo.
The following adverse reactions occurred with on-demand tadalafil tablets when administered at the recommended dose in placebo-controlled clinical trials (see Table 1).
Table 1: In the eight major placebo-controlled phase 3 studies conducted with on-demand tadalafil tablets for the treatment of ED (including one study in patients with diabetes), the incidence was ≥2% in the tadalafil tablet (10 or 20 mg) treatment group and was higher than the placebo group for adverse reactions occurring during treatment
Adverse reactions placebo (N=476) tadalafil 5 mg (N=151) tadalafil 10 mg (N=394) tadalafil 20 mg (N=635) headache 5%11%11%15% dyspepsia 1%4%8%10% back pain 3%3%5%6% myalgia 1%1%4%3% nasal congestion 1%2%3%3% flushinga 1%2%3%3% limb pain 1%1%3%3%a Flushing including: facial flushing and flushing
Once-daily tadalafil tablets for ED
In three placebo-controlled phase 3 studies lasting 12 or 24 weeks, the mean age was 58 years (range 21 to 82) and the termination rate due to adverse events was 4.1% in patients treated with tadalafil compared with 2.8% in placebo-treated patients.
The following adverse reactions were reported in clinical trials lasting 12 weeks (see Table 2).
Table 2: In the three major 12-week placebo-controlled phase 3 studies conducted with once-daily administration of tadalafil tablets for ED (including one study in patients with diabetes), the incidence was ≥2% in the tadalafil tablet once-daily administration (2.5 or 5 mg) treatment group and was higher than the placebo group for adverse reactions occurring during treatment.
Adverse reactions placebo (N=248) tadalafil 2.5 mg (N=196) tadalafil 5 mg (N=304) headache 5%3%6% dyspepsia 2%4%5% nasopharyngitis 4%4%3% back pain 1%3%3% upper respiratory tract infection 1%3%3% flushing 1%1%3% myalgia 1%2%2% cough 0%4%2% diarrhea 0%1%2% nasal congestion 0%2% 2% limb pain 0%1%2% urinary tract infection 0%2% 0% gastroesophageal reflux disease 0%2%1% abdominal pain 0%2%1% A 24-week placebo-controlled phase 3 clinical study reported the following adverse reactions (see Table 3).
Table 3: In one 24-week placebo-controlled phase 3 study conducted with once-daily dosing of tadalafil tablets for ED, the incidence was ≥2% in the tadalafil tablet once-daily dosing (2.5 or 5 mg) treatment group and was higher than the placebo group for adverse reactions occurring during treatment
Adverse events placebo (N=94) tadalafil 2.5 mg (N=96) tadalafil 5 mg (N=97) nasopharyngitis 5% 6% 6% gastroenteritis 2% 3% 5% back pain 3% 5% 2% upper respiratory tract infection 0% 3% 4% dyspepsia 1% 4% 1% gastroesophageal reflux disease 0% 3% 2% myalgia 2% 4% 1% hypertension 0% 1% 3% nasal congestion 0% 0% 4% daily One dose of tadalafil tablets for ED combined with BPH
In three placebo-controlled clinical trials lasting 12 weeks (two conducted in patients with BPH and one in patients with ED combined with BPH) with a mean age of 63 years (range: 44 to 93 years), the rate of discontinuation due to adverse events was 3.6% in patients treated with tadalafil compared with 1.6% in placebo-treated patients. Adverse reactions leading to trial discontinuation reported by at least 2 patients in the tadalafil-treated group included headache, epigastric pain, and myalgia. The following adverse reactions were reported (see Table 4)
Table 4: In the 3 clinical studies (including 2 once-daily tadalafil tablets for BPH and 1 once-daily tadalafil tablet for ED combined with BPH) that were placebo-controlled for 12 weeks, the incidence was ≥1% in the treatment with tadalafil tablets administered once-daily (5 mg) and was higher than the placebo group for adverse reactions occurring during treatment
Adverse reactions placebo
(N=576) Tadalafil 5mg
(N=581) Headache 2.3% 4.1% Dyspepsia 0.2% 2.4% Back pain 1.4% 2.4% Nasopharyngitis 1.6% 2.1% Diarrhea 1.0% 1.4% Limb pain 0.0% 1.4% Myalgia 0.3% 1.2% Dizziness 0.5% 1.0% In addition, less frequent occurrences reported in controlled clinical trials of tadalafil tablets for BPH or ED combined with BPH adverse reactions (<1%) included: gastroesophageal reflux disease, epigastric pain, nausea, vomiting, arthralgia, and muscle cramps.
The incidence of back pain and myalgia is shown in Tables 1 through 4. In clinical pharmacology trials with tadalafil, back pain or myalgia generally occurred 12 to 24 hours after administration and usually resolved within 48 hours. Tadalafil treatment-induced back pain/myalgia is characterized by diffuse bilateral lower back, hip, thigh, or thoracolumbar muscle discomfort that is exacerbated in the prone position. Generally, the severity of pain that occurs is mild or moderate and resolves without treatment, but a lower incidence of severe back pain has been reported (all reports <5%). If treatment was required, acetaminophen or NSAIDs were generally effective; however, in the few subjects who required treatment, weak narcotics (e.g., codeine) were used. Overall, approximately 0.5% of all subjects taking tadalafil tablets on an as-needed basis discontinued treatment because of back pain/myalgia. In the 1-year open extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic tests, including measures of inflammation, muscle damage, and kidney damage, indicated no medically significant pathologic basis. See Tables 2, 3, and 4 for the incidence of once-daily tadalafil tablets for ED, BPH, and ED combined with BPH. Adverse effects of back pain and myalgia were generally mild or moderate in the studies of once-daily tadalafil tablets, with a discontinuation rate of <1% in the various studies for all indications.
In all placebo-controlled clinical trials of on-demand tadalafil tablets for ED, diarrhea occurred more frequently in patients 65 years of age and older taking tadalafil tablets (2.5% of patients).
In all studies of tadalafil tablets, reports of color vision changes were rare (<0.1% of patients).
Other less frequent (<2%) adverse events reported in controlled clinical trials of once-daily or as-needed tadalafil tablets are noted in the following subsections. The causal relationship of these events to tadalafil tablets is not clear. This list does not include very minor events, events with no clear relationship to the drug, and inaccurate and meaningless reports.
Systemic – weakness, facial edema, fatigue, pain, peripheral edema
Cardiovascular – angina pectoris, chest pain, hypotension, myocardial infarction, upright hypotension, palpitations, syncope, tachycardia
Digestive – abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, elevated r-glutamyl transferase (GGTP, Gamma Glutamyl Transpeptidase), loose stools, nausea, epigastric pain, vomiting, gastroesophageal reflux disease, bleeding hemorrhoids, rectal bleeding
Musculoskeletal – joint pain, neck pain
Nervous – dizziness, hyperalgesia, insomnia, sensory abnormalities, drowsiness, vertigo
Kidney and urinary – kidney damage
Respiratory – dyspnea, rhinorrhea, pharyngitis
Skin and adnexa – itching, rash, sweating
Eyes – blurred vision, altered color vision, conjunctivitis (including conjunctival congestion), eye pain, increased tearing, swollen eyelids
Ear – sudden decrease or loss of hearing, tinnitus
Genitourinary – increased erections, spontaneous penile erections
Post-marketing experience
The following adverse reactions were identified following the approval of tadalafil tablets for marketing. Because these adverse reactions were reported spontaneously in an indeterminate size population, it was not possible to reliably estimate their incidence or establish a causal relationship with drug exposure levels. Reasons for selecting these events included severity, frequency of reporting, lack of a clear alternative cause, or both of these reasons.
Cardiovascular and cerebrovascular – Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported post-marketing in temporal association with tadalafil administration. Most of these patients (not all) had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse, and rarely occurred after taking the drug but without sexual intercourse. Others were reported hours to days after sexual intercourse with tadalafil tablets. It cannot be determined whether these events are directly related to a combination of these factors, tadalafil tablets, sexual intercourse, the patient’s pre-existing cardiovascular disease, or other factors (see [Precautions]).
Systemic – Hypersensitivity reactions, including urticaria, Sjölder’s syndrome, and exfoliative dermatitis.
Neurological – migraine, epilepsy, and seizures, transient amnesia
Ocular – visual field loss, retinal vein occlusion, retinal artery occlusion
Non-arteritic Anterior Ischemic Optic Neuropathy (NAION, Non-arteritic Anterior Ischemic Neuropathy), a cause of vision loss including permanent blindness, is rare after marketing with phosphodiesterase 5 (PDE 5, Phosphodiesterase 5) inhibitors, including those associated with tadalafil Dalafil tablets have been reported in a temporal relationship. Most, but not all, of these patients had pre-existing anatomic or vascular risk factors for the development of NAION, including but not limited to: small cup disc (“optic disc crowding”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking (see [Caution]).
Ear – Cases of sudden hearing reduction or loss have been reported post-marketing in association with the use of PDE5 inhibitors, including tadalafil tablets, over time. Adverse events in the ear that may have been caused by medical conditions or other factors have been reported in some cases. In most cases, medical follow-up information was limited. It could not be determined whether these events were directly related to the use of tadalafil tablets, the patient’s pre-existing risk factors for loss of hearing, a combination of these factors, or other factors (see [Precautions]).
Genitourinary – Persistent erection (see [Precautions]).
[Contraindications].
Contraindicated in persons with hypersensitivity to any of the ingredients in this product.
Nitrates
Tadalafil tablets are strictly contraindicated in patients who are taking any form of nitrates, whether administered regularly and/or intermittently. Clinical pharmacology studies have shown that tadalafil tablets may enhance the antihypertensive effect of nitrates (see [Pharmacology and Toxicology]).
Hypersensitivity reactions
Tadalafil Tablets should not be administered to patients with known severe hypersensitivity to tadalafil. Hypersensitivity reactions have been reported, including Sjöld’s syndrome and exfoliative dermatitis (see [Adverse Reactions]).
Guanylate Cyclase (GC) Stimulants
PDE5 inhibitors, including tadalafil tablets, may enhance the antihypertensive effect of GC stimulants.
[Caution].
Evaluation of erectile dysfunction and BPH should include an appropriate medical evaluation to determine possible unknown etiology, and treatment options.
Before prescribing tadalafil tablets, care needs to be taken to
Cardiovascular
Because cardiac risk is correlated to some degree with sexual behavior, physicians should consider the patient’s cardiovascular health status. Therefore, treatment of erectile dysfunction, including tadalafil tablets, should not be used in men for whom sexual activity is not recommended due to a pre-existing cardiovascular condition. Patients who develop symptoms at the onset of sexual activity should be advised to avoid sexual activity and seek immediate treatment.
Physicians should discuss with patients the steps they should take if they develop angina requiring nitroglycerin treatment after taking tadalafil tablets. Patients taking tadalafil tablets should consider giving nitrates only for the treatment of life-threatening conditions; otherwise, nitrates should be considered at least 48 hours after the last dose of tadalafil tablets. Even in such cases, nitrates should be given only with close medical monitoring and appropriate hemodynamic testing. Therefore, patients who develop angina after taking tadalafil tablets should seek immediate treatment (see [Contraindications]).
Patients with left ventricular outflow tract obstruction (e.g., aortic stenosis and congenital hypertrophic subaortic stenosis) may be particularly sensitive to the effects of vasodilators, including PDE5 inhibitors.
The following patient populations with cardiovascular disease were not included in clinical safety and efficacy trials of tadalafil tablets, and therefore, until further information is available, tadalafil tablets are not recommended for use in patients who
– Have had a myocardial infarction for at least 90 days
– Unstable angina pectoris or previous angina pectoris during sexual intercourse
– Heart failure of class 2 or higher as defined by the New York Heart Association within the past 6 months
– Uncontrolled arrhythmia, hypotension (<90/50mmHg) or uncontrolled hypertension
– Previous stroke within the past 6 months
As with other PDE5 inhibitors, tadalafil has a mild systemic vasodilatory effect that may result in a transient decrease in blood pressure. In a clinical pharmacology study, tadalafil 20 mg caused a mean maximum supine blood pressure reduction of 1.6/0.8 mmHg in healthy subjects relative to placebo (see [Pharmacology and Toxicology]). Although this effect is not expected to affect most patients, physicians should carefully consider whether patients with pre-existing cardiovascular disease may be adversely affected by the vasodilatory effects of tadalafil before prescribing tadalafil tablets. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the effects of vasodilators, including PDE5 inhibitors.
Possible drug interactions with once-daily doses of tadalafil tablets
Physicians should be aware that once-daily dosing of tadalafil tablets can produce sustained plasma tadalafil concentrations and should take this into account when evaluating possible interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives, and strong inhibitors of CYP3A4) or with heavy alcohol consumption.
Prolonged erections
With these drugs, prolonged erections of more than 4 hours are rare as well as persistent erectile dysfunction (painful erections of more than 6 hours). If persistent erectile dysfunction is not treated promptly, irreversible damage to erectile tissue may occur. Patients with erections longer than 4 hours should seek emergency medical attention regardless of whether they are painful or not.
Tadalafil tablets should be used with caution in patients with factors predisposing to persistent erectile dysfunction (e.g., sickle cell anemia, multiple myeloma, or leukemia) or anatomical defects of the penis (e.g., abnormal curvature, cavernous fibrosis, or penile sclerosis).
Eye reactions
Physicians should advise patients to discontinue all phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil tablets, immediately and seek medical attention if sudden loss of vision in one or both eyes occurs. Such an event may be a symptom of non-vascular anterior ischemic optic neuropathy (NAION), a rare condition that is a cause of reduced visual acuity, including permanent blindness, and has been reported rarely after all PDE5 inhibitors have been marketed. The annual incidence of NAION has been reported in the literature to be 2.5-11.8/100,000 in men aged ≥50. An observational crossover design case study evaluated the risk of NAION episodes with PDE5 inhibitor-like medications immediately prior to the onset of NAION (within 5 half-lives) versus earlier use of PDE5 inhibitors. The results showed an approximately 2-fold increased risk of NAION with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported consistent results with a risk estimate of 2.27 (95% CI 0.99, 5.20). In these studies, other risk factors for NAION (e.g., optic disc “crowding”) may also contribute to NAION episodes.
However, neither the rare postmarketing reports nor the association of PDE5 inhibitors with NAION in these observational studies have demonstrated a causal relationship between the use of PD5 inhibitors and NAION (see [Adverse Reactions]).
Physicians should consider whether the use of PDE5 inhibitors may adversely affect patients with potential risk factors for NAION. Individuals with a history of NAION have an increased risk of reoccurrence of NAION. Therefore, PDE5 inhibitors, including tadalafil tablets, should be used with caution in these patients; and such drugs should be used when the expected benefit outweighs the risk. Individuals with low optic nerve cup/disk ratios are also considered to be at higher risk for NAION compared to the general population; however, there is insufficient evidence to support this abnormality for future screening of PDE5 inhibitor, including tadalafil tablet, users.
Patients with inherited retinal degenerative disorders, including retinitis pigmentosa, were not included in clinical trials, and tadalafil tablets are not recommended for use in these patients.
Sudden Hearing Loss
If sudden hearing loss or hearing loss occurs, physicians should advise patients to stop taking PDE5 inhibitors, including tadalafil tablets, and to seek immediate medical attention. These events may be accompanied by tinnitus and dizziness and are temporally related to the use of PDE5 inhibitors, including tadalafil tablets. It cannot be determined whether these events are directly related to the use of PDE5 inhibitors or other factors (see [ADVERSE REACTIONS]).
Alpha-blockers and antihypertensives
Physicians should discuss with patients the possibility that tadalafil tablets potentiate the hypotensive effects of alpha-blockers and antihypertensives (see [Drug Interactions] and [Pharmacologic Toxicology]).
Caution should be exercised when combining PDE5 inhibitors with alpha-blockers. PDE5 inhibitors, including tadalafil tablets, and alpha-adrenergic receptor blockers are vasodilators with hypotensive effects. When vasodilators are combined, they can have a superimposed effect on blood pressure. In some patients, the combination of these two drugs can result in a significant decrease in blood pressure (see [Pharmacologic Toxicology] and [Drug Interactions]), which may lead to symptomatic hypotension (e.g., fainting). The following conditions should be considered.
ED
– Patients should be stable on alpha-blocker therapy prior to the use of PDE5 inhibitors. Patients who have been shown to be hemodynamically unstable on alpha-blockers alone are at increased risk of symptomatic hypotension when combined with a PDE5 inhibitor.
– Patients who are stable on alpha-blocker therapy should begin PDE5 inhibitor therapy at the lowest recommended dose.
– In patients already taking optimal doses of PDE5 inhibitors, alpha-blocker therapy should be started at the lowest dose. Gradually increasing the dose of alpha-blockers while taking a PDE5 inhibitor may lower blood pressure further.
– The safety of combining PDE5 inhibitors and alpha-blockers may be affected by other factors, including intravascular hypovolemia, and other antihypertensive drugs.
(See [Dosage] and [Drug Interactions]).
BPH
The effectiveness of combining alpha-blockers with tadalafil tablets for the treatment of BPH has not been adequately studied, and the combination of tadalafil tablets with alpha-blockers is not recommended for the treatment of BPH because of the potential vasodilating effect of combining these two drugs, which can result in lower blood pressure.
– Patients receiving alpha-blockers for BPH should discontinue alpha-blockers for at least one day prior to initiating once-daily dosing of tadalafil tablets for BPH.
Renal impairment
Take tadalafil tablets as needed
For patients with end-stage renal disease with creatinine clearance <30 mL/min or on dialysis, limit the dose of tadalafil tablets to 5 mg, no more than once every 72 hours. In patients with creatinine clearance of 30 to 50 mL/min, the starting dose of tadalafil tablets should be 5 mg no more than once daily, with the maximum dose limited to 10 mg no more than once every 48 hours (see [Dosage]).
Once daily dose of tadalafil tablets
ED
Because of the increased exposure to tadalafil (AUC, Area Under Curve), limited clinical experience, and the fact that dialysis does not affect clearance, once-daily dosing of tadalafil tablets is not recommended for patients with creatinine clearance <30 mL/min.
ED combined with BPH
Once-daily tadalafil tablets are not recommended for patients with creatinine clearance <30 mL/min due to increased tadalafil exposure (AUC), limited clinical experience, and the inability of dialysis to affect clearance. No data are available for Chinese patients with creatinine clearance of 30 to 50 mL/min.
Liver damage
Take tadalafil tablets as needed
The dose of tadalafil tablets should not exceed 10 mg in patients with mild or moderate hepatic impairment. There is insufficient information available for patients with severe hepatic impairment and therefore tadalafil tablets are not recommended (see [Dosage]).
Once daily dosing of tadalafil tablets
Once-daily tadalafil tablets have not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if once-daily tadalafil tablets are prescribed to these patients. There is insufficient information available for patients with severe hepatic impairment and therefore tadalafil tablets are not recommended (see [DOSAGE]).
Alcohol
Patients should be aware that both alcohol and the PDE5 inhibitor tadalafil tablets are mild vasodilators. When combined with a mild vasodilator, their respective blood pressure lowering effects may be elevated. Therefore, physicians should inform patients that heavy alcohol consumption (e.g., 5 units or more) combined with tadalafil tablets may increase the likelihood of upright signs and symptoms, including increased heart rate, decreased upright blood pressure, dizziness, and headache (see [DOSAGE AND ADMINISTRATION] and [PHARMACOLOGY AND TOXICOLOGY]).
Combined with strong inhibitors of cytochrome P450 3A4 (CYP3A4)
Tadalafil tablets are mainly metabolized by CYP3A4 in the liver. In patients taking strong CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole, tadalafil tablets are limited to a dose of 10 mg as needed, no more than once every 72 hours (see [Drug Interactions]). In patients with a combination of strong CYP3A4 inhibitors and once-daily tadalafil tablets, the dose of tadalafil tablets should not exceed 2.5 mg (see [Dosage]).
Combination with other PDE5 inhibitors or erectile dysfunction treatment
The safety and efficacy of Tadalafil Tablets in combination with other PDE5 inhibitors or erectile dysfunction treatments have not been studied. Advise patients not to use tadalafil tablets and other PDE5 inhibitors together.
Effect on bleeding
In vitro studies have confirmed that tadalafil is a selective inhibitor of PDE5, which is found in blood platelets. Tadalafil 20 mg does not delay bleeding when administered in combination with aspirin relative to aspirin alone. There is no experience with tadalafil tablets in patients with abnormal bleeding or significantly active peptic ulcers. Although tadalafil tablets did not prolong bleeding in healthy subjects, patients with bleeding abnormalities or significantly active peptic ulcers should be administered with caution and a careful risk-benefit assessment should be performed.
Counseling of patients about sexually transmitted diseases
Tadalafil tablets do not provide protection against sexually transmitted diseases. Advise patients to take protective measures against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV, Human Immunodeficiency Virus).
Consider other urologic conditions before starting treatment for BPH
Other urologic conditions that may cause similar symptoms should be considered before starting treatment with tadalafil tablets for BPH. In addition, prostate cancer and BPH may co-exist.
[For pregnant and lactating women].
Pregnant women
Risk Summary
Tadalafil is not intended for use in women. There are no data on the use of tadalafil in pregnant women to know the risk of any adverse developmental outcomes associated with the drug. In animal reproduction studies, tadalafil at doses up to 11 times the maximum recommended human dose (MRHD, Maximum Recommended Human Dose, 20 mg/day) given orally during organogenesis produced no adverse developmental effects in pregnant rats or mice (see data below).
Animal Data-
Animal reproduction studies have shown no evidence of teratogenicity, embryotoxicity, or fetal toxicity in pregnant rats or mice given tadalafil orally during the organogenesis period at exposure levels up to 11 times the recommended maximum human dose (MRHD, 20 mg/day). In a prenatal/postnatal developmental study, the survival of postnatal pups was reduced when maternal tadalafil was given at doses reaching more than 10 times the MRHD by AUC. Symptoms of maternal toxicity occurred at doses above 16 times the MRHD according to the AUC. Surviving fetal pups had normal developmental and reproductive performance (see [Pharmacologic Toxicology]).
Another prenatal and postnatal developmental study in rats at dose levels of 60, 200 and 1000 mg/kg observed reduced survival of postnatal pups. The NOEL (No Observed Effect Level) for maternal toxicity was 200 mg/kg/day and the NOEL for developmental toxicity was 30 mg/kg/day.The exposure levels for this dose were approximately 16 and 10 times the human AUC at MRHD 20 mg, respectively.
Tadalafil and/or its metabolites can cross the rat placenta, resulting in exposure of fetal litters.
Lactating women
Risk Summary
Tadalafil tablets should not be used in women. No information is available on the secretion of tadalafil and/or its metabolites in human milk, the effect on breastfed children, or the effect on the amount of breast milk produced. Tadalafil and/or its metabolites are detectable in the milk of lactating rats at concentrations approximately 2.4 times higher than plasma concentrations.
Infertility in fertile males and females Based on data from three studies in adult males, tadalafil decreased sperm concentrations in both the 10 mg tadalafil administration for 6 months and the 20 mg tadalafil administration for 9 months study. This effect was not observed in another study of tadalafil 20 mg administered for 6 months. There was no adverse effect of either tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the reduced sperm concentration in the first two studies is unclear, and no studies have evaluated the effect of tadalafil on male fertility. In animal studies, a reduction in spermatogenesis was observed in dogs, but not in rats.
[Pediatric Use].
Tadalafil tablets are not intended for use in pediatric patients. safety and efficacy have not been established in patients under 18 years of age.
Geriatric Use]
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 or older. Of the total number of subjects in clinical studies of tadalafil for BPH (including ED combined 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 in older subjects (>65 and ≥75 years of age), compared to younger subjects (≤65 years of age). However, in all placebo-controlled clinical studies of tadalafil tablets for the treatment of ED on an as-needed basis, diarrhea occurred more frequently (2.5% of patients) when tadalafil tablets were administered to patients 65 years of age and older (see [Adverse Reactions]). No dose adjustment based on age is necessary. However, it should be considered that some older individuals are more sensitive to the drug (see [Pharmacology and Toxicology]).
Drug Interactions]
Potential for pharmacokinetic interactions with tadalafil tablets
Nitrates – Clinical pharmacology studies have shown that tadalafil tablets may enhance the antihypertensive effect of nitrates, therefore tadalafil tablets are contraindicated in patients taking any form of organic nitrates. In patients taking tadalafil tablets, nitrates should be considered only for the treatment of life-threatening conditions, and otherwise at least 48 hours after the last dose of tadalafil tablets. Even in such cases, nitrates should be given only with close medical monitoring and appropriate hemodynamic testing (see [Contraindications], [Dosage], and [Pharmacologic Toxicology]).
Alpha-blockers – Caution should be exercised when PDE5 inhibitors are combined with alpha-blockers. PDE5 inhibitors, including tadalafil tablets, and alpha-adrenoceptor blockers are vasodilators with hypotensive effects. When vasodilators are combined, there may be a superimposed effect on blood pressure. The clinical pharmacology of tadalafil in combination with doxazosin, tamsulosin, or alfuzosin has been studied (see [Precautions], [Dosage], and [Pharmacology and Toxicology]).
Antihypertensives – PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the hypotensive effects of specific antihypertensive drugs (amiodarone, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). The combination of tadalafil with these drugs resulted in a slight decrease in blood pressure relative to placebo (see [Precautions] and [Pharmacologic Toxicology]).
Alcohol – Both alcohol and the PDE5 inhibitor tadalafil are mild vasodilators. When mild vasodilators are combined, their respective blood pressure-lowering effects may be elevated. Heavy alcohol consumption (e.g., 5 units or more) combined with tadalafil tablets may increase the likelihood of upright signs and symptoms, including increased heart rate, decreased upright blood pressure, dizziness, and headache. Tadalafil does not affect the plasma concentration of alcohol, nor does alcohol affect the plasma concentration of tadalafil (see [Precautions] and [Pharmacology and Toxicology]).
The effect of other drugs on tadalafil tablets (see [Dosage] and [Precautions]).
Antacids – Antacids (magnesium hydroxide/aluminium hydroxide) reduce the apparent absorption rate of tadalafil when administered concomitantly with tadalafil, but have no effect on the AUC of tadalafil.
H2 antagonists (e.g., nizatidine)-a significant increase in gastric pH upon coadministration with nizatidine had no significant effect on pharmacokinetics.
Cytochrome P450 inhibitors – Tadalafil tablets are substrates of CYP3A4 and are primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 increase the exposure levels of tadalafil.
CYP3A4 (e.g., ketoconazole) – Relative to tadalafil 20 mg alone, ketoconazole (400 mg/day), a potent and selective inhibitor of CYP3A4, increased the AUC of tadalafil 20 mg single dose by 312% and the Cmax (maximum observed plasma concentration) by 22%. Ketoconazole (200 mg/day) increased the AUC of tadalafil 10 mg by 107% and the Cmax by 15% relative to tadalafil 10 mg administered alone (see [DOSAGE]).
Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, may also increase tadalafil exposure levels.
The HIV protease inhibitor, ritonavir (500 mg or 600 mg twice daily up to steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, relative to 20 mg tadalafil single dosing, increased the AUC of tadalafil 20 mg single dosing 32% increase and 30% decrease in Cmax. Ritonavir (200 mg twice daily), relative to tadalafil 20 mg alone, increased the AUC of tadalafil 20 mg single dose by 124% with no change in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors are also likely to increase tadalafil exposure levels (see [DOSAGE]).
Cytochrome P450 inducers – Studies have shown that drugs that induce CYP3A4 can reduce exposure levels of tadalafil.
CYP3A4 (e.g., rifampin) – Rifampin (600 mg/day), a CYP3A4 inducer, reduced the AUC of tadalafil by 88% and the Cmax by 46% compared to tadalafil 10 mg administered alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin and phenobarbital, may also reduce tadalafil exposure levels. No dose adjustment is required. Decreased exposure levels resulting from concomitant administration of tadalafil with rifampin or other CYP3A4 inducers would reduce the efficacy of once-daily dosing of tadalafil tablets by an unknown amount.
Effects of Tadalafil Tablets on Other Drugs
Aspirin-Tadalafil does not enhance aspirin-induced prolongation of bleeding time.
Cytochrome P450 Substrates – For drugs metabolized by cytochrome P450 (CYP) isoenzymes, tadalafil tablets are not expected to have clinically significant inhibition or induction of clearance. Studies have shown that tadalafil does not inhibit or induce the P450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
CYP1A2 (e.g., theophylline)-Tadalafil has no significant effect on the pharmacokinetics of theophylline. Tadalafil slightly increases theophylline-induced heart rate acceleration (3 beats/min) when administered in combination with theophylline.
CYP2C9 (e.g., warfarin)-tadalafil had no significant effect on the AUC of S-warfarin or R-warfarin and no effect on warfarin-induced changes in prothrombin time.
CYP3A4 (e.g. midazolam or lovastatin)-Tadalafil had no significant effect on the AUC of midazolam or lovastatin.
P-glycoprotein (e.g., digoxin)-tadalafil (40 mg once daily) co-administration for 10 days had no significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.
[Drug Overdose].
In healthy subjects with single doses up to 500 mg and patients with multiple daily doses up to a total of 100 mg, the adverse events were similar to those at lower doses. If overdose occurs, standard supportive therapy should be used. Hemodialysis is not very helpful in the elimination of tadalafil.
Pharmacology and Toxicology
Pharmacological effects
During sexual stimulation, the penis erects due to increased blood flow to the penis caused by relaxation of the penile arteries and smooth muscles of the penile corpus cavernosum. This response is mediated by nitric oxide (NO) release from 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 penile corpus cavernosum. Inhibition of phosphodiesterase 5 (PDE5) enhances erectile function by increasing cGMP.
PDE5 is present in penile cavernous smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum and pancreas. In vitro studies have shown that tadalafil is a selective inhibitor of PDE5. Since sexual stimulation is required to stimulate local release of NO, tadalafil inhibition of PDE5 is not meaningful in the absence of sexual stimulation.
PDE5 inhibition affects cGMP concentrations in the penile corpus cavernosum and pulmonary arteries, and the same has been observed in smooth muscle and blood vessels of the prostate and bladder, and the mechanism of action for reducing BPH symptoms is not yet clear.
In vitro studies have shown that tadalafil has a stronger effect on PDE5 than on other phosphodiesterases. These studies show that tadalafil is more than 10,000 times more potent against PDE5 than against PDE1, PDE2, PDE4 and PDE7 in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs; more than 10,000 times more potent than against PDE3 in the heart and blood vessels; about 700 times more potent than against PDE6 in the retina, which is involved in phototransduction; and more potent than against PDE11 is found in human prostate, testis, skeletal muscle and other tissues. In vitro, tadalafil inhibits recombinant PDE11A1 and, at therapeutic concentrations, inhibits PDE11A4 activity to a lesser extent. The physiological effects and clinical implications of PDE11 inhibition in humans are unclear.
Toxicological studies
General toxicity.
Vasculitis was seen in mice, rats and dogs given tadalafil. Lymphatic necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes of mice and rats when free tadalafil exposure reached 2 to 33 times the exposure (AUC) at the maximum recommended human dose (MRHD) of 20 mg. The incidence of diffuse arteritis was increased in dogs when it reached 1 to 54 times; in the 12-month canine toxicity test, diffuse arteritis was not seen when it reached 14 to 18 times, and 2 dogs showed a significant decrease in leukocytes (neutrophils) and decreased platelets and signs of inflammation, which recovered 2 weeks after discontinuation of the drug.
Genotoxicity.
Results of the tadalafil Ames test, mouse lymphocyte forward mutation test, human lymphocyte chromosome aberration test and rat micronucleus test were negative.
Reproductive toxicity.
No effects on fertility, reproductive behavior or reproductive organ morphology were observed in male or female rats given tadalafil 400 mg/kg/day orally (equivalent to 14 or 26 times the MRHD based on free tadalafil exposure). In dogs given tadalafil for 3 to 12 months, 20% to 100% of animals showed irreversible varicocele epithelial cell degeneration and atrophy associated with the administration, and 40% to 75% of animals in the ≥10 mg/kg/day dose group showed reduced spermatogenic counts. Systemic exposure of free tadalafil at the no observed toxic response dose (NOAEL) was similar to that at the MRHD dose. No testicular changes associated with administration were seen in rats or mice given tadalafil 400 mg/kg/day for 2 consecutive years.
No teratogenicity, embryotoxicity, or fetal toxicity was seen in pregnant rats or mice given tadalafil during the organogenesis phase at exposures (AUC) up to 11 times that of MRHD.
In a rat perinatal developmental toxicity assay, postnatal pup survival was reduced when maternal tadalafil was given at levels higher than 10 times the MRHD exposure (AUC); maternal toxicity occurred at exposure levels higher than 16 times the MRHD exposure level, but growth and development of surviving pups were not affected.
In a perinatal developmental toxicity test in rats, reduced pup survival at birth was seen with tadalafil at doses of 60, 200 and 1000 mg/kg. The maternal NOEL was 200 mg/kg/day (approximately 16 times the AUC for MRHD exposure) and the NOEL for developmental toxicity was 30 mg/kg/day (approximately 10 times the AUC for MRHD exposure). Tadalafil and/or its metabolites are able to cross the placenta.
Carcinogenicity.
No carcinogenicity was seen with tadalafil administered at doses up to 400 mg/kg/day in a 2-year carcinogenicity test in rats or mice. Exposure in mice was approximately 10 times greater than exposure in human males at 20 mg of MRHD, and approximately 14 and 26 times greater in male and female rats, respectively, based on the AUC of free tadalafil.
Clinical Pharmacology
Effects on blood pressure
Compared to placebo, there was no significant difference in systolic and diastolic blood pressure in supine (mean maximum decrease of 1.6/0.8 mmHg, respectively) and in standing (mean maximum decrease of 0.2/4.6 mmHg, respectively) in healthy male subjects receiving tadalafil 20 mg. In addition, there were no significant changes in heart rate.
Effect on blood pressure when administered in combination with nitrates
Clinical pharmacology studies have shown that tadalafil (5-20 mg) enhances the antihypertensive effect of nitrates. Therefore, tadalafil tablets are strictly contraindicated in patients taking any form of nitrates (see [Contraindications]).
One study evaluated the extent of nitroglycerin and tadalafil interactions that may require nitroglycerin in emergency situations following tadalafil administration. This was a double-blind, placebo-controlled, crossover study in 150 male subjects (including patients with diabetes and/or controlled hypertension) who received a once-daily 20 mg dose of tadalafil or matching placebo for a total of 7 days. After the last dose of tadalafil, subjects were given a single 0.4 mg sublingual dose of nitroglycerin (NTG, Nitroglycerin) at pre-specified time points (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil administration). This study was conducted to determine when there was no significant blood pressure interaction after tadalafil administration. This study observed a significant interaction between tadalafil and NTG at each time point during the first 24 hours after administration. At 48 hours according to most hemodynamic indices, no interaction between tadalafil and NTG was observed, but subjects with more tadalafil had a greater reduction in blood pressure at this time point compared to placebo. At 48 hours, this interaction was not detected (see Figure 1).
Figure 1: Maximum change in mean blood pressure induced by sublingual nitroglycerin at 2 (supine only), 4, 8, 24, 48, 72 and 96 hours after the last dose of tadalafil 20 mg or placebo (tadalafil-placebo, point estimates and 90% CI)
Therefore, tadalafil tablets should not be administered concomitantly with nitrates. In patients taking tadalafil tablets, nitrates should be considered for administration only for the treatment of life-threatening conditions, and otherwise at least 48 hours after the last dose of tadalafil tablets. Even in such cases, nitrates should be given only with close medical monitoring and appropriate hemodynamic testing (see [Contraindications]).
Effect on blood pressure when administered in combination with alpha-blockers
Six randomized, double-blind, crossover clinical pharmacology trials investigated possible drug interactions between tadalafil and alpha-blockers in healthy male subjects (see [DOSAGE] and [PRECAUTIONS]). Four of the studies gave single doses of tadalafil to healthy male subjects taking an alpha-blocker daily (for at least 7 days). The other two studies gave daily oral alpha-blockers (for at least 7 days) to male subjects who were given repeated daily doses of tadalafil.
Doxazosin – Three clinical pharmacology studies of tadalafil were conducted with doxazosin, an alpha1-adrenoceptor blocker.
A crossover design was used in the first doxazosin study in 2 cycles, in which a single oral dose of 20 mg of tadalafil or placebo was given to healthy subjects who received doxazosin 8 mg orally once daily (N=18 subjects). After doxazosin administration for at least 7 days, doxazosin and tadalafil or placebo were given simultaneously (see Table 5 and Figure 2).
Table 5: Doxazosin Study 1: Mean Maximum Reduction in Systolic Blood Pressure (95% CI)
Mean maximum reduction in systolic blood pressure net of placebo (mmHg) tadalafil 20 mg supine position 3.6 (1.5, 8.8) standing position 9.8 (4.1, 15.5)
Figure 2: Doxazosin Study 1: Mean change in systolic blood pressure relative to baseline
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Subjects with one or more standing systolic blood pressures less than 85 mmHg or a reduction in standing systolic blood pressure from baseline of more than 30 mmHg were considered outliers. There were nine and three abnormalities after tadalafil and placebo administration, respectively. After tadalafil and placebo administration, 5 and 2 subjects, respectively, were abnormal because the reduction in standing systolic blood pressure from baseline exceeded 30 mmHg, while 5 and 1 subject were abnormal because the standing systolic blood pressure was less than 85 mmHg. Serious adverse events that may be related to blood pressure effects were evaluated. No such adverse events were reported in the placebo group. Two such events were reported in the tadalafil group. 1 subject developed vertigo 7 hours after dosing and it lasted for about 5 days. This subject had previously experienced a mild episode of vertigo while receiving doxazosin and placebo. Another subject experienced dizziness 25 minutes after dosing that lasted for 1 day. No fainting was reported.
In the second doxazosin study, a single oral dose of 20 mg of tadalafil was given to healthy subjects who received doxazosin orally at 4 or 8 mg/day. The study was conducted in 3 parts (N=72 subjects), each with a 3-cycle crossover.
In part A (N=24), the dose of doxazosin was increased to 4 mg for subjects administered once daily at 8 am. Tadalafil was administered at 8 am, 4 pm or 8 pm daily. There was no placebo control.
In part B (N=24), the dose of doxazosin was increased to 4 mg for subjects administered once daily at 8 am. Tadalafil was administered at 8 am, 4 pm or 8 pm daily. There was no placebo control.
In part C (N=24), the dose of doxazosin was increased to 8 mg for subjects administered once daily at 8 am. In this part, tadalafil or placebo was given at 8 am or 8 pm.
Table 6 and Figure 3 give the mean maximum reduction in systolic blood pressure net of placebo over 12 hours after dosing in the placebo control part (Part C).
Table 6: Doxazosin Study 2 (Part C): Mean Maximum Decrease in Systolic Blood Pressure
Mean maximum reduction in systolic blood pressure net of placebo (mmHg) tadalafil 20 mg, 8 am tadalafil 20 mg, 8 pm ambulatory blood pressure monitoring (ABPM, Ambulatory Blood Pressure Monitoring)78
Figure 3: Doxazosin Study 2 (Part C): Time-matched Mean Change in Systolic Blood Pressure Relative to Baseline
Blood pressure was measured by ambulatory blood pressure monitoring (ABPM) every 15 to 30 minutes for 36 hours after tadalafil or placebo administration. If one or more systolic blood pressure readings <85 mmHg or a decrease in systolic blood pressure relative to time-matched baseline >30 mmHg were recorded during the analysis period, the subject was an abnormal.
Of the 24 subjects in Part C, 16 subjects in the tadalafil group were abnormal and 6 subjects in the placebo group were abnormal within 24 hours of tadalafil or placebo administration at 8 am. Of these, 5 and 2 abnormalities in the tadalafil or placebo groups, respectively, were due to a systolic blood pressure <85 mmHg, whereas 15 and 4 abnormalities were due to a decrease in systolic blood pressure relative to baseline >30 mmHg.
Seventeen subjects in the tadalafil group and seven subjects in the placebo group were classified as abnormal within 24 hours after the 8 pm dosing. Of these, 10 and 2 abnormalities in the tadalafil or placebo groups, respectively, were due to a systolic blood pressure <85 mmHg, while 15 and 5 abnormalities were due to a decrease in systolic blood pressure relative to baseline >30 mmHg.
A number of other subjects in both the tadalafil and placebo groups were judged to be abnormal after 24 hours.
Serious adverse events that may be related to blood pressure effects were evaluated. In this study (N=72 subjects), two occurred in the tadalafil group (one subject experienced symptomatic hypotension beginning 10 hours after dosing and lasting approximately 1 hour, and another subject experienced dizziness beginning 11 hours after dosing and lasting for 2 minutes). No such adverse events occurred in the placebo group. Prior to tadalafil administration, one subject experienced a serious event (dizziness) during doxazosin introduction.
In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once-daily dosing of tadalafil 5 mg or placebo in a two-cycle crossover design. after 7 days, the starting dose of doxazosin was 1 mg, which was gradually increased to 4 mg/day during the last 21 days of each cycle (7 days 1 mg; 7 days 2 mg; 7 days 4 mg doxazosin). The results are shown in Table 7.
Table 7: Doxazosin Study 3: Mean maximum reduction in systolic blood pressure (95% CI)
Mean maximum reduction in systolic blood pressure tadalafil 5 mg day 1 4 mg doxazosin supine 2.4 (-0.4, 5.2) standing -0.5 (-4.0, 3.1) day 7 4 mg doxazosin supine 2.8 (-0.1, 5.7) standing 1.1 (-2.9, 5.0) On the first day of each doxazosin dose at 30 and 15 pre-dose minutes, and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after doxazosin administration, and on day 7 of 4 mg doxazosin administration, blood pressure was measured manually.
After the first dose of doxazosin 1 mg, there were no abnormalities in the tadalafil 5 mg group and one abnormal standing systolic blood pressure reduction relative to baseline of >30 mmHg with placebo.
After the first dose of doxazosin 2mg, there were 2 abnormalities in the tadalafil 5mg group and no abnormalities with placebo because of the reduction in standing systolic blood pressure relative to baseline of >30mmHg.
After the first dose of doxazosin 4mg, there were no abnormalities in the tadalafil 5mg group and 2 abnormalities in the placebo because of a reduction in standing systolic blood pressure relative to baseline>30mmHg. After the first dose of doxazosin 4 mg, there was one abnormal in the tadalafil 5 mg group and three abnormal in the placebo group due to standing systolic blood pressure & lt;85 mm Hg. On the seventh day after doxazosin 4 mg administration, there were no abnormal in the tadalafil 5 mg group, one patient in the placebo group had a reduction in standing systolic blood pressure relative to baseline of >30 mm Hg, and one patient had a reduction in standing systolic blood pressure & lt;85 mm Hg. All adverse events that may be related to blood pressure effects were mild or moderate. In this study, two syncopal episodes occurred, one subject after tadalafil 5 mg alone and the other after concomitant administration of tadalafil 5 mg and doxazosin 4 mg.
Tamsulosin – In the first tamsulosin study, a single oral dose of 10, 20 mg of tadalafil or placebo was given to healthy subjects taking tamsulosin (a selective adrenergic alpha 1A receptor blocker) 0.4 mg once daily in a crossover design over 3 cycles (N=18 subjects). Tadalafil or placebo was given at least 7 days after tamsulosin administration and 2 hours after tamsulosin administration.
Table 8: Tamsulosin Study 1: Mean Maximum Reduction in Systolic Blood Pressure (95% CI)
Mean maximum reduction in systolic blood pressure (mmHg) net of placebo Tadalafil 10 mg Tadalafil 20 mg Supine position 3.2 (2.3, 8.6) 3.2 (2.3, 8.7) Standing position 1.7 (4.7, 8.1) 2.3 (4.1, 8.7) At 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours after tadalafil or placebo administration. Blood pressure was measured manually. There were 2, 2 and 1 abnormalities in the tadalafil 10 mg, 20 mg and placebo groups, respectively (subjects with a standing systolic blood pressure decrease of >30 mmHg relative to baseline at one or more time points). No subject had a standing systolic blood pressure <85 mm Hg. There were no serious adverse events that could be related to blood pressure effects. No fainting occurred.
In the second tamsulosin study, healthy subjects (N=39 treated; 35 completed) were given once daily for 14 days in a two-cycle crossover design with tadalafil 5 mg or placebo. Tamsulosin 0.4 mg was added once daily on the last 7 days of each cycle.
Table 9: Tamsulosin Study 2: Mean maximum reduction in systolic blood pressure (95% CI)
Mean maximum reduction in systolic blood pressure net of placebo Tadalafil 5 mg tamsulosin day 1 supine -0.1 (-2.2, 1.9) standing 0.9 (-1.4, 3.2) tamsulosin day 7 supine 1.2 (-1.2, 3.6) standing 1.2 (-1.0, 3.5) 30 and 15 minutes before tamsulosin administration on day 1, day 6 and day 7, and Blood pressure was measured manually 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours after dosing. Those without abnormalities (subjects with a standing systolic blood pressure decrease of >30 mmHg relative to baseline at one or more time points). One subject on placebo combined with tamsulosin (day 7), and one subject on tadalafil combined with tamsulosin (day 6), had a standing blood pressure <85 mm Hg. There were no serious adverse events that could be related to blood pressure effects. No fainting occurred.
Alfuzosin – Tadalafil 20 mg or placebo was administered as a single oral dose in a 2-cycle crossover design in healthy subjects taking alfuzosin hydrochloride (an adrenergic alpha 1A receptor blocker) 10 mg extended-release tablets once daily (N=17 completed subjects). After at least 7 days of alfuzosin administration, tadalafil or placebo was administered 4 hours after alfuzosin administration.
Table 10: Alfuzosin study: mean maximum reduction in systolic blood pressure (95% CI)
Mean maximum reduction in systolic blood pressure (mmHg) net of placebo Tadalafil 20mg supine 2.2 (-0.9, -5.2) standing 4.4 (-0.2, 8.9) Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20 and 24 hours after tadalafil or placebo administration. There was one abnormality in the tadalafil 20 mg group (systolic blood pressure less than 85 mmHg in the standing position). No subject had a reduction in standing systolic blood pressure from baseline of more than 30 mm Hg at one or more time points. there were no serious adverse events that could be related to blood pressure effects. No fainting occurred.
Effect on Blood Pressure When Administered in Combination with Antihypertensive Drugs
Amiodarone – One study evaluated the interaction of amiodarone (5 mg once daily) with tadalafil 10 mg. Tadalafil had no effect on the blood concentrations of amiodarone, and amiodarone had no effect on the blood concentrations of tadalafil. In subjects taking amiodarone, the mean reduction in supine systolic/diastolic blood pressure relative to placebo due to tadalafil was 3/2 mm Hg. A similar study using tadalafil 20 mg showed no clinically significant difference between tadalafil and placebo in subjects taking amiodarone.
Angiotensin II receptor blockers (with or without other antihypertensive agents) – This study evaluated the interaction of angiotensin II receptor blockers with tadalafil 20 mg. Subjects in the study took a marketed angiotensin II receptor blocker, alone, or as one of the components in a combination product, or as part of a multidrug antihypertensive regimen. After administration, ambulatory blood pressure measurements revealed a systolic/diastolic difference of 8/4 mmHg between tadalafil and placebo.
Bendroflumethiazide – One study evaluated the interaction of bendroflumethiazide (2.5 mg once daily) with tadalafil 10 mg. After administration, in subjects taking bendroflumethiazide, the tadalafil 10 mg group caused a mean supine systolic/diastolic blood pressure reduction of 6/4 mmHg compared to the placebo group.
Enalapril – One study evaluated the interaction of enalapril (10 to 20 mg once daily) with tadalafil 10 mg. After administration, in subjects taking enalapril, the tadalafil 10 mg group caused a mean supine systolic/diastolic blood pressure reduction of 4/1 mmHg compared to the placebo group.
Metoprolol – One study evaluated the interaction of extended-release metoprolol (25 to 200 mg once daily) with tadalafil 10 mg. After administration, in subjects taking metoprolol, the tadalafil 10 mg group caused a mean supine systolic/diastolic blood pressure reduction of 5/3 mmHg compared to the placebo group.
Effects on blood pressure when administered concomitantly with alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of tadalafil with alcohol was evaluated in 3 clinical pharmacology studies. In 2 of the studies, the dose of alcohol given was 0.7 g/kg, equivalent to 6 oz of 80 proof (US strength) vodka (equivalent to 180 ml of 40 proof white wine) in men weighing 80 kg. The dose of tadalafil was 10 mg in one study and 20 mg in the other. in both studies, all patients consumed the the entire dose of alcohol. One of the studies confirmed a blood alcohol concentration of 0.08%. In both studies, clinically significant reductions in blood pressure occurred in more patients with tadalafil combined with alcohol compared to alcohol alone. Upright dizziness occurred in some subjects, and upright hypotension was observed in some patients. When tadalafil 20 mg was combined with a lower dose of alcohol (0.6 g/kg, equivalent to 4 ounces of 80 proof (US strength) vodka (equivalent to 120 mL of 40 proof white wine) consumed over 10 minutes by a male weighing 80 kg), no upright hypotension was observed, the incidence of dizziness was similar to that of alcohol alone, and the antihypertensive effect of alcohol was not enhanced.
Tadalafil does not affect the plasma concentration of alcohol, nor does alcohol affect the plasma concentration of tadalafil.
Effect on Exercise Stress Test
A separate clinical pharmacology trial investigated the effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance. This blinded crossover trial had 23 patients with stable coronary artery disease and confirmed exercise-induced cardiac ischemia. The primary endpoint was the time to onset of cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo) and was not clinically significant. Further statistical analysis demonstrated that for time to onset of ischemia, tadalafil was not inferior to placebo. It is important to note that in this study, a clinically significant reduction in blood pressure was observed in subjects in the tadalafil group who took sublingual nitroglycerin after exercise, consistent with the nature of tadalafil’s ability to enhance the antihypertensive effect of nitrates.
Effects on visual acuity
Using the FarnsworthMunsell 100hue color test, it was demonstrated that a single oral dose of a phosphodiesterase inhibitor produced a transient dose-related impairment in color discrimination (blue/green), with a maximum effect near peak plasma concentration. This result is consistent with the inhibition of PDE6, which is related to phototransduction in the retina. In a study evaluating the effect of a single dose of tadalafil 40 mg on visual acuity (N=59), no effect on visual acuity, intraocular pressure or pupillometry was observed. In all clinical studies of tadalafil tablets, reports of changes in color vision were rare (<0.1% of patients).
Effects on sperm characteristics
Three trials were conducted in men taking tadalafil 10 mg daily (for 6 consecutive months) and 20 mg daily (for 6 consecutive months and 9 consecutive months) to study the effect of tadalafil on sperm characteristics. In all three studies, no adverse effects on sperm morphology or sperm viability were observed. In the 6-month study with 10 mg tadalafil, and in the 9-month study with 20 mg tadalafil, the results showed a decrease in mean sperm concentration relative to placebo, but these differences were not clinically significant. In contrast, this effect was not observed in the 6-month study with 20 mg tadalafil administration. In addition, there were no adverse effects of 10 or 20 mg tadalafil on reproductive hormones, testosterone, luteinizing hormone, or follicle stimulating hormone compared to the placebo group.
Effects on cardiac electrophysiology
A randomized, double-blind, placebo- and positive-drug (ibrit IV administration) controlled crossover study was conducted in 90 healthy male subjects aged 18 to 53 years to evaluate the effect of a single administration of 100 mg tadalafil up to peak plasma concentration on the QT interval. The mean QTc (Fridericia QT corrected) change for tadalafil relative to placebo was 3.5 ms (two-sided 90% CI=1.9, 5.1). The mean QTc (individual QT corrected) change for tadalafil relative to placebo was 2.8 ms (bilateral 90% CI=1.2, 4.4). The 100 mg dose of tadalafil (5 times the recommended maximum dose) was chosen because this dose produced exposure levels that encompassed those observed with tadalafil in combination with strong inhibitors of CYP3A4 or in patients with renal injury. In this study, 100 mg of tadalafil increased heart rate by a mean of 3.1 beats per minute compared to the placebo group.
[Pharmacokinetics].
Foreign trial data
In healthy subjects, the AUC of tadalafil increased proportionally with dose in the dose range of 2.5 to 20 mg. Steady-state blood levels were reached within 5 days with once-daily dosing, and exposure levels were approximately 1.6 times higher than after a single dose. In a separate study of healthy male subjects, mean tadalafil concentrations were determined after a single dose of tadalafil 20 mg, as well as after a single dose of 5 mg and multiple doses once daily (see Figure 4).
Figure 4: Plasma tadalafil concentrations (mean ± SD) after tadalafil 20 mg single dose, and 5 mg single and once daily multiple doses
Absorption – After a single oral administration, tadalafil reached the mean maximum observed plasma concentration (Cmax) between 30 minutes and 6 hours (median time 2 hours). The absolute bioavailability of tadalafil tablets after oral administration has not been clarified.
The rate and extent of tadalafil absorption is not affected by food, so tadalafil tablets may be taken with or without food.
Distribution – The mean apparent volume of distribution following oral administration was approximately 63 liters, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil is protein bound within plasma.
In healthy subjects, less than 0.0005% of the dose administered appeared within the semen.
Metabolism – Tadalafil is metabolized primarily by CYP3A4 to catechol metabolites. Catechol undergoes extensive methylation and glucuronidation to form methyl catechol and methyl catechol glucuronide conjugates, respectively. The major circulating metabolite is methyl catechol glucuronide. The concentration of methyl catechol is less than 10% of the glucuronide concentration. In vitro data suggest that the observed metabolite concentrations do not produce pharmacological activity.
Elimination – The mean oral clearance of tadalafil in healthy subjects was 2.5 L/hour, with a mean half-life of 17.5 hours. 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).
Elderly – Oral tadalafil clearance is lower in healthy elderly subjects (65 years of age or older), resulting in a 25% higher AUC than in healthy subjects 19 to 45 years of age, with no effect on Cmax. No separate dose adjustment based on age is required. However, the higher sensitivity of the drug in certain older individuals should be taken into account (see [DOSAGE]).
Children – Tadalafil has not been evaluated in individuals under 18 years of age (see [DOSAGE AND ADMINISTRATION]).
Diabetic patients – After administration of tadalafil 10 mg in male patients with diabetes, the AUC was reduced by approximately 19% and the Cmax by approximately 5% compared to healthy subjects. No dose adjustment was required.
Liver damage
In clinical pharmacology studies, tadalafil administered at a dose of 10 mg had an AUC similar to that of healthy subjects in subjects with mild and moderate hepatic impairment (Child-Pugh class A or B). No information is available on the administration of more than 10 mg of tadalafil daily in patients with hepatic impairment. There are limited data on patients with severe liver impairment (Child-Pugh Class C). (See [Dosage] and [Precautions]).
Renal Impairment
In single-dose tadalafil (5 to 10 mg) clinical pharmacology studies, the AUC of tadalafil doubled in patients with mild (creatinine clearance 51 to 80 ml/min) or moderate (creatinine clearance 31 to 50 ml/min) renal impairment. In subjects with end-stage renal disease undergoing hemodialysis, a twofold increase in Cmax and a 2.7- to 4.1-fold increase in AUC after a single administration of 10 or 20 mg of tadalafil. Exposure levels of total methylcatechol (free + glucuronidated) were 2 to 4 times higher in subjects with impaired renal function than in those with normal renal function. Dialysis (administered 24 to 30 hours after dosing) 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. The incidence and severity of back pain at a dose of 5 mg was not significantly different from the general population. In patients undergoing dialysis, no cases of back pain were reported with 10 to 20 mg of tadalafil (see [DOSAGE AND ADMINISTRATION] and [PRECAUTIONS]).
Imported Drug Trial Data in China
A double-blind, parallel-group, placebo-controlled, single-dose tadalafil 10 mg and 20 mg, triple-crossover pharmacokinetic trial was conducted in 24 healthy Chinese male subjects to study the pharmacokinetic profile of a single dose of 10 mg or 20 mg tadalafil in healthy Chinese men (see Figure 5, Table 11 for results).
Table 11: Geometric mean (CV%) of pharmacokinetic parameters after a single oral dose of 10 mg versus 20 mg tadalafil
Pharmacokinetic parameters 10 mg tadalafil tablets 20 mg tadalafil tablets Cmax (ng/mL) 172 (23.5) 274 (23.5) tmaxa (h) 3.00 (1.00 to 4.00) 4.00 (0.50 to 4.00) t1/2b (h) 17.9 (11.7 to 33.3) 18.7 (10.8 to 33.7) AUC (0-tlast) (ng-h/mL) 3750 (28.7) 7180 (30.9) AUC (0-∞) (ng-h/mL) 3820 (29.2) 7370 (31.8) CL/F (L/h) 2.61 (29.2) 2.71 (31.8) VZ/F (L) 67.6 (22.4) 73.2 ( 20.0)a Mean (range)
bGeometric mean (range)
Figure 5: Serum tadalafil concentration-time profiles after single dose oral administration of 10 mg and 20 mg tadalafil
(Mean ± SD)
Storage】Sealed and stored at room temperature (10~30℃).
Package】Aluminum-plastic plate packaging (PVC solid pharmaceutical rigid tablets, aluminum foil for pharmaceutical packaging)
5mg: 1 tablet/plate/box, 4 tablets/plate×1 plate/box, 4 tablets/plate×2 plate/box, 4 tablets/plate×3 plate/box, 7 tablets/plate×1 plate/box, 7 tablets/plate×2 plate/box, 7 tablets/plate×4 plate/box, 10 tablets/plate×1 plate/box, 10 tablets/plate×2 plate/box, 10 tablets/plate×3 plate/box, 12 tablets/plate×1 plate/box, 12 tablets/plate×3 plate/box, 14 tablets/ plate×1 plate/box, 14 tablets/plate×2 plate/box, 14 tablets/plate×4 plate/box, 15 tablets/plate×1 plate/box, 15 tablets/plate×2 plate/box, 15 tablets/plate×4 plate/box.
20mg: 1 tablet/plate/box, 2 tablets/plate×1 plate/box, 2 tablets/plate×2 plate/box, 2 tablets/plate×3 plate/box, 2 tablets/plate×4 plate/box, 3 tablets/plate×1 plate/box, 3 tablets/plate×2 plate/box, 3 tablets/plate×3 plate/box, 3 tablets/plate×4 plate/box; 4 tablets/plate×1 plate/box, 4 tablets/plate×2 plate/box, 4 tablets/plate×3 plate/box; 5 tablets/plate×1 plate/ Box, 5 tablets/plate x 2 plates/box, 5 tablets/plate x 3 plates/box; 7 tablets/plate x 1 plate/box, 7 tablets/plate x 2 plates/box, 7 tablets/plate x 4 plates/box, 7 tablets/plate x 10 plates/box.
【Validity】24 months
【Execution standard
【Approval number】
【Drug marketing license holder
Name: Nanjing Zhengke Pharmaceutical Co.
Registered Address: No. 3, Huimei Road, Nanjing Economic and Technological Development Zone
Manufacturer
Company Name: Nanjing Zhengke Pharmaceutical Co.
Address: No. 3, Huimei Road, Nanjing Economic and Technological Development Zone
Postal Code: 210038
Contact：025-85666130
Fax: 025-85666123
Web address: http://www.whdongbao.com/http://www.zenkom.cn