Tadalafil tablets

Pharmacological action During sexual stimulation, the penis becomes erect due to increased penile blood flow caused by relaxation of the penile artery and corpus cavernosum smooth muscle. This reaction is mediated by nitric oxide (NO) released by nerve endings and endothelial cells, which stimulates smooth muscle cells to synthesize cyclic guanosine monophosphate (cGMP). cGMP causes smooth muscle relaxation and increases blood flow into the corpus cavernosum. Inhibition of phosphodiesterase 5 (PDE5) enhances erectile function by increasing the amount of cGMP. PDE5 inhibition can affect the concentration of cGMP in the corpus cavernosum and pulmonary artery. The same situation is also observed in the smooth muscle and blood vessels of the anterior lacrimal gland and frontal bladder. The mechanism of action for alleviating BPH symptoms is not yet clear. PDE5 is present in the corpus cavernosum smooth muscle, blood vessels 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, tadalafil will not inhibit PDE5 in the absence of sexual stimulation. 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 found in the heart, brain, blood vessels, liver, white blood cells, skeletal muscle, and other organs. It is more than 10,000 times stronger than PDE3 found in the heart and blood vessels. It is about 700 times stronger than PDE6, which is involved in the light pathway in the retina, and more than 9,000 times stronger than PDE8, PDE9, and PDE10. It is 14 times stronger than PDE11A1 and 40 times stronger than 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 impact of PDE11 inhibition in humans are not clear. Toxicology studies General toxicity: Vasculitis was observed in mice, rats, and dogs when tadalafil was administered. When the exposure to free tadalafil reached 2 to 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 it reached 1 to 54 times, the incidence of diffuse arteritis in dogs increased. In the 12-month dog toxicity experiment, when it reached 14 to 18 times, no diffuse arteritis was observed. Two dogs showed a significant decrease in white blood cells (neutrophils), thrombocytopenia, and inflammatory symptoms, which recovered after 2 weeks of drug withdrawal. The results of the genotoxic tadalafil Ames test, mouse lymphocyte forward mutation test, human lymphocyte chromosome aberration test, and rat micronucleus test were all negative. Reproductive toxicity: Male or female rats were orally administered tadalafil at 400 mg/kg/day (equivalent to 14 or 26 times the MRHD based on free tadalafil exposure), and no effects on fertility, reproductive behavior, or reproductive organ morphology were observed. Dogs were given tadalafil for 3 to 12 months, and 20% to 100% of the animals experienced irreversible degeneration and atrophy of the seminiferous tubule epithelial cells related to administration, and 40% to 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-toxicity-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. Pregnant rats or mice were given tadalafil during organogenesis, and no teratogenicity, embryotoxicity, or fetotoxicity was observed when the exposure (AUC) reached 11 times the MRHD. In a rat perinatal developmental toxicity study, when the mother was given tadalafil at an exposure (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 exposure level, maternal toxicity occurred, but the growth and development of surviving pups were not affected. In a rat perinatal developmental toxicity study, tadalafil at doses of 60, 200 and 1000 mg/kg was observed to reduce the survival rate of the pups after birth. The maternal no observed toxicity level (NOEL) was 200 mg/kg/day (approximately 16 times the MRHD exposure AUC), and the developmental toxicity NOEL was 30 mg/kg/day (approximately 10 times the MRHD exposure AUC). Tadalafil and/or other metabolites can cross the placenta. 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 that in males taking MRHD 20 mg, and in male and female rats it was approximately 14 and 6 times, respectively.

The main ingredient of this product is tadalafil. Chemical name: 6-(1,3-benzodioxolan-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl, (6R,12aR)-pyrazino[1'2':1,6]pyridino[3,4-b]indole-1,4-dione Molecular formula: C22H19N3O4 Molecular weight: 389.41

This product is a yellow film-coated tablet, which appears white after removing the coating.

Treats erectile dysfunction.

Taking tadalafil tablets is not affected by food, and sexual stimulation is required for tadalafil tablets to be effective. Erectile dysfunction Take tadalafil tablets as needed* For most patients, the recommended starting dose of tadalafil tablets as needed is 10 mg, taken before sexual intercourse. * Depending on individual efficacy and tolerability, the dose can be increased to 20 mg or reduced to 5 mg. The maximum recommended frequency of medication for most patients is once a day. * 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 patients to take tadalafil tablets in the best way. Take tadalafil tablets once a day* The recommended starting dose of tadalafil tablets taken once a day is 2.5 mg, taken at approximately the same time every day, regardless of when sexual intercourse occurs. * Depending on individual efficacy and tolerability, the dose of tadalafil tablets taken once a day can be increased to 5 mg. The risk-benefit balance should be based on the patient's specific circumstances to select an appropriate treatment plan. Special Populations Use of Tadalafil Tablets on Demand Renal Impairment Creatinine Clearance 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]). Take Tadalafil Tablets Once Daily Erectile Dysfunction Creatinine Clearance < 30 mL/min or hemodialysis: It is not recommended to take Tadalafil Tablets once a day (see [Precautions]) Hepatic Impairment Take Tadalafil Tablets on Demand * Mild or moderate (Child Pugh Class A or B): The dose of Tadalafil Tablets should not exceed 10 mg, once a day. Once-daily use of Tadalafil Tablets has not been extensively evaluated in patients with hepatic impairment and should therefore be used with caution. * Severe (Child Pugh Class C): Tadalafil Tablets are not recommended (see "Precautions"). Once-daily tadalafil tablets * Mild or moderate (Child-Pugh class 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. * Severe (Child-Pugh class C): Tadalafil tablets are not recommended (see "Precautions"). Elderly For patients aged 65 years, no dose adjustment is required. Concomitant use of nitrates is strictly prohibited with any form of nitrates (see "Contraindications"). Alpha-blockers When tadalafil tablets are used in combination with alpha-blockers, patients receiving alpha-blocker therapy should be stabilized before initiating tadalafil tablets and start at the lowest recommended dose (see "Precautions"). CYP3A4 inhibitors: Take tadalafil tablets as needed: For patients who are taking strong CYP3A4 inhibitors, such as ketoconazole or ritonavir, the maximum recommended dose of tadalafil tablets is 10 mg, not to exceed once every 72 hours (see "Precautions" and "Drug Interactions"). Take tadalafil tablets once a day: For patients who are taking strong CYP3A4 inhibitors, such as ketoconazole or ritonavir, the recommended dose is not more than 2.5 mg (see "Precautions" and "Drug Interactions").

Clinical Research Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials worldwide, more than 9,000 men have taken tadalafil. In trials of once-daily tadalafil tablets, 1,434, 905, and 115 patients were treated for at least 6 months, 1 year, and 2 years, respectively. For as-needed tadalafil tablets, more than 1,300 and 1,000 subjects were treated for at least 6 months and 1 year, respectively. As-needed tadalafil tablets In the eight major placebo-controlled Phase 3 studies lasting 12 weeks, the mean age was 59 years (range 22-88), and the percentage of patients who withdrew due to adverse events was 3.1% for patients who received tadalafil 10 mg or 20 mg, compared with 1.4% for patients who received placebo. The following adverse events occurred with tadalafil tablets taken as needed, as recommended in placebo-controlled clinical trials (see Table 1). Once-daily tadalafil tablets In three placebo-controlled Phase 3 studies lasting 12 or 24 weeks, the mean age was 58 years (range, 21-82), and the percentage of patients who withdrew due to adverse events was 4.1% for tadalafil-treated patients, compared with 2.8% for placebo-treated patients. The following adverse events were reported in clinical trials lasting 12 weeks (see Table 2): The following adverse events were reported in a 24-week placebo-controlled Phase 3 clinical study (see Table 3): The incidence of back pain and myalgia is described in Tables 1 and 2. In clinical pharmacology trials of tadalafil, back pain and myalgia generally occurred 12 to 24 hours after dosing and usually resolved within 48 hours. Back pain/myalgia caused by tadalafil treatment is characterized by diffuse discomfort in the muscles of the lower extremities, buttocks, thighs, or thoracolumbar region, which is exacerbated by lying down. In general, pain that occurred was mild or moderate in severity and resolved without treatment, but there were lower rates of severe back pain reported (5% of all reports). If treatment was required, acetaminophen or nonsteroidal anti-inflammatory drugs were generally effective; however, a few subjects who required treatment used weak narcotics (such as codeine). Overall, approximately 0.5% of all subjects taking tadalafil as needed discontinued treatment due to back pain/myalgia. In the 1-year open-label extension study, back pain and myalgia were reported by 5.5% and 1.3% of patients, respectively. Diagnostic tests, including measures of inflammation, muscle damage, and renal injury, showed no medically significant pathological basis. The incidence of once-daily tadalafil tablets is described in Table 2. In studies of once-daily tadalafil tablets, back pain and myalgia events were generally mild or moderate, with a withdrawal rate of 0.3%. Reports of changes in color vision were rare (0.1% of patients) in all tadalafil tablet studies. The following subsections identify other less common (2%) adverse events reported in controlled clinical trials with once-daily or as-needed tadalafil tablets. The causal relationship to tadalafil tablets is unclear for these events. This list does not include very mild events, events with no clear relationship to the drug, and inaccurate and meaningless reports. General - Asthenia, facial edema, fatigue, pain Cardiovascular - angina, chest pain, hypotension, myocardial infarction, orthostatic hypotension, palpitations, syncope, tachycardia Digestive - abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, increased GGTP, loose stools, nausea, epigastric pain, vomiting Musculoskeletal - arthralgia, cervical pain Neurological - dizziness, hypoesthesia, insomnia, paresthesia, somnolence, vertigo Respiratory - dyspnea, epistaxis, pharyngitis Skin and Appendages - pruritus, rash, sweating Ocular - blurred vision, color vision changes, conjunctivitis (including conjunctival injection), eye pain, increased tearing, eyelid swelling Ear - sudden decrease or loss of hearing, tinnitus Urogenital - increased erections, spontaneous penile erections Postmarketing Experience The following adverse reactions have been reported post-approval for tadalafil tablets. They were selected based on their severity, frequency of reporting, lack of clear other causes, or the sum of all the above. Because these adverse reactions are reported spontaneously in a population of uncertain size, their incidence cannot be reliably estimated or a causal relationship to drug exposure established. This list does not include adverse events reported in clinical trials; those events are listed in this Clinical Experience section. Cardiovascular and Cerebrovascular - Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in a temporal relationship to tadalafil use. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events occurred during or shortly after sexual intercourse, and a few occurred after taking the drug but not engaging in sexual intercourse. Others were reported hours to days after taking tadalafil tablets and engaging in sexual intercourse. It is unclear whether these events are directly related to tadalafil tablets, sexual intercourse, the patient's preexisting cardiovascular disease, or other factors (see Precautions). Systemic - Hypersensitivity reactions, including urticaria, Stevens-Johnson 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), a cause of vision loss including permanent blindness, has been reported rarely in the postmarketing period in association with phosphodiesterase 5 (PDE5) inhibitors, including tadalafil tablets. Most, but not all, of these patients had preexisting anatomical or vascular risk factors for the development of NAION, including, but not limited to, small cup and disc size ("optic disc crowding"), age over 50 years, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is unclear whether these events were directly related to the use of PDE5 inhibitors, the patients' preexisting vascular risk factors or anatomical defects, a combination of these factors, or other factors (see Precautions). Otology - Cases of sudden hearing loss or hypothermia have been reported postmarketing in association with the use of PDE5 inhibitors, including tadalafil tablets. In some cases, medical conditions or other factors were reported that may have contributed to the otic adverse events. In most cases, medical follow-up information was limited. It is not possible to determine whether these events are directly related to the use of tadalafil tablets, the patients' pre-existing risk factors for hearing loss, a combination of these factors, or other factors (see Precautions). Genitourinary - Persistent erections (see Precautions).

Nitrates Patients who are taking any form of nitrates, either regularly and/or intermittently, should not take tadalafil. Clinical pharmacology studies have shown that tadalafil can enhance the hypotensive effect of nitrates. This is believed to be the result of the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway (see "Pharmacology and Toxicology"). Hypersensitivity Reactions Patients with known hypersensitivity to tadalafil should not take tadalafil. Hypersensitivity reactions, including Stevens-Johnson syndrome and exfoliative dermatitis, have been reported (see "Adverse Reactions"). Guanylate cyclase (GC) stimulators Patients who are taking GC stimulators (such as riociguat) should not take Cialis. PDE5 inhibitors, including Cialis, may enhance the hypotensive effect of GC stimulators.

Precautions for children: Tadalafil tablets cannot be used in pediatric patients. Safety and effectiveness have not been established in patients under 18 years of age. Pregnancy and lactation precautions: Pregnancy Category B (FDA pregnancy safety category) - Tadalafil is not for use in women. There are no adequate, well-controlled studies of tadalafil tablets in pregnant women. Animal reproduction studies in rats and mice showed no evidence of harm to the fetus. Non-teratogenic effects - Animal reproduction studies have shown that there is no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil is administered to pregnant rats or mice during organogenesis at exposure levels up to 11 times the maximum recommended human dose (MRHD). In one of the two rat perinatal/postnatal development studies, the survival of pups after birth was reduced when maternal tadalafil doses reached more than 10 times the MRHD based on AUC. Based on AUC, symptoms of maternal toxicity occurred at doses exceeding 16 times the MRHD. Surviving fetuses had normal development and reproductive performance (see "Pharmacology and Toxicology"). Tadalafil tablets cannot be used in women during lactation. It is not known whether tadalafil is secreted in human breast milk. Although tadalafil or some metabolites of tadalafil are secreted in rats through breast milk, drug levels in animal milk cannot accurately predict drug levels in human milk. Elderly precautions: 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. No overall differences in efficacy or safety were observed in subjects over 65 years of age compared with younger subjects. However, in all placebo-controlled clinical trials of tadalafil tablets for the treatment of erectile dysfunction, patients 65 years of age and older experienced diarrhea more frequently (2.5% of patients) when taking tadalafil tablets (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 "Pharmacology and Toxicology").

Potential for pharmacokinetic interactions with tadalafil tablets Nitrates - Clinical pharmacology studies have shown that tadalafil tablets can enhance the hypotensive effect of nitrates, so patients 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 should only be given under close medical supervision and appropriate hemodynamic monitoring (see "Contraindications", "Dosage and Administration", and "Pharmacology and Toxicology"). Alpha-blockers - Caution should be used when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including tadalafil tablets, and alpha-adrenergic receptor blockers are vasodilators with hypotensive effects. When vasodilators are used together, there may be an additive effect on blood pressure. Clinical pharmacology studies have been conducted on the co-administration of tadalafil with doxazosin or tamsulosin (see Precautions, Dosage and Administration, and Pharmacology and Toxicology). Antihypertensives - PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies have been conducted to evaluate the effect of tadalafil on the hypotensive effects of specific antihypertensive drugs (amiodarone, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Co-administration of tadalafil with these drugs resulted in a small decrease in blood pressure relative to placebo (see Precautions and Pharmacology and Toxicology). Alcohol - Both alcohol and the PDE5 inhibitor tadalafil are mild vasodilators. The hypotensive effects of each mild vasodilator may be enhanced when taken together. Consuming large amounts of alcohol (e.g., 5 units or more) 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, nor does alcohol affect the plasma concentration of tadalafil (see "Precautions" and "Pharmacology and Toxicology"). Effects of other drugs on tadalafil tablets (see "Dosage and Administration" and "Precautions"). 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. H2 antagonists (such as nizatidine) - After co-administration with nizatidine, gastric pH is significantly increased, with 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 level of tadalafil. CYP3A4 (e.g., ketoconazole) - Ketoconazole (400 mg/day), a selective and potent inhibitor of CYP3A4, increased the AUC of a single 20 mg dose of tadalafil by 312% and Cmax by 22% relative to tadalafil 20 mg alone. Ketoconazole (200 mg/day) increased the AUC of a single 10 mg dose of tadalafil by 107% and Cmax by 15% relative to tadalafil 10 mg alone (see Dosage and Administration). Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, may also increase tadalafil exposure. HIV protease inhibitors - ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased the AUC of a single dose of tadalafil 20 mg by 32% and decreased Cmax by 30% relative to a single dose of tadalafil 20 mg. Ritonavir (200 mg twice daily) increased the AUC of a single dose of tadalafil 20 mg by 124% relative to tadalafil 20 mg alone, with no change in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors are also likely to increase tadalafil exposure (see "Dosage and Administration"). Cytochrome P450 inducers - Studies have shown that drugs that can induce CYP3A4 can reduce tadalafil exposure. CYP3A4 (e.g., rifampin) - Rifampin (600 mg/day), a CYP3A4 inducer, decreased tadalafil AUC by 88% and Cmax by 46% compared to tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, may also reduce tadalafil exposure. No dose adjustment is necessary. The magnitude of the reduction in exposure resulting from coadministration of tadalafil with rifampin or other CYP3A4 inducers is unknown and could reduce the efficacy of once-daily tadalafil. Effects of Tadalafil on Other Drugs Aspirin - Tadalafil does not potentiate aspirin-induced prolongation of bleeding time. Cytochrome P450 Substrates - Tadalafil is not expected to cause 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 the P450 isoenzymes CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. CYP1A2 (e.g., theophylline) - Tadalafil has no significant effect on the pharmacokinetics of theophylline. When tadalafil is coadministered with theophylline, theophylline-induced heart rate increase (3 beats/minute) is slightly increased. CYP2C9 (e.g., warfarin) - Tadalafil has no significant effect on the AUC of S-warfarin or R-warfarin, nor on the change in prothrombin time caused by warfarin. CYP3A4 (e.g., midazolam or lovastatin) - Tadalafil has no significant effect on the AUC of midazolam or lovastatin. Coadministration of P-tadalafil (eg, digoxin)-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.

Store at room temperature

20mg

36 months

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