TADALAFIL- tadalafil_tablet, film coated

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation. in vitro In vitro, Effects on Blood Pressure Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of tadalafil in patients taking any form of nitrates is contraindicated [see Contraindications (4. 1) see Therefore, tadalafil administration with nitrates is contraindicated. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications (4. 1) Effect on Blood Pressure When Administered With Alpha-Blockers Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects [see Dosage and Administration (2. 7) Warnings and Precautions (5. 6) Doxazosin In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects). Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing ( see Table 5: Doxazosin (8 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg Supine 3. 8) Standing 9. 5) Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Outliers were defined as subjects with a standing systolic blood pressure of 30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. No such events were reported following placebo. Two such events were reported following administration of tadalafil. Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days. This subject previously experienced a mild episode of vertigo on doxazosin and placebo. Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day. No syncope was reported. In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily. The study (N=72 subjects) was conducted in three parts, each a 3-period crossover. In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a. Tadalafil was administered at either 8 a. There was no placebo control. In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p. In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a. In this part, tadalafil or placebo were administered at either 8 a. The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 6 and Figure 3. Table 6: Doxazosin (8 mg/day) Study 2 (Part C): Mean Maximal Decrease in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg at 8 a. Tadalafil 20 mg at 8 p. Ambulatory Blood-Pressure Monitoring (ABPM) 7 8 Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a. dosing of tadalafil or placebo. Of these, 5 and 2 were outliers due to systolic BP 30 mm Hg following tadalafil and placebo, respectively. During the 24-hour period after 8 p. dosing, 17 subjects were categorized as outliers following administration of tadalafil and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP 30 mm Hg, following tadalafil and placebo, respectively. Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the period beyond 24 hours. In the study (N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and dizziness in another subject that began 11 hours after dosing and lasted 2 minutes). In the period prior to tadalafil dosing, one severe event (dizziness) was reported in a subject during the doxazosin run-in phase. Table 7: Doxazosin Study 3: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure Tadalafil 5 mg Day 1 of 4 mg Doxazosin Supine 2. 2) Standing -0. 1) Day 7 of 4 mg Doxazosin Supine 2. 7) Standing 1. 9, 5) Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4 mg), as well as on the seventh day of 4 mg doxazosin administration. Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier on placebo due to a decrease from baseline in standing systolic BP of >30 mm Hg. There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There was one outlier on tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP 30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure <85 mm Hg. All adverse events potentially related to blood pressure effects were rated as mild or moderate. There were two episodes of syncope in this study, one subject following a dose of tadalafil 5 mg alone, and another subject following coadministration of tadalafil 5 mg and doxazosin 4 mg. Tamsulosin Table 8: Tamsulosin (0. 4 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 10 mg Tadalafil 20 mg Supine 3. 7) Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points) following administration of tadalafil 10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood-pressure effects were reported. In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of tamsulosin 0. 4 mg was added for the last seven days of each period. Table 9: Tamsulosin Study 2: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure Tadalafil 5 mg Day 1 of 0. 4 mg Tamsulosin Supine -0. 9) Standing 0. 2) Day 7 of 0. 4 mg Tamsulosin Supine 1. 6) Standing 1. 5) Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin administration. There were no outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day 7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood pressure were reported. Alfuzosin Table 10: Alfuzosin (10 mg/day) Study: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg Supine 2. 2) Standing 4. 9) Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure 30 mm Hg at one or more time points. No severe adverse events potentially related to blood pressure effects were reported. Effects on Blood Pressure When Administered with Antihypertensives Amlodipine c c tadalafil-fig1 tadalafil-fig2 tadalafil-fig3 Over a dose range of 2. 5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1. 6-fold greater than after a single dose. Mean tadalafil concentrations measured after the administration of a single oral dose of 20 mg and single and once daily multiple doses of 5 mg, from a separate study, ( see Absorption max The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil may be taken with or without food. Distribution Less than 0. 0005% of the administered dose appeared in the semen of healthy subjects. Metabolism In vitro Excretion Geriatric max [see Use in Specific Populations (8. 5) Patients with Diabetes Mellitus max Patients with BPH max tadalafil-fig4.

erectile dysfunction (ED) ( 1. 1 the signs and symptoms of benign prostatic hyperplasia (BPH) ( 1. 2 ED and the signs and symptoms of BPH (ED/BPH) ( 1. 3 If tadalafil tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks ( 1. 4 Tadalafil tablets are indicated for the treatment of erectile dysfunction (ED). Tadalafil tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Tadalafil tablets are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH). If tadalafil tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil tablets decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil tablets beyond 26 weeks is unknown [see Clinical Studies (14.

Do not split tadalafil tablets; entire dose should be taken. Tadalafil tablets for use as needed: ED: Starting dose: 10 mg as needed prior to sexual activity. Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability. Improves erectile function compared to placebo up to 36 hours post dose. Not to be taken more than once per day (2. 1) Tadalafil tablets for once daily use: ED: 2. 5 mg taken once daily, without regard to timing of sexual activity. May increase to 5 mg based upon efficacy and tolerability (2. 2) BPH: 5 mg, taken at approximately the same time every day (2. 3) ED and BPH: 5 mg, taken at approximately the same time every day (2. 4) Tadalafil tablets may be taken without regard to food (2. 5) The recommended starting dose of tadalafil tablets for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity. The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients. Tadalafil tablets for use as needed were shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of tadalafil tablets, this should be taken into consideration. The recommended starting dose of tadalafil tablets for once daily use is 2. 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. The tadalafil tablets dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability. The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day. When therapy for BPH is initiated with tadalafil tablets and finasteride, the recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. Tadalafil tablets may be taken without regard to food. Renal Impairment Tadalafil Tablets for Use as Needed Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours. Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions (5. 7) Use in Specific Populations (8. 7) Tadalafil Tablets for Once Daily Use Erectile Dysfunction Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended [see Warnings and Precautions (5. 7) and Use in Specific Populations (8. Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance 30 to 50 mL/min: A starting dose of 2. 5 mg is recommended. An increase to 5 mg may be considered based on individual response. Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended [see Warnings and Precautions (5. 7) ] Hepatic Impairment Tadalafil Tablets for Use as Needed Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of tadalafil tablets once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised. Severe (Child Pugh Class C): The use of tadalafil tablets is not recommended [see Warnings and Precautions (5. 8) Use in Specific Populations (8. 6) Tadalafil Tablets for Once Daily Use Mild or moderate (Child Pugh Class A or B): Tadalafil tablets for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients. 8) and Use in Specific Populations (8. 6) ] Nitrates Concomitant use of nitrates in any form is contraindicated [see Contraindications (4. 1) Alpha-Blockers ED [see Warnings and Precautions (5. 6) Drug Interactions (7. 1) Clinical Pharmacology (12. 2) BPH [see Warnings and Precautions (5. 6) , Drug Interactions (7. 1) , and Clinical Pharmacology (12. 2) ] CYP3A4 Inhibitors Tadalafil Tablets for Use as Needed [see Warnings and Precautions (5. 10) Drug Interactions (7. 2) Tadalafil Tablets for Once Daily Use [see Warnings and Precautions (5. 10) and Drug Interactions (7.

1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www. gov/medwatch Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of tadalafil for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For tadalafil for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively. Tadalafil for Use as Needed for ED In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3. 1%, compared to 1. 4% in placebo treated patients. When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported ( see Table 1: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Clinical Studies (Including a Study in Patients with Diabetes) for Tadalafil for Use as Needed for ED a Adverse Reaction 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% Flushing a 1% 2% 3% 3% Pain in limb 1% 1% 3% 3% Tadalafil for Once Daily Use for ED In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4. 1%, compared to 2. 8% in placebo-treated patients. The following adverse reactions were reported ( see Table 2: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil for Once Daily Use (2. 5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes) for Tadalafil for Once Daily Use for ED Adverse Reaction Placebo (N=248) Tadalafil 2. 5 mg Tadalafil 5 mg 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% Pain in extremity 0% 1% 2% Urinary tract infection 0% 2% 0% Gastroesophageal reflux disease 0% 2% 1% Abdominal pain 0% 2% 1% The following adverse reactions were reported ( see Table 3: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil for Once Daily Use (2. 5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Tadalafil for Once Daily Use for ED Adverse Reaction Placebo (N=94) Tadalafil 2. 5 mg 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% Tadalafil for Once Daily Use for BPH and for ED and BPH see Table 4: Treatment-Emergent Adverse Reactions Reported by >=1% of Patients Treated with Tadalafil for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo-Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Tadalafil for Once Daily Use for BPH and One Study for ED and BPH Adverse Reaction Placebo (N=576) Tadalafil 5 mg (N=581) Headache 2. 1% Dyspepsia 0. 4% Back pain 1. 4% Nasopharyngitis 1. 1% Diarrhea 1% 1. 4% Pain in extremity 0% 1. 4% Myalgia 0. 2% Dizziness 0. 5% 1% Additional, less frequent adverse reactions (<1%) reported in the controlled clinical trials of tadalafil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm. [see Use in Specific Populations (8. 5) The following adverse reactions have been identified during post approval use of tadalafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Cardiovascular and Cerebrovascular [see Warnings and Precautions (5. 1) Body as a Whole Nervous Ophthalmologic Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking [see Warnings and Precautions (5. 4) Otologic [see Warnings and Precautions (5. 5) Urogenital [see Warnings and Precautions (5.

Administration of tadalafil tablets to patients using any form of organic nitrate is contraindicated. Tadalafil tablets were shown to potentiate the hypotensive effect of nitrates ( 4. 1 History of known serious hypersensitivity reaction to tadalafil tablets or ADCIRCA registered 4. 2 Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4. 3 Administration of tadalafil tablets to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil tablets were shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology (12. 2) Tadalafil tablets are contraindicated in patients with a known serious hypersensitivity to tadalafil tablets or ADCIRCA registered [see Adverse Reactions (6. 2) Do not use tadalafil tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including tadalafil tablets, may potentiate the hypotensive effects of GC stimulators.

Hepatic Impairment (2. 6) Mild or Moderate: Dosage adjustment may be needed. Severe: Use is not recommended. Renal Impairment ( 2. 7) Patients with creatinine clearance 30 to 50 mL/min: Dosage adjustment may be needed. Patients with creatinine clearance less than 30 mL/min or on hemodialysis: For use as needed: Dose should not exceed 5 mg every 72 hours. Once daily use is not recommended. Risk Summary There are no data with the use of tadalafil in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day ( see Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In a prenatal/postnatal developmental study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance. Risk Summary There is no information on the presence of tadalafil and/or metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Tadalafil and/or its metabolites are present in the milk of lactating rats at concentrations approximately 2. 4-fold greater than found in the plasma. Infertility [see Clinical Pharmacology (12. 2) Based on studies in animals, a decrease in spermatogenesis was observed in dogs, but not in rats [see Nonclinical Toxicology (13. 1) Tadalafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years have not been established. Juvenile Animal Study No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60, 200, and 1000 mg/kg/day to juvenile rats on postnatal days 14 to 90. The highest plasma tadalafil exposures (AUC) achieved were approximately 10-fold that observed at the MRHD. Of the total number of subjects in ED clinical studies of tadalafil, approximately 19 percent were 65 and over, while approximately 2 percent were 75 and over. Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over. In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and >=75 years of age) and younger subjects (<=65 years of age). However, in placebo-controlled studies with tadalafil for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil (2. 5% of patients) [see Adverse Reactions (6. 1) [see Clinical Pharmacology (12. 3) In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C). [see Dosage and Administration (2. 6) Warnings and Precautions (5. 8) In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in C max [see Dosage and Administration (2.

Tadalafil can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol ( 7. 1 CYP3A4 inhibitors (e. , ketoconazole, ritonavir) increase tadalafil exposure ( 2. 2 Tadalafil for use as needed: no more than 10 mg every 72 hours Tadalafil for once daily use: dose not to exceed 2. 5 mg CYP3A4 inducers (e. , rifampin) decrease tadalafil exposure ( 7. 2 Nitrates [see Dosage and Administration (2. 7) , Contraindications (4. 1) Clinical Pharmacology (12. 2) Alpha-Blockers [see Dosage and Administration (2. 7) Warnings and Precautions (5. 6) Clinical Pharmacology (12. 2) Antihypertensives [see Warnings and Precautions (5. 2) Alcohol [see Warnings and Precautions (5. 9) Clinical Pharmacology (12. 2) [See Dosage and Administration (2. 10) 2 CYP3A4 (e. , Ketoconazole) max max [see Dosage and Administration (2. 7) HIV Protease inhibitor max max [see Dosage and Administration (2. 7) Cytochrome P450 Inducers CYP3A4 (e. , Rifampin) max Cytochrome P450 Substrates CYP1A2 (e. , Theophylline) CYP2C9 (e. , Warfarin) CYP3A4 (e. , Midazolam or Lovastatin) P-glycoprotein (e.

OVERDOSAGE
Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis in vitro in vitro in vivo Impairment of Fertility There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years. Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks after stopping treatment.
CLINICAL STUDIES
The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24-weeks duration, involving over 4000 patients. Tadalafil, when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED). Tadalafil was studied in the general ED population in 7 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the U. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve-sparing radical prostatectomy. In these 7 trials, tadalafil was taken as needed, at doses ranging from 2. 5 mg to 20 mg, up to once per day. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted. Several assessment tools were used to evaluate the effect of tadalafil on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at the end of a treatment-free baseline period and subsequently at follow-up visits after randomization. The IIEF EF domain has a 30-point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into the partner’s vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient. Results in ED Population in U. Trials see Table 11: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary U. Trials Study A Study B Placebo Tadalafil 20 mg Placebo Tadalafil 20 mg (N=49) (N=146) p-value (N=48) (N=159) p-value EF Domain Score Endpoint 13. 5 Change from baseline -0. 001 Insertion of Penis (SEP2) Endpoint 39% 62% 43% 77% Change from baseline 2% 26% <0. 001 2% 32% <0. 001 Maintenance of Erection (SEP3) Endpoint 25% 50% 23% 64% Change from baseline 5% 34% <0. 001 4% 44% <0. 001 Results in General ED Population in Trials Outside the U. see Table 12: Mean Endpoint and Change from Baseline for the EF Domain of the IIEF in the General ED Population in Five Primary Trials Outside the U. a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil Study C Endpoint [Change from baseline] 15 [0. 9 [4] 20 [5. 001 Study D Endpoint [Change from baseline] 14. 001 Study E Endpoint [Change from baseline] 18. 1] 25 [8] p<0. 001 Study F a Endpoint [Change from baseline] 12. 001 Study G Endpoint [Change from baseline] 14. 001 Table 13: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 2 (“Were you able to insert your penis into the partner’s vagina?”) in the General ED Population in Five Pivotal Trials Outside the U. a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Study C Endpoint [Change from baseline] 49% [6%] 57% [15%] 73% [29%] p=0. 001 Study D Endpoint [Change from baseline] 46% [2%] 56% [18%] 68% [15%] p=0. 001 Study E Endpoint [Change from baseline] 55% [10%] 77% [35%] 85% [35%] p<0. 001 Study F a Endpoint [Change from baseline] 42% [-8%] 81% [27%] p<0. 001 Study G Endpoint [Change from baseline] 45% [-6%] 73% [21%] 76% [21%] p<0. 001 Table 14: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 3 (“Did your erection last long enough for you to have successful intercourse?”) in the General ED Population in Five Pivotal Trials Outside the U. a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Study C Endpoint [Change from baseline] 26% [4%] 38% [19%] 58% [32%] p=0. 001 Study D Endpoint [Change from baseline] 28% [4%] 42% [24%] 51% [26%] p<0. 001 Study E Endpoint [Change from baseline] 43% [15%] 70% [48%] 78% [50%] p<0. 001 Study F a Endpoint [Change from baseline] 27% [1%] 74% [40%] p<0. 001 Study G Endpoint [Change from baseline] 32% [5%] 57% [33%] 62% [29%] p<0. 001 In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking tadalafil, compared to patients on placebo. Therefore, in all 7 primary efficacy and safety studies, tadalafil showed statistically significant improvement in patients’ ability to achieve an erection sufficient for vaginal penetration and to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire and by SEP diaries. Efficacy Results in ED Patients with Diabetes Mellitus see Table 15: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in ED Patients with Diabetes Placebo Tadalafil 10 mg Tadalafil 20 mg (N=71) (N=73) (N=72) p-value EF Domain Score Endpoint [Change from baseline] 12. 001 Insertion of Penis (SEP2) Endpoint [Change from baseline] 30% [-4%] 57% [22%] 54% [23%] <0. 001 Maintenance of Erection (SEP3) Endpoint [Change from baseline] 20% [2%] 48% [28%] 42% [29%] <0. 001 Efficacy Results in ED Patients following Radical Prostatectomy see Table 16: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in Patients who Developed ED Following Bilateral Nerve-Sparing Radical Prostatectomy Placebo Tadalafil 20 mg (N=102) (N=201) p-value EF Domain Score Endpoint [Change from baseline] 13. 001 Insertion of Penis (SEP2) Endpoint [Change from baseline] 32% [2%] 54% [22%] <0. 001 Maintenance of Erection (SEP3) Endpoint [Change from baseline] 19% [4%] 41% [23%] <0. 001 Results in Studies to Determine the Optimal Use of Tadalafil The efficacy and safety of tadalafil for once daily use in the treatment of erectile dysfunction has been evaluated in 2 clinical trials of 12-weeks duration and 1 clinical trial of 24-weeks duration, involving a total of 853 patients. Tadalafil, when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED). Tadalafil was studied in the general ED population in 2 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12- and 24-weeks duration, respectively. One of these studies was conducted in the United States and one was conducted in centers outside the U. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. Tadalafil was taken once daily at doses ranging from 2. Timing of sexual activity was not restricted relative to when patients took tadalafil. Results in General ED Population The primary efficacy and safety study conducted outside the U. included 268 patients, with a mean age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0. 4% Hispanic, and 10% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Ninety-three percent of patients reported ED of at least 1-year duration. In each of these trials, conducted without regard to the timing of dose and sexual intercourse, tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary ( see In the 6 month double-blind study, the treatment effect of tadalafil did not diminish over time. Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Tadalafil for Once Daily Use Studies a b c Study H a Study I b Placebo Tadalafil 2. 5 mg Tadalafil 5 mg Placebo Tadalafil 5 mg (N=94) (N=96) (N=97) p-value (N=54) (N=109) p-value EF Domain Score Endpoint 14. 8 Change from baseline 1. 001 Insertion of Penis (SEP2) Endpoint 51% 65% 71% 52% 79% Change from baseline 5% 24% c 26% c <0. 001 11% 37% c <0. 001 Maintenance of Erection (SEP3) Endpoint 31% 50% 57% 37% 67% Change from baseline 10% 31% c 35% c <0. 001 13% 46% c <0. 001 Efficacy Results in ED Patients with Diabetes Mellitus see Table 18: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Tadalafil for Once Daily Use Study in ED Patients with Diabetes a Placebo Tadalafil 2. 5 mg Tadalafil 5 mg (N=100) (N=100) (N=98) p-value EF Domain Score Endpoint 14. 2 Change from baseline 1. 001 Insertion of Penis (SEP2) Endpoint 43% 62% 61% Change from baseline 5% 21% a 29% a <0. 001 Maintenance of Erection (SEP3) Endpoint 28% 46% 41% Change from baseline 8% 26% a 25% a <0. 001 The efficacy and safety of tadalafil for once daily use for the treatment of the signs and symptoms of BPH was evaluated in 3 randomized, multinational, double-blinded, placebo-controlled, parallel-design, efficacy and safety studies of 12 weeks duration. Two of these studies were in men with BPH and one study was specific to men with both ED and BPH [see Clinical Studies (14. 4) The primary efficacy endpoint in the two studies that evaluated the effect of tadalafil for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Q max The results for BPH patients with moderate to severe symptoms and a mean age of 63. 2 years (range 44 to 87) who received either tadalafil 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively. Table 19: Mean IPSS Changes in BPH Patients in Two Tadalafil for Once Daily Use Studies Study J Study K Placebo Tadalafil 5 mg Placebo Tadalafil 5 mg (N=205) (N=205) p-value (N=164) (N=160) p-value Total Symptom Score (IPSS) Baseline 17. 1 Change from Baseline to -2. 004 In Study J, the effect of tadalafil 5 mg once daily on maximum urinary flow rate (Q max max In Study K, the effect of tadalafil 5 mg once daily on Q max max Efficacy Results in Patients with BPH initiating Tadalafil and Finasteride Tadalafil with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint ( see Table 20: Mean Total IPSS Changes in BPH Patients in a Tadalafil for Once Daily Use Study Together with Finasteride a b c Placebo and finasteride 5 mg Tadalafil 5 mg and finasteride 5 mg Treatment difference n (N=350) a n (N=345) a p-value b Total Symptom Score (IPSS) Baseline c 349 17. 1 Change from Baseline to Week 4 b 340 -2. 3 330 -4 -1. 001 Change from Baseline to Week 12 b 318 -3. 001 Change from Baseline to Week 26 b 295 -4. 022 In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil with finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (tadalafil/finasteride 13. 7, placebo/finasteride 15. 1) was observed at week 4 (tadalafil/finasteride 3. 7, placebo/finasteride -1. 001), week 12 (tadalafil/finasteride 4. 7, placebo/finasteride 0. 001), and week 26 (tadalafil/finasteride 4. 7, placebo/finasteride 0; p<0. tadalafil-fig5. jpg tadalafil-fig6. jpg tadalafil-fig7. jpg The efficacy and safety of tadalafil for once daily use for the treatment of ED, and the signs and symptoms of BPH, in patients with both conditions was evaluated in one placebo-controlled, multinational, double-blind, parallel-arm study which randomized 606 patients to receive either tadalafil 2. 5 mg, 5 mg, for once daily use or placebo. ED severity ranged from mild to severe and BPH severity ranged from moderate to severe. The full study population had a mean age of 63 years (range 45 to 83) and was 93% White, 4% Black, 3% other races; 16% were of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included. In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). The efficacy results for patients with both ED and BPH, who received either tadalafil 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8. Tadalafil 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. Tadalafil 5 mg for once daily use also resulted in statistically significant improvement in SEP3. Tadalafil 2. 5 mg did not result in statistically significant improvement in the total IPSS. Table 21: Mean IPSS and IIEF EF Domain Changes in the Tadalafil 5 mg for Once Daily Use Study in Patients with ED and BPH Placebo Tadalafil 5 mg p-value Total Symptom Score (IPSS) (N=193) (N=206) Baseline 18. 5 Change from Baseline to Week 12 -3. 001 EF Domain Score (IIEF EF) (N=188) (N=202) Baseline 15. 5 Endpoint 17. 9 Change from Baseline to Week 12 1. 001 Table 22: Mean SEP Question 3 Changes in the Tadalafil 5 mg for Once Daily Use Study in Patients with ED and BPH Placebo Tadalafil 5 mg (N=187) (N=199) p-value Maintenance of Erection (SEP3) Baseline 36% 43% Endpoint 48% 72% Change from Baseline to Week 12 12% 32% <0. 001 Tadalafil for once daily use resulted in improvement in the IPSS total score at the first scheduled observation (week 2) and throughout the 12 weeks of treatment ( see In this study, the effect of tadalafil 5 mg once daily on Q max max tadalafil-fig8.
Patient Information
Tadalafil Tablets USP (ta da'' la fil) adalafil Tablets? can cause your blood pressure to drop suddenly to an unsafe level if they are taken with certain other medicines. take any medicines called “nitrates.” Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide mononitrate. Some recreational drugs called “poppers” also contain nitrates, such as amyl nitrite and butyl nitrite. Do not take tadalafil tablets if you take medicines called guanylate cyclase stimulators which include: Riociguat (Adempas registered Ask your healthcare provider or pharmacist if you are not sure if any of your medicines are nitrates or guanylate cyclase stimulators, such as riociguat. “Who Should Not Take T adalafil Tablets?” tadalafil tablets remains in your body for more than 2 days. “Can Other Medicines Affect Tadalafil Tablets?” “What Are The Possible Side Effects Of Tadalafil Tablets?” Tadalafil Tablets? men with erectile dysfunction (ED) men with symptoms of benign prostatic hyperplasia (BPH) men with both ED and BPH Tadalafil Tablets for the Treatment of ED cure ED increase a man’s sexual desire protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your healthcare provider about ways to guard against sexually transmitted diseases. serve as a male form of birth control Tadalafil tablets are only for men over the age of 18, including men with diabetes or who have undergone prostatectomy. Tadalafil Tablets? Do not take tadalafil tablets if you: take any medicines called “nitrates”. use recreational drugs called “poppers” like amyl nitrite and butyl nitrite. (See “What Is The Most Important Information I Should Know About Tadalafil Tablets?” take any medicines called guanylate cyclase stimulators, such as riociguat. are allergic to tadalafil tablets or ADCIRCA registered rash hives swelling of the lips, tongue, or throat difficulty breathing or swallowing Call your healthcare provider or get help right away if you have any of the symptoms of an allergic reaction listed above. Tadalafil Tablets? Only your healthcare provider and you can decide if tadalafil tablets are right for you. have heart problems have pulmonary hypertension have low blood pressure or have had a stroke have liver problems have kidney problems or require dialysis have retinitis pigmentosa, have ever had severe vision loss, including a condition called NAION have stomach ulcers have a bleeding problem have a deformed penis shape have had an erection that lasted more than 4 hours have blood cell problems Can Other Medicines Affect Tadalafil Tablets? medicines called nitrates (see “What Is The Most Important Information I Should Know About Tadalafil Tablets?” medicines called guanylate cyclase stimulators, such as riociguat (Adempas registered medicines called alpha blockers. These include Hytrin registered registered registered registered registered registered registered other medicines to treat high blood pressure (hypertension) medicines called HIV protease inhibitors, such as ritonavir (Norvir registered registered some types of oral antifungals such as ketoconazole (Nizoral registered registered some types of antibiotics such as clarithromycin (Biaxin registered registered other medicines or treatments for ED. tadalafil tablets are also marketed as ADCIRCA for the treatment of pulmonary arterial hypertension. Do not take both tadalafil tablets and ADCIRCA. Do not take sildenafil citrate (Revatio registered How Should I Take Tadalafil Tablets? Take tadalafil tablets exactly as your healthcare provider prescribes them. Your healthcare provider will prescribe the dose that is right for you. Some men can only take a low dose of tadalafil tablets or may have to take them less often, because of medical conditions or medicines they take. Do not change your dose or the way you take tadalafil tablets without talking to your healthcare provider. Your healthcare provider may lower or raise your dose, depending on how your body reacts to tadalafil tablets and your health condition. Tadalafil tablets may be taken with or without meals. If you take too much tadalafil, call your healthcare provider or emergency room right away. How Should I Take Tadalafil Tablets for Symptoms of BPH? tadalafil tablets are taken once daily. Do not take tadalafil tablets more than one time each day. Take one tadalafil tablet every day at about the same time of day. If you miss a dose, you may take it when you remember but do not take more than one dose per day. How Should I Take Tadalafil Tablets for ED? tadalafil tablets - either for use as needed OR for use once daily. for use as needed: Do not take tadalafil tablets more than one time each day. Take one tadalafil tablet before you expect to have sexual activity. You may be able to have sexual activity at 30 minutes after taking tadalafil tablet and up to 36 hours after taking it. You and your healthcare provider should consider this in deciding when you should take tadalafil tablets before sexual activity. Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets. Your healthcare provider may change your dose of tadalafil tablets depending on how you respond to the medicine, and on your health condition. OR Tadalafil tablets for once daily use is a lower dose you take every day. Do not take tadalafil tablets more than one time each day. Take one tadalafil tablet every day at about the same time of day. You may attempt sexual activity at any time between doses. If you miss a dose, you may take it when you remember but do not take more than one dose per day. Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets. Your healthcare provider may change your dose of tadalafil tablets depending on how you respond to the medicine, and on your health condition. How Should I Take Tadalafil Tablets for Both ED and the Symptoms of BPH? tadalafil tablets are taken once daily. Do not take tadalafil tablets more than one time each day. Take one tadalafil tablet every day at about the same time of day. You may attempt sexual activity at any time between doses. If you miss a dose, you may take it when you remember but do not take more than one dose per day. Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets. What Should I Avoid While Taking Tadalafil Tablets? Do not use other ED medicines or ED treatments while taking tadalafil tablets. Do not drink too much alcohol when taking tadalafil tablets (for example, 5 glasses of wine or 5 shots of whiskey). Drinking too much alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate, or lowering your blood pressure. What Are The Possible Side Effects Of Tadalafil Tablets? “What Is The Most Important Information I Should Know About Tadalafil Tablets?” tadalafil tablets are: Tadalafil Tablets? tadalafil tablets and all medicines out of the reach of children. Tadalafil Tablets: Tadalafil Tablets? Manufactured for: Burel Pharmaceuticals, LLC Aurobindo Pharma Limited

PD-Rx Pharmaceuticals, Inc.

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