TADALAFIL- tadalafil_tablet

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. Effects on Blood Pressure Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1. 8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0. 6 mm Hg, respectively). In addition, there was no significant effect on heart rate. Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 mg 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 )] A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0. 4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable ( see Figure 1: Mean Maximal Change in Blood Pressure (Tadalafil Minus Placebo, Point Estimate with 90% CI) in Response to Sublingual Nitroglycerin at 2 (Supine Only), 4, 8, 24, 48, 72, and 96 Hours after the Last Dose of Tadalafil 20 mg or Placebo 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 ) and 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) Figure 2: Doxazosin Study 1: Mean Change from Baseline in Systolic Blood Pressure 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 less than 85 mm Hg or a decrease from baseline in standing systolic blood pressure of greater than 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 greater than 30 mm Hg, while five and one subject were outliers due to standing systolic BP less than 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 mg 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 Figure 3: Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic Blood Pressure Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings of less than 85 mm Hg were recorded or one or more decreases in systolic blood pressure of greater than 30 mm Hg from a time-matched baseline occurred during the analysis interval. 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 less than 85 mm Hg, while 15 and 4 were outliers due to a decrease from baseline in systolic BP of greater than 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 less than 85 mm Hg, while 15 and 5 subjects were outliers due to a decrease from baseline in systolic BP of greater than 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. In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. After 7 days, doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin). The results are shown in Table 7. 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. 0) 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 greater than 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 greater than 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 greater than 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 less than 85 mm Hg. Following the seventh day of doxazosin 4 mg, there were no outliers on tadalafil 5 mg, one subject on placebo had a decrease greater than 30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure less than 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 greater than 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 less than 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 greater than 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 less than 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 less than 85 mm Hg) following administration of tadalafil 20 mg. There were no subjects with a decrease from baseline in standing systolic blood pressure of greater than 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 Angiotensin II receptor blockers Bendrofluazide Enalapril Metoprolol Effects on Blood Pressure When Administered 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 these, alcohol was administered at a dose of 0. 7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in one study and 20 mg in another. In both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of these two studies, blood alcohol levels of 0. 08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of alcohol (0. 6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to alcohol alone, and the hypotensive effects of alcohol were not potentiated. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. Effects on Exercise Stress Testing The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. Effects on Vision Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupilometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (less than 0. 1% of patients). Effects on Sperm Characteristics Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 mg or 20 mg of tadalafil compared to placebo. Effects on Cardiac Electrophysiology The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide) -controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QT c c figure1 figure2 figure3 Over a dose range of 2. 5 mg 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 Figure 4: Plasma tadalafil concentrations (mean +/- SD) following a single 20-mg tadalafil dose and single and once daily multiple doses of 5 mg Absorption max The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil 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 figure4.

Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: 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 is 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 is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil 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 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 mL/min 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 and 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 Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance 30 mL/min 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 have not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised. Severe (Child Pugh Class C): The use of tadalafil tablets are not recommended [see Warnings and Precautions ( 5. 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. 6 Nitrates [see Contraindications ( 4. 1 Alpha-Blockers ED [see Warnings and Precautions ( 5. 2 BPH see Warnings and Precautions ( 5. 2 CYP3A4 Inhibitors Tadalafil tablets for Use as Needed [see Warnings and Precautions ( 5. 2 Tadalafil tablets for Once Daily Use [see Warnings and Precautions ( 5.

Most common adverse reactions (greater than or equal to 2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and pain in limb ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of tadalafil tablets 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 tablets for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively. Tadalafil tablets for Use as Needed for 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 greater than or equal to 2% of Patients Treated with Tadalafil tablets (10 mg 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 tablets 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 tablets 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 greater than or equal to 2% of Patients Treated with Tadalafil for Once Daily Use (2. 5 mg 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 tablets for Once Daily Use for ED Adverse Reaction 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% 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 greater than or equal to 2% of Patients Treated with Tadalafil tablets for Once Daily Use (2. 5 mg or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Tadalafil tablets for Once Daily Use for ED Adverse Reaction 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% Tadalafil tablets for Once Daily Use for BPH and for ED and BPH In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3. 6% compared to 1. 6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported ( see Table 4: Treatment-Emergent Adverse Reactions Reported by greater than or equal to 1% of Patients Treated with Tadalafil tablets 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 tablets 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. 4% Pain in extremity 0. 4% Myalgia 0. 2% Dizziness 0. 0% Additional, less frequent adverse reactions (less than 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. Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (less than 5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e. , codeine) was used. Overall, approximately 0. 5% of all subjects treated with tadalafil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5. 3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of tadalafil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of less than 1% across all indications. Across placebo-controlled studies with tadalafil for use as needed for ED, diarrhea was reported more frequently inpatients 65 years of age and older who were treated with tadalafil (2. 5% of patients) [see Use in Specific Populations ( 8. 5 The following section identifies additional, less frequent events (less than 2%) reported in controlled clinical trials of tadalafil for once daily use or use as needed. A causal relationship of these events to tadalafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful: Body as a Whole Cardiovascular Digestive Musculoskeletal Nervous Renal and Urinary Respiratory Skin and Appendages Ophthalmologic Otologic Urogenital 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 [see Warnings and Precautions ( 5. 4 Otologic [see Warnings and Precautions ( 5. 5 Urogenital [see Warnings and Precautions ( 5.

Administration of tadalafil to patients using any form of organic nitrate is contraindicated. Tadalafil was shown to potentiate the hypotensive effect of nitrates ( 4. 1 History of known serious hypersensitivity reaction to Tadalafil or ADCIRCA registered 4. 3 Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology ( 12. 2 Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil (Tadalafil tablets or ADCIRCA registered [see Adverse Reactions ( 6. 2 Do not use Tadalafil in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including Tadalafil, 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 mL/min 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 Tadalafil is not indicated for use in females. 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 Data). Data Animal Data 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 studies 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. In another rat prenatal and postnatal development study at doses of 60 mg/kg, 200 mg/kg, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats. Risk Summary Tadalafil is not indicated for use in females 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 Based on the data from 3 studies in adult males, tadalafil decreased sperm concentrations in the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. There was no adverse effect of tadalafil 10 mg or 20 mg on mean concentrations of testosterone, luteinizing hormone or follicle stimulating hormone. The clinical significance of the decreased sperm concentrations in the two studies is unknown. There have been no studies evaluating the effect of tadalafil on fertility in men [see Clinical Pharmacology ( 12. 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. A randomized, double-blind, placebo-controlled trial in pediatric patients (7 to 14 years of age) with Duchenne muscular dystrophy, who received tadalafil 0. 3 mg/kg, tadalafil 0. 6 mg/kg, or placebo daily for 48 weeks failed to demonstrate any benefit of treatment with tadalafil on a range of assessments of muscle strength and performance. Juvenile Animal Study No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60 mg/kg/day, 200 mg/kg/day, 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 (greater than 65 and greater than or equal to75 years of age) and younger subjects (less than or equal to 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. 8 In clinical pharmacology studies using single-dose tadalafil (5 mg to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 mL/min to 80 mL/min. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2. 8-fold increase in AUC following single-dose administration of 10 mg or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2-to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with creatinine clearance 30 mL/min to 50 mL/min. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10-or 20-mg tadalafil, there were no reported cases of back pain.

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. 2 Alpha-Blockers [see Dosage and Administration ( 2. 2 Antihypertensives [see Warnings and Precautions ( 5. 2 Alcohol [see Warnings and Precautions ( 5. 2 [See Dosage and Administration ( 2. 10 Antacids H2 Antagonists (e. Nizatidine Cytochrome P450 Inhibitors [see Dosage and Administration ( 2. 7 [see Dosage and Administration ( 2. 7 Cytochrome P450 Inducers Aspirin Cytochrome P450 Substrates 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 US. 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 30point 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 US Trials see Table 11: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US 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% <. 001 2% 32% <. 001 Maintenance of Erection (SEP3) Endpoint 25% 50% 23% 64% Change from baseline 5% 34% <. 001 4% 44% <. 001 Results in General ED Population in Trials Outside the US 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 US a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Study C Endpoint [Change from baseline] 15. 001 Study D Endpoint [Change from baseline] 14. 001 Study E Endpoint [Change from baseline] 18. 001 Study F a Endpoint [Change from baseline] 12. 001 Study G Endpoint [Change from baseline] 14. 001 p 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 US a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Study C Endpoint [Change from baseline] 49% [6%] 57% [15%] 73% [29%] p=. 001 Study D Endpoint [Change from baseline] 46% [2%] 56% [18%] 68% [15%] p=. 001 Study E Endpoint [Change from baseline] 55% [10%] 77% [35%] 85% [35%] p<. 001 Study F a Endpoint [Change from baseline] 42% [-8%] 81% [27%] p<. 001 Study G Endpoint [Change from baseline] 45% [-6%] 73% [21%] 76% [21%] p<. 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 US a Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Study C Endpoint [Change from baseline] 26% [4%] 38% [19%] 58% [32%] p=. 001 Study D Endpoint [Change from baseline] 28% [4%] 42% [24%] 51% [26%] p<. 001 Study E Endpoint [Change from baseline] 43% [15%] 70% [48%] 78% [50%] p<. 001 Study F a Endpoint [Change from baseline] 27% [1%] 74% [40%] p<. 001 Study G Endpoint [Change from baseline] 32% [5%] 57% [33%] 62% [29%] p<. 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%] <. 001 Maintenance of Erection (SEP3) Endpoint [Change from baseline] 20% [2%] 48% [28%] 42% [29%] <. 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%] <. 001 Maintenance of Erection (SEP3) Endpoint [Change from baseline] 19% [4%] 41% [23%] <. 001 Results in Studies to Determine the Optimal Use of Tadalafil Two studies were conducted to assess the efficacy of tadalafil In the first of these studies, 348 patients with ED were randomized to placebo or tadalafil tablets 20 mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24 hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The results demonstrated a difference between the placebo group and the tadalafil group at each of the pre-specified timepoints. At the 24-hour timepoint, (more specifically, 22 to 26 hours), 53/144 (37%) patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the tadalafil The efficacy and safety of tadalafil 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 US. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. Tadalafil Results in General ED Population The primary efficacy and safety study conducted outside the US 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 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 <. 001 11% 37% c <. 001 Maintenance of Erection (SEP3) Endpoint 31% 50% 57% 37% 67% Change from baseline 10% 31% c 35% c <. 001 13% 46% c <. 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 <. 001 Maintenance of Erection (SEP3) Endpoint 28% 46% 41% Change from baseline 8% 26% a 25% a <. 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. In each of these 2 trials, tadalafil 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks. Table 19: Mean IPSS Changes in BPH Patients in Two Tadalafil Tablets 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 Week 12 -2. 004 Figure 5: Mean IPSS Changes in BPH Patients by Visit in Study J Figure 6: Mean IPSS Changes in BPH Patients by Visit in Study K 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 Tadalafil 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 5mg 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 Figure 7: Mean Total IPSS Changes By Visit in BPH Patients Taking Tadalafil for Once Daily Use Together With Finasteride 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. 1; p less than. 001), week 12 (tadalafil/finasteride 4. 7, placebo/finasteride 0. 6; p less than. 001), and week 26 (tadalafil/finasteride 4. 0; p less than. figure5 figure6 figure7 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). Timing of sexual activity was not restricted relative to when patients took tadalafil. 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% <. 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 Figure 8: Mean IPSS Changes in ED/BPH Patients by Visit in Study L In this study, the effect of tadalafil 5 mg once daily on Q max max figure8.
Patient Information
Tadalafil Tablets, USP Read this important information before you start taking tadalafil tablets and each time you get a refill. There may be new information. You may also find it helpful to share this information with your partner. This information does not take the place of talking with your healthcare provider. You and your healthcare provider should talk about tadalafil tablets when you start taking it and at regular checkups. If you do not understand the information, or have questions, talk with your healthcare provider or pharmacist. What Is The Most Important Information I Should Know About tadalafil tablets? Tadalafil tablets can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. Do not take tadalafil tablets if you 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 tadalafil tablets?” After taking a single tablet, some of the active ingredient of 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?” 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 ED is a condition where the penis does not fill with enough blood to harden and expand when a man is sexually excited, or when he cannot keep an erection. A man who has trouble getting or keeping an erection should see his healthcare provider for help if the condition bothers him. Tadalafil tablets helps increase blood flow to the penis and may help men with ED get and keep an erection satisfactory for sexual activity. Once a man has completed sexual activity, blood flow to his penis decreases, and his erection goes away. cure ED increase a man’s sexual desire protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your health care 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 for the Treatment of Symptoms of BPH BPH is a condition that happens in men, where the prostate gland enlarges which can cause urinary symptoms. Tadalafil tablets for the Treatment of ED and Symptoms of BPH ED and symptoms of BPH may happen in the same person and at the same time. Men who have both ED and symptoms of BPH may take tadalafil tablets for the treatment of both conditions. Tadalafil tablets are not for women or children. Tadalafil tablets must be used only under a healthcare provider’s care. Who Should Not Take Tadalafil Tablets? 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 or any of its ingredients. 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. What Should I Tell My Healthcare Provider Before Taking Tadalafil Tablets? Only your healthcare provider and you can decide if tadalafil tablets are right for you. have heart problems have pulmonary hypertension have ever had severe vision loss, including a condition called NAION have a deformed penis shape have had an erection that lasted more than 4 hours Can Other Medicines Affect Tadalafil Tablets? see “What Is The Most Important Information I Should Know About Tadalafil Tablets?” registered registered registered registered registered registered registered registered registered registered registered registered registered registered How Should I Take Tadalafil Tablets? How Should I Take Tadalafil Tablets for Symptoms of BPH? For symptoms of BPH, Tadalafil Tablets is taken once daily. How Should I Take tadalafil tablets for ED? Tadalafil tablets for use as needed: Your healthcare provider may change your dose of tadalafil tablets depending on how you respond to the medicine, and on your health condition. OR How Should I Take Tadalafil Tablets for Both ED and the Symptoms of BPH? What Should I Avoid While Taking tadalafil tablets? What Are The Possible Side Effects Of Tadalafil Tablets? “What Is The Most Important Information I Should Know About Tadalafil Tablets?” The most common side effects with tadalafil tablets are Uncommon side effects include An erection that won’t go away (priapism). If you get an erection that lasts more than 4 hours, get medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to your penis, including the inability to have erections. In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including tadalafil tablets) reported a sudden decrease or loss of vision in one or both eyes. It is uncertain whether PDE5 inhibitors directly cause the vision loss. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including tadalafil tablets, and call a healthcare provider right away. Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely reported in people taking PDE5 inhibitors, including tadalafil tablets. It is not possible to determine whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking tadalafil tablets and contact a healthcare provider right away. These are not all the possible side effects of tadalafil tablets. For more information, ask your healthcare provider or pharmacist. How Should I Store Tadalafil Tablets? Keep tadalafil tablets and all medicines out of the reach of children. General Information About tadalafil tablets: This is a summary of the most important information about tadalafil tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about tadalafil tablets that is written for health providers. What Are The Ingredients In tadalafil tablets? Inactive ingredients: microcrystalline cellulose, lactose monohydrate croscarmellose sodium, sodium lauryl sulphate, low-substituted hydroxypropyl cellulose and magnesium stearate. #All trademarks are the properties of their respective owners Revised: 05/2020 Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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