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 In vitro Effects on Blood Pressure Effects on Blood Pressure When Administered with Nitrates [see Contraindications ( 4. 1 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 [see Contraindications ( 4. 1 [see Dosage and Administration ( 2. 6 Doxazosin 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) 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 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. 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. No syncope was reported. 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 Bendrofluazide Enalapril Metoprolol Effects on Blood Pressure When Administered with Alcohol Effects on Exercise Stress Testing Effects on Vision Effects on Sperm Characteristics Effects on Cardiac Electrophysiology c c fig1 fig fig 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 Distribution Metabolism In vitro Excretion Geriatric max [see Use in Specific Populations ( 8. 5 Patients with Diabetes Mellitus max Patients with BPH max fig.

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 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 recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day. 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 [see Warnings and Precautions ( 5. 7 ) and Use in Specific Populations ( 8. Erectile Dysfunction [see Warnings and Precautions ( 5. 7 Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia [see Warnings and Precautions ( 5. 7 Hepatic Impairment [see Warnings and Precautions ( 5. 8 ) and Use in Specific Populations ( 8. [see Warnings and Precautions ( 5. 6 Nitrates [see Contraindications ( 4. 1 Alpha-Blockers ED [see Warnings and Precautions ( 5. 6 ), Drug Interactions ( 7. 1 ), and Clinical Pharmacology ( 12. 2 [see Warnings and Precautions ( 5. 2 Tadalafil Tablets for Once Daily Use [see Warnings and Precautions ( 5.

Most common adverse reactions (>=2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and pain in limb ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. , at 1-888-943-3210 or 1-855-926-3384 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 tablets for Use as Needed for ED see Table 1 Table 1: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil Tablets (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 Tablets for Use as Needed for ED 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% a The term flushing includes: facial flushing and flushing Table 2: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil Tablets 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 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) over 24 weeks treatment duration in one placebo-controlled clinical study: Table 3: Treatment-Emergent Adverse Reactions Reported by >=2% of Patients Treated with Tadalafil Tablets 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 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 Table 4: Treatment-Emergent Adverse Reactions Reported by >=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 (<1%) reported in the controlled clinical trials of tadalafil tablets 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 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 tablets. 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 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 was 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 (Tadalafil tablets or ADCIRCAregistered). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [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 Data Animal Data Risk Summary 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. 2 Based on studies in animals, a decrease in spermatogenesis was observed in dogs, but not in rats [ see Nonclinical Toxicology ( 13. 1 Tadalafil tablets are 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 Additional information describing a clinical study in which efficacy was not demonstrated is approved for Eli Lilly and Company’s CIALIS (tadalafil) tablets. However, due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 tablets for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil tablets (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 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 tablets can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol ( 7. 1 CYP3A4 inhibitors (e. ketoconazole, ritonavir) increase tadalafil tablets exposure ( 2. 2 Tadalafil tablets for use as needed: no more than 10 mg every 72 hours Tadalafil tablets for once daily use: dose not to exceed 2. 5 mg CYP3A4 inducers (e. rifampin) decrease tadalafil tablets exposure ( 7. 2 Nitrates [see Dosage and Administration ( 2. 2 Alpha-Blockers [see Dosage and Administration ( 2. 2 Antihypertensives [see Warnings and Precautions (5. 6) and Clinical Pharmacology ( 12. 2 Alcohol [see Warnings and Precautions (5. 9) and Clinical Pharmacology ( 12. 2 [See Dosage and Administration (2. 7) and Warnings and Precautions (5. Antacids H 2 Cytochrome P450 Inhibitors CYP3A4 (e. , Ketoconazole) max [see Dosage and Administration (2. HIV Protease inhibitor max max [see Dosage and Administration (2. max Aspirin 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 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 tablets, when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED). Results in ED Population in US Trials 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 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 Placebo TADALAFIL TADALAFIL TADALAFIL 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 a 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 Placebo TADALAFIL TADALAFIL TADALAFIL 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 a 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 Placebo TADALAFIL TADALAFIL TADALAFIL 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 a 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 tablets, compared to patients on placebo. Efficacy Results in ED Patients with Diabetes Mellitus 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 Tablets The efficacy and safety of tadalafil tablets 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 tablets, when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED). Results in General ED Population see Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Tadalafil Tablets for Once Daily Use Studies 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 a b c 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 Tablets for Once Daily Use Study in ED Patients with Diabetes 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 a The efficacy and safety of tadalafil tablets 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 max 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 In Study J, the effect of tadalafil tablets 5 mg once daily on maximum urinary flow rate (Q max max max Efficacy Results in Patients with BPH initiating Tadalafil Tablets and Finasteride Table 20: Mean Total IPSS Changes in BPH Patients in a Tadalafil Tablets for Once Daily Use Study Together with Finasteride Placebo and finasteride 5 mg TADALAFIL 5mg and finasteride 5 mg Treatment difference n (N=350) 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. 001 Change from Baseline to Week 12 b 318 -3. 001 Change from Baseline to Week 26 b 295 -4. 022 a b c fig fig fig The efficacy and safety of tadalafil tablets 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 tablets 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. Table 21: Mean IPSS and IIEF EF Domain Changes in the Tadalafil Tablets 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 Tablets 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 tablets 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 max max fig.

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