Tadalafil

INDICATIONS AND USAGE Tadalafil Tablets are phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: • erectile dysfunction (ED) ( Error! Hyperlink reference not valid. ) • the signs and symptoms of benign prostatic hyperplasia (BPH) ( Error! Hyperlink reference not valid. ) • ED and the signs and symptoms of BPH (ED/BPH) ( Error! Hyperlink reference not valid. ) If Tadalafil Tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks ( Error! Hyperlink reference not valid. ). 1.1 Erectile Dysfunction Tadalafil Tablets are indicated for the treatment of erectile dysfunction (ED). 1.2 Benign Prostatic Hyperplasia Tadalafil Tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). 1.3 Erectile Dysfunction and Benign Prostatic Hyperplasia Tadalafil Tablets are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH). 1.4 Limitation of Use 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 ( Error! Hyperlink reference not valid. )] .

DOSAGE AND ADMINISTRATION 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 ( Error! Hyperlink reference not valid. ). • 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 ( Error! Hyperlink reference not valid. ). • BPH: 5 mg, taken at approximately the same time every day ( Error! Hyperlink reference not valid. ) • ED and BPH: 5 mg, taken at approximately the same time every day ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) • Tadalafil Tablets may be taken without regard to food ( Error! Hyperlink reference not valid. ). 2.1 Tadalafil Tablets for Use as Needed for Erectile Dysfunction • 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 was 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. 2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction • 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. 2.3 Tadalafil Tablets for Once Daily Use for Benign Prostatic Hyperplasia • The recommended dose of Tadalafil Tablets for once daily use is 5 mg, taken at approximately the same time every day. • When therapy for BPH is initiated with Tadalafil Tablets and finasteride, the recommended dose of Tadalafil Tablets for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. 2.4 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia 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. 2.5 Use with Food Tadalafil Tablets may be taken without regard to food. 2.6 Use in Specific Populations Renal Impairment Tadalafil Tablets for Use as Needed • Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours. • Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( Error! Hyperlink reference not valid. )] . 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 ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( Error! Hyperlink reference not valid. )] . Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia • Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response. • Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil Tablets for once daily use is not recommended [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( Error! Hyperlink reference not valid. )] . Hepatic Impairment Tadalafil Tablets for Use as Needed • Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of Tadalafil Tablets once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised. • Severe (Child Pugh Class C): The use of Tadalafil Tablets is not recommended [see Warnings and Precautions ( Error! Hyperlink reference not valid. )and Use in Specific Populations ( Error! Hyperlink reference not valid. )] . 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. • Severe (Child Pugh Class C): The use of Tadalafil Tablets is not recommended [see Warnings and Precautions ( Error! Hyperlink reference not valid. )and Use in Specific Populations ( Error! Hyperlink reference not valid. )] . 2.7 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated [see Contraindications ( Error! Hyperlink reference not valid. )] . Alpha-Blockers ED — When Tadalafil Tablets are coadministered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and Tadalafil Tablets should be initiated at the lowest recommended dose [see Warnings and Precautions ( 5.6 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . BPH — Tadalafil Tablets are not recommended for use in combination with alpha-blockers for the treatment of BPH [see Warnings and Precautions ( 5.6 ), Drug Interactions ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . CYP3A4 Inhibitors Tadalafil Tablets for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of Tadalafil Tablets is 10 mg, not to exceed once every 72 hours [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Drug Interactions ( Error! Hyperlink reference not valid. )] . Tadalafil Tablets for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Drug Interactions ( Error! Hyperlink reference not valid. )] .

WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options. Before prescribing tadalafil tablets, it is important to note the following: Patients should not use tadalafil tablets if sex is inadvisable due to cardiovascular status ( 5.1 ). Use of tadalafil tablets with alpha-blockers, antihypertensives or substantial amounts of alcohol (≥5 units) may lead to hypotension ( 5.6 , 5.9 ). Tadalafil tablets are not recommended in combination with alpha-blockers for the treatment of BPH because efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering. Caution is advised when tadalafil tablets are used as a treatment for ED in men taking alpha-blockers. ( 2.7 , 5.6 , 7.1 , 12.2 ) Patients should seek emergency treatment if an erection lasts >4 hours. Use tadalafil tablets with caution in patients predisposed to priapism ( 5.3 ). Patients should stop tadalafil tablets and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of non-arteritic anterior ischemic optic neuropathy (NAION). Tadalafil tablets should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION. Patients with a "crowded" optic disc may also be at an increased risk of NAION ( 5.4 , 6.2 ). Patients should stop tadalafil tablets and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5 ). Prior to initiating treatment with tadalafil tablets for BPH, consideration should be given to other urological conditions that may cause similar symptoms ( 5.14 ). 5.1 Cardiovascular Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including tadalafil tablets, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention. Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of tadalafil tablets. In such a patient, who has taken tadalafil tablets, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil tablets before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking tadalafil tablets should seek immediate medical attention. [see Contraindications ( 4.1 ) and Patient Counseling Information ( 17.1 )] . Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors. The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for tadalafil tablets, and therefore until further information is available, tadalafil tablets are not recommended for the following groups of patients: myocardial infarction within the last 90 days unstable angina or angina occurring during sexual intercourse New York Heart Association Class 2 or greater heart failure in the last 6 months uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension stroke within the last 6 months. As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects [see Clinical Pharmacology ( 12.2 )] . While this effect should not be of consequence in most patients, prior to prescribing tadalafil tablets, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors. 5.2 Potential for Drug Interactions When Taking Tadalafil Tablets for Once Daily Use Physicians should be aware that tadalafil tablets for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol [see Drug Interactions ( 7.1 , 7.2 , 7.3 )] . 5.3 Prolonged Erection There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. Tadalafil tablets should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease). 5.4 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including tadalafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥50. An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period. The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34). A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20). Other risk factors for NAION, such as the presence of "crowded" optic disc, may have contributed to the occurrence of NAION in these studies. Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ( 6.2 )] . Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including tadalafil, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including tadalafil, for this uncommon condition. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and

CONTRAINDICATIONS Administration of tadalafil tablets to patients using any form of organic nitrate is contraindicated. In clinical pharmacology studies, tadalafil tablets were shown to potentiate the hypotensive effect of nitrates ( 4.1 ). History of known serious hypersensitivity reaction to tadalafil tablets or ADCIRCA ® ( 4.2 ). Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3 ). 4.1 Nitrates Administration of tadalafil tablets to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil tablets were shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology ( 12.2 )] . 4.2 Hypersensitivity Reactions Tadalafil tablets are contraindicated in patients with a known serious hypersensitivity to tadalafil (or ADCIRCA ® ). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions ( 6.2 )] . 4.3 Concomitant Guanylate Cyclase (GC) Stimulators 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. 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.

DRUG INTERACTIONS • Tadalafil can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol ( Error! Hyperlink reference not valid. ). • CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase Tadalafil exposure ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. ) requiring dose adjustment: o Tadalafil for use as needed: no more than 10 mg every 72 hours o Tadalafil for once daily use: dose not to exceed 2.5 mg • CYP3A4 inducers (e.g. rifampin) decrease Tadalafil exposure ( Error! Hyperlink reference not valid. ). 7.1 Potential for Pharmacodynamic Interactions with Tadalafil Nitrates - Administration of Tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, Tadalafil was shown to potentiate the hypotensive effect of nitrates. 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 Dosage and Administration ( Error! Hyperlink reference not valid. ), Contraindications ( Error! Hyperlink reference not valid. ), and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . Alpha-Blockers - Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin. [see Dosage and Administration ( Error! Hyperlink reference not valid. ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . Antihypertensives - PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. [see Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . Alcohol - Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Clinical Pharmacology ( Error! Hyperlink reference not valid. )] . 7.2 Potential for Other Drugs to Affect Tadalafil [See Dosage and Administration ( Error! Hyperlink reference not valid. ) and Warnings and Precautions ( Error! Hyperlink reference not valid. )] . Antacids - Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil. H2 Antagonists (e.g. Nizatidine) - An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics. Cytochrome P450 Inhibitors - Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure. CYP3A4 (e.g., Ketoconazole) - Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone [see Dosage and Administration ( Error! Hyperlink reference not valid. )] . Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure. HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see Dosage and Administration ( Error! Hyperlink reference not valid. )] . Cytochrome P450 Inducers - Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure. CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of Tadalafil for once daily use; the magnitude of decreased efficacy is unknown. 7.3 Potential for Tadalafil to Affect Other Drugs Aspirin - Tadalafil did not potentiate the increase in bleeding time caused by aspirin. Cytochrome P450 Substrates - Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. CYP1A2 (e.g. Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed. CYP2C9 (e.g. Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin. CYP3A4 (e.g. Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin. P-glycoprotein (e.g. Digoxin) - Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects

ADVERSE REACTIONS 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 VKT Pharma Pvt. Ltd at 1 844-387-1231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience 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 ED In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients. When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported ( see Table 1) for tadalafil tablets for use as needed: 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 a The term flushing includes: facial flushing and flushing 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) in clinical trials of 12 weeks duration: 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 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). 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 2.3% 4.1% Dyspepsia 0.2% 2.4% Back pain 1.4% 2.4% Nasopharyngitis 1.6% 2.1% Diarrhea 1.0% 1.4% Pain in extremity 0.0% 1.4% Myalgia 0.3% 1.2% Dizziness 0.5% 1.0% 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. 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 (<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.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with tadalafil tablets 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 5.5% and 1.3% 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 tablets for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of tadalafil tablets for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of <1% across all indications. Across 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 Use in Specific Populations ( 8.5 )] . Across all studies with any tadalafil tablets dose, reports of changes in color vision were rare (<0.1% of patients). The following section identifies additional, less frequent events (<2%) reported in controlled clinical trials of tadalafil tablets for once daily use or use as needed. A causal relationship of these events to tadalafil tablets 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 — asthenia, face edema, fatigue, pain, peripheral edema Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia Digestive — abnormal liver functi

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism for reducing BPH symptoms has not been established. Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas. In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues (e.g., adrenal cortex). In vitro , tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined. 12.2 Pharmacodynamics 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 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 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 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of tadalafil tablets 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). 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 tablets administration with nitrates is contraindicated. In a patient who has taken tadalafil tablets, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil tablets 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 )] . In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alpha-blocker. In two studies, a daily oral alpha-blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil. Doxazosin — Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha[1]-adrenergic blocker. 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 and Figure 2). Table 5: Doxazosin (8 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal Tadalafil decrease in systolic blood pressure (mm Hg) 20 mg Supine 3.6 (-1.5, 8.8) Standing 9.8 (4.1, 15.5) 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 <85 mm Hg or a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. No such events were reported following placebo. Two such events were reported following administration of tadalafil. Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days. This subject previously experienced a mild episode of vertigo on doxazosin and placebo. Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day. No syncope was reported. In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin,