tadalafil

Warning and Precautions (5.4) 05/2017

1 INDICATIONS AND USAGE Tadalafil tablets USP are 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 USP are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks (1.4). 1.1 Erectile Dysfunction Tadalafil tablets USP are indicated for the treatment of erectile dysfunction (ED). 1.2 Benign Prostatic Hyperplasia Tadalafil tablets USP 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 USP are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH). 1.4 Limitation of Use If tadalafil tablets USP are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil tablets USP decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil tablets USP beyond 26 weeks is unknown [see Clinical Studies (14.3)] .

2 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 (2.1). • Tadalafil tablet 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 (2.3, 2.4) •Tadalafil tablets may be taken without regard to food (2.5). 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 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. 2.2 Tadalafil Tablet for Once Daily Use for Erectile Dysfunction · The recommended starting dose of tadalafil tablet 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 tablet dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability. 2.3 Tadalafil Tablet for Once Daily Use for Benign Prostatic Hyperplasia · The recommended dose of tadalafil tablet for once daily use is 5 mg, taken at approximately the same time every day. · When therapy for BPH is initiated with tadalafil tablet and finasteride, the recommended dose of tadalafil tablet for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. 2.4 Tadalafil Tablet for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia The recommended dose of tadalafil tablet 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 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 Tablet for Once Daily Use Erectile Dysfunction · Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablet for once daily use is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)] . 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 tablet for once daily use is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)] . 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 tablet 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 tablet …

3 DOSAGE FORMS AND STRENGTHS Tadalafil tablets 2.5 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘336’ on one side and plain on other side. Tadalafil tablets 5 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘337’ on one side and plain on other side. Tadalafil tablets 10 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘338’ on one side and plain on other side. Tadalafil tablets 20 mg are yellow to light yellow, oval shaped, beveled edge, coated tablets debossed with ‘L339’ on one side and plain on other side. Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg (3).

4 CONTRAINDICATIONS 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®(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 was 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.

6 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 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 tablet 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 mg 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 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 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 Tadalafil Tablet 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 Tablet 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 Tablet 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 Tablet 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 Tablet 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 Tablet for Once Daily Use for B …

7 DRUG INTERACTIONS · Tadalafil tablets can potentiate the hypotensive effects of nitrates, alpha blockers, antihypertensives or alcohol (7.1). · CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase tadalafil tablets exposure (2.7, 5.10, 7.2) requiring dose adjustment: · Tadalafil tablets for use as needed: no more than 10 mg every 72 hours · Tadalafil tablet for once daily use: dose not to exceed 2.5 mg · CYP3A4 inducers (e.g. rifampin) decrease tadalafil tablets exposure (7.2). 7.1 Potential for Pharmacodynamic Interactions with Tadalafil Tablets Nitrates - Administration of tadalafil tablets to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, tadalafil tablet was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken tadalafil tablet, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil tablet 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 (2.7), Contraindications (4.1), and Clinical Pharmacology (12.2)] . Alpha-Blockers - Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including tadalafil tablets, 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 (2.7), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2)] . 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 (12.2)] . 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 tablets 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 (5.9) and Clinical Pharmacology (12.2)] . 7.2 Potential for Other Drugs to Affect Tadalafil Tablets [See Dosage and Administration (2.7) and Warnings and Precautions (5.10)] . 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. H 2 Antagonists (e.g. Nizatidine) - An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics. Cytochrome P450 Inhibitors - Tadalafil tablets are 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 C max by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 m …

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment (2.6, 5.8, 8.6): · Mild or Moderate: Dosage adjustment may be needed. · Severe: Use is not recommended. Renal Impairment (2.6, 5.7, 8.7): · 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. 8.1 Pregnancy Risk Summary Tadalafil tablets are not indicated for use in females. There are no data with the use of tadalafil tablets 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 study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance. In another rat prenatal and postnatal development study at doses of 60, 200, 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. 8.2 Lactation Risk Summary Tadalafil tablets are 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. 8.3 Females and Males of Reproductive Potential 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)]. 8.4 Pediatric Use 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. A randomized, double-blind, placebo-controlled trial in pediatric patients (7 to 14 years of age) with Duchenne muscular dystrophy, who received tadalafil tablets 0.3 mg/kg, tadalafil tablets 0.6 mg/kg, or placebo dailyfor48 weeks failed to demonstrate any benefit of treatment with tadalafil tablets 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, 200, and 1000 mg/kg/day to juvenile rats on postnatal days 14 to 90. The highest plasma tadalafil e …

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.

11 DESCRIPTION Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41. The structural formula is: The chemical designation is pyrazino[1’,2’:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a white to off white powder that is slightly soluble in dichloromethane and very slightly soluble in methanol. Tadalafil tablets USP are available as round shaped tablets (2.5 mg, 5 mg and 10 mg) and oval shaped tablets (20 mg) for oral administration. Each tablet contains 2.5 mg, 5 mg, 10 mg, or 20 mg of tadalafil and the following inactive ingredients: hydroxy propyl cellulose, lactose monohydrate, croscarmellose sodium, sodium lauryl sulphate, povidone k-25, colloidal silicone dioxide, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 6000, talc and iron oxide yellow. Structure

10 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tadalafil tablets USP 2.5 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘336’ on one side and plain on other side. NDC Number Size 62332-177-30 bottle of 30 Tablets with child-resistant closure 62332-177-71 bottle of 500 Tablets 62332-177-91 bottle of 1000 Tablets 62332-177-15 30 Tablets (2 blisters of 15 tablets) Tadalafil tablets USP 5 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘337’ on one side and plain on other side. NDC Number Size 62332-178-30 bottle of 30 Tablets with child-resistant closure 62332-178-71 bottle of 500 Tablets 62332-178-91 bottle of 1000 Tablets 62332-178-15 30 Tablets (2 blisters of 15 tablets) Tadalafil tablets USP 10 mg are yellow to light yellow, round shaped, beveled edge, coated tablets debossed with ‘338’ on one side and plain on other side. NDC Number Size 62332-179-30 bottle of 30 Tablets with child-resistant closure 62332-179-71 bottle of 500 Tablets 62332-179-91 bottle of 1000 Tablets Tadalafil tablets USP 20 mg are yellow to light yellow, oval shaped, beveled edge, coated tablets debossed with ‘L339’ on one side and plain on other side. NDC Number Size 62332-180-30 bottle of 30 Tablets with child-resistant closure 62332-180-71 bottle of 500 Tablets 62332-180-91 bottle of 1000 Tablets 16.2 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children.