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 ( 14.3)] .

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

Hepatic Impairment

2.7 Concomitant Medications

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.

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 Tablets, 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.Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Tadalafil Tablets, 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 . 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 Tablets, 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 Tablets, for this uncommon condition.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 Tablets, 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 Tablets, for this uncommon condition.

Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.

5.5 Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including Tadalafil Tablets, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil Tablets. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1, 6.2)] .

5.6 Alpha-blockers and Antihypertensives

Physicians should discuss with patients the potential for Tadalafil Tablets to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)] .

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. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)] , which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

5.7 Renal Impairment

5.8 Hepatic Impairment

5.9 Alcohol

Patients should be made aware that both alcohol and Tadalafil Tablets, 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. Therefore, physicians should inform patients that 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 [see Clinical Pharmacology ( 12.2)] .

5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)

Tadalafil Tablets are metabolized predominantly by CYP3A4 in the liver. The dose of Tadalafil Tablets for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole [see Drug Interactions ( 7.2)] . In patients taking potent inhibitors of CYP3A4 and Tadalafil Tablets for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration ( 2.7)] .

5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies

The safety and efficacy of combinations of Tadalafil Tablets and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take Tadalafil Tablets with other PDE5 inhibitors, including ADCIRCA.

5.12 Effects on Bleeding

Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Tadalafil Tablets have not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Tadalafil Tablets have not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.

5.13 Counseling Patients About Sexually Transmitted Diseases

The use of Tadalafil Tablets offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.

5.14 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH

Prior to initiating treatment with Tadalafil Tablets for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

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.

6.2 Postmarketing Experience

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 — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Tadalafil Tablets without sexual activity. Others were reported to have occurred hours to days after the use of Tadalafil Tablets and sexual activity. It is not possible to determine whether these events are related directly to Tadalafil Tablets, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions ( 5.1)] .

Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis

Nervous — migraine, seizure and seizure recurrence, transient global amnesia

Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of PDE5 inhibitors, including Tadalafil Tablets. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. [see Warnings and Precautions ( 5.4)] .

Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including Tadalafil Tablets. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Tadalafil Tablets, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions ( 5.5)] .

Urogenital — priapism [see Warnings and Precautions ( 5.3)] .

7.1 Potential for Pharmacodynamic Interactions with Tadalafil Tablets

7.2 Potential for Other Drugs to Affect Tadalafil Tablets

[See Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.10)] .

7.3 Potential for Tadalafil Tablets to Affect Other Drugs

8.1 Pregnancy

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.

Juvenile Animal Study

No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60, 200, and 1000 mg/kg/day to juvenile rats on postnatal days 14 to 90. The highest plasma tadalafil exposures (AUC) achieved were approximately 10-fold that observed at the MRHD.

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.

8.5 Geriatric Use

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)] . No dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered. [see Clinical Pharmacology ( 12.3)] .

8.6 Hepatic Impairment

In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C). [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.8)] .

8.7 Renal Impairment

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 and 2.7- to 4.8-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with creatinine clearance 30 to 50 mL/min. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10- or 20-mg tadalafil, there were no reported cases of back pain. [see Dosage and Administration ( 2.6) and Warnings and Precautions ( 5.7)] .

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

12.3 Pharmacokinetics

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 Figure 4) to healthy male subjects are depicted in Figure 4.

Figure 4: Plasma tadalafil concentrations (mean ± SD) following a single 20-mg tadalafil dose and single and once daily multiple doses of 5 mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

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.

14.1 Tadalafil Tablets for Use as Needed for ED

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, were shown to be effective in improving erectile function in men with erectile dysfunction (ED).

Tadalafil Tablets were studied in the general ED population in 7 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the US. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve-sparing radical prostatectomy.

In these 7 trials, Tadalafil Tablets were taken as needed, at doses ranging from 2.5 to 20 mg, up to once per day. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.

Several assessment tools were used to evaluate the effect of Tadalafil Tablets on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at the end of a treatment-free baseline period and subsequently at follow-up visits after randomization. The IIEF EF domain has a 30-point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into the partner's vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.

14.2 Tadalafil Tablets for Once Daily Use for ED

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, were shown to be effective in improving erectile function in men with erectile dysfunction (ED).

Tadalafil Tablets were studied in the general ED population in 2 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12- and 24-weeks duration, respectively. One of these studies was conducted in the United States and one was conducted in centers outside the US. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. Tadalafil Tablets were taken once daily at doses ranging from 2.5 to 10 mg. Food and alcohol intake were not restricted. Timing of sexual activity was not restricted relative to when patients took Tadalafil Tablets.

14.3 Tadalafil Tablets 5 mg for Once Daily Use for Benign Prostatic Hyperplasia (BPH)

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)] . The first study (Study J) randomized 1058 patients to receive either Tadalafil Tablets 2.5 mg, 5 mg, 10 mg or 20 mg for once daily use or placebo. The second study (Study K) randomized 325 patients to receive either Tadalafil Tablets 5 mg for once daily use or placebo. The full study population was 87% White, 2% Black, 11% other races; 15% was of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.

The primary efficacy endpoint in the two studies that evaluated the effect of Tadalafil Tablets for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Q max), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study J and as a safety endpoint in Study K.

The results for BPH patients with moderate to severe symptoms and a mean age of 63.2 years (range 44 to 87) who received either Tadalafil Tablets 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively.

In each of these 2 trials, Tadalafil Tablets 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks.

Figure 5: Mean IPSS Changes in BPH Patients by Visit in Study J

Figure 6: Mean IPSS Changes in BPH Patients by Visit in Study K

In Study J, the effect of Tadalafil Tablets 5 mg once daily on maximum urinary flow rate (Q max) was evaluated as a secondary efficacy endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (Tadalafil Tablets 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.

In Study K, the effect of Tadalafil Tablets 5 mg once daily on Q max was evaluated as a safety endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (Tadalafil Tablets 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.

Efficacy Results in Patients with BPH initiating Tadalafil Tablets and Finasteride – Tadalafil Tablets for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate (>30 cc) for up to 26 weeks. This additional double-blinded, parallel-design study of 26 weeks duration randomized 696 men to initiate either Tadalafil Tablets 5 mg with finasteride 5 mg or placebo with finasteride 5 mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as erectile dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.

Tadalafil Tablets with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint ( see Table 20). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at week 4 (Tadalafil Tablets -4.0, placebo -2.3: p<.001) and the score remained decreased through 26 weeks (Tadalafil Tablets -5.5, placebo -4.5; p=.022). However, the magnitude of the treatment difference between placebo/finasteride and Tadalafil Tablets/finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in Table 20 and in Figure 7. The incremental benefit of Tadalafil Tablets beyond 26 weeks is unknown.

Figure 7: Mean Total IPSS Changes By Visit in BPH Patients Taking Tadalafil Tablets for Once Daily Use Together With Finasteride

In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil Tablets with finasteride (N=203) were compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (Tadalafil Tablets/finasteride 13.7, placebo/finasteride 15.1) was observed at week 4 (Tadalafil Tablets/finasteride 3.7, placebo/finasteride -1.1; p<.001), week 12 (Tadalafil Tablets/finasteride 4.7, placebo/finasteride 0.6; p<.001), and week 26 (Tadalafil Tablets/finasteride 4.7, placebo/finasteride 0.0; p<.001).

14.4 Tadalafil Tablets 5 mg for Once Daily Use for ED and BPH

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.

In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). Timing of sexual activity was not restricted relative to when patients took Tadalafil Tablets.

The efficacy results for patients with both ED and BPH, who received either Tadalafil Tablets 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8.

Tadalafil Tablets 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. Tadalafil Tablets 5 mg for once daily use also resulted in statistically significant improvement in SEP3. Tadalafil Tablets 2.5 mg did not result in statistically significant improvement in the total IPSS.

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 Figure 8).

Figure 8: Mean IPSS Changes in ED/BPH Patients by Visit in Study L

In this study, the effect of Tadalafil Tablets 5 mg once daily on Q max was evaluated as a safety endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (Tadalafil Tablets 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.

16.1 How Supplied

Tadalafil Tablets, USP are supplied as follows:

Four strengths of round, pale yellow to yellow tablets are available in different sizes, and supplied in the following package sizes:

16.2 Storage

Store at 25°C (77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

17.1 Nitrates

Physicians should discuss with patients the contraindication of Tadalafil Tablets with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Tadalafil Tablets with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

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 Warnings and Precautions ( 5.1)] .

17.2 Guanylate Cyclase (GC) Stimulators

Physicians should discuss with patients the contraindication of Tadalafil Tablets with any use of a GC stimulator, such as riociguat, for pulmonary arterial hypertension. Patients should be counseled that the concomitant use of Tadalafil Tablets with GC stimulators may cause blood pressure to drop to an unsafe level.

17.3 Cardiovascular Considerations

Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Physicians should advise patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity and seek immediate medical attention [see Warnings and Precautions ( 5.1)] .

17.4 Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should discuss with patients the potential for Tadalafil Tablets to augment the blood-pressure-lowering effect of alpha-blockers, and antihypertensive medications [see Warnings and Precautions ( 5.6), Drug Interactions ( 7.1), and Clinical Pharmacology ( 12.2)] .

17.5 Potential for Drug Interactions When Taking Tadalafil Tablets for Once Daily Use

Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing Tadalafil Tablets for once daily use, especially the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of cytochrome P450 3A4) and with substantial consumption of alcohol. [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.6), Drug Interactions ( 7.1, 7.2), Clinical Pharmacology ( 12.2), and Clinical Studies ( 14.2)] .

17.6 Priapism

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. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.

17.7 Sudden Loss of Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including Tadalafil Tablets, 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 cause of decreased vision, including possible permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Physicians should discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadalafil Tablets, for this uncommon condition [see Warnings and Precautions ( 5.4) and Adverse Reactions ( 6.2)] .

17.8 Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including Tadalafil Tablets, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil Tablets. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1, 6.2)] .

17.9 Alcohol

Patients should be made aware that both alcohol and Tadalafil Tablets, 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. Therefore, physicians should inform patients that 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 [see Warnings and Precautions ( 5.9), Drug Interactions ( 7.1), and Clinical Pharmacology ( 12.2)] .

17.10 Sexually Transmitted Disease

The use of Tadalafil Tablets offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.

17.11 Recommended Administration

Physicians should instruct patients on the appropriate administration of Tadalafil Tablets to allow optimal use.

For Tadalafil Tablets for use as needed in men with ED, patients should be instructed to take one tablet at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours.

For Tadalafil Tablets for once daily use in men with ED or ED/BPH, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity. Tadalafil Tablets are effective at improving erectile function over the course of therapy.

For Tadalafil Tablets for once daily use in men with BPH, patients should be instructed to take one tablet at approximately the same time every day.

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34120018911A                                                                                                                Revised: 12/2018

Manufactured by:

Qilu Pharmaceutical (Hainan) Co., Ltd.

Haikou, 570314, China

Manufactured for:

Apotex Corp.

Weston, Florida, USA 33326