TADALAFIL- tadalafil tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
TADALAFIL (UNII: 742SXX0ICT) (TADALAFIL - UNII:742SXX0ICT)
Available from:
Aphena Pharma Solutions - Tennessee, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Tadalafil tablets are indicated for the treatment of erectile dysfunction (ED). Tadalafil tablets are indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Tadalafil tablets are indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).       If tadalafil tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of tadalafil decreases from 4 weeks until 26 weeks, and the incremental benefit of tadalafil beyond 26 weeks is unknown [see Clinical Studies (14.3)] . Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology (12.2)] . Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil (Tadalafil tablets or ADCIRCA® ). Hypersensitiv
Product summary:
Tadalafil tablets USP 2.5 mg are light-orange yellow colored, oval shaped, biconvex beveled edge, film coated tablets with debossing "A9" on one side and "2.5" on other side. Bottles of 30                                                   13668-565-30 Bottles of 500                                                 13668-565-05 Carton of 100 (10x10) Unit dose Tablets       13668-565-74                                                                Tadalafil tablets USP 5 mg are yellow colored, oval shaped, biconvex beveled edge, film coated tablets with debossing "B1" on one side and "5" on other side. Bottles of 30                                                   13668-566-30 Bottles of 500                                                 13668-566-05 Carton of 100 (10x10) Unit dose Tablets       13668-566-74                                                      Tadalafil tablets USP 10 mg are yellow colored, oval shaped, biconvex beveled edge, film coated tablets with debossing "A15" on one side and "10" on other side. Bottles of 30                                                   13668-567-30 Bottles of 500                                                 13668-567-05 Carton of 100 (10x10) Unit dose Tablets       13668-567-74                                                          Tadalafil tablets USP 20 mg are yellow colored, oval shaped, biconvex beveled edge, film coated tablets with debossing "A16" on one side and "20" on other side. Bottles of 30                                                   13668-568-30 Bottles of 500                                                 13668-568-05 Carton of 100 (10x10) Unit dose Tablets       13668-568-74                                                      Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature] . Keep this and all medication out of the reach of children.
Authorization status:
Abbreviated New Drug Application
Authorization number:
71610-303-04, 71610-303-06, 71610-303-12

TADALAFIL- tadalafil tablet

Aphena Pharma Solutions - Tennessee, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TADALAFIL TABLETS safely and

effectively. See full prescribing information for TADALAFIL TABLETS.

TADALAFIL tablets, for oral use

Initial U.S. Approval: 2003

RECENT MAJOR CHANGES

Warnings and Precautions (5.4) 05/2017

INDICATIONS AND USAGE

Tadalafil tablets are a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: (1)

erectile dysfunction (ED) (1.1)

the signs and symptoms of benign prostatic hyperplasia (BPH) (1.2)

ED and the signs and symptoms of BPH (ED/BPH) (1.3)

If tadalafil tablets are used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks (1.4). (1)

DOSAGE AND ADMINISTRATION

Tadalafil tablets for use as needed:

ED: Starting dose: 10 mg as needed prior to sexual activity. Increase to 20 mg or decrease to 5 mg based upon

efficacy/tolerability. Improves erectile function compared to placebo up to 36 hours post dose. Not to be taken more

than once per day (2.1).

Tadalafil tablets for once daily use:

ED: 2.5 mg taken once daily, without regard to timing of sexual activity. May increase to 5 mg based upon efficacy and

tolerability (2.2).

BPH: 5 mg, taken at approximately the same time every day (2.3)

ED and BPH: 5 mg, taken at approximately the same time every day (2.3,2.4)

Tadalafil tablets may be taken without regard to food (2.5).

DOSAGE FORMS AND STRENGTHS

Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg (3). (3)

CONTRAINDICATIONS

Administration of tadalafil to patients using any form of organic nitrate is contraindicated. Tadalafil was shown to

potentiate the hypotensive effect of nitrates (4.1).

History of known serious hypersensitivity reaction to tadalafil or ADCIRCA . (4.2).

Administration with guanylate cyclase (GC) stimulators, such as riociguat (4.3).

WARNINGS AND PRECAUTIONS

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).

ADVERSE REACTIONS

Most common adverse reactions (≥2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and

pain in limb (6.1). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-

To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch (6)

DRUG INTERACTIONS

Tadalafil can potentiate the hypotensive effects of nitrates, alpha-blockers, antihypertensives or alcohol (7.1).

CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase tadalafil 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 tablets for once daily use: dose not to exceed 2.5 mg

CYP3A4 inducers (e.g. rifampin) decrease tadalafil exposure (7.2).

USE IN SPECIFIC POPULATIONS

Hepatic Impairment (2.6, 5.8, 8.6): (8)

Mild or Moderate: Dosage adjustment may be needed.

Severe: Use is not recommended.

Renal Impairment (2.6, 5.7, 8.7): (8)

Patients with creatinine clearance 30 to 50 mL/min: Dosage adjustment may be needed.

Patients with creatinine clearance less than 30 mL/min or on hemodialysis: For use as needed: Dose should not exceed

5 mg every 72 hours. Once daily use is not recommended.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 3/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Erectile Dysfunction

1.2 Benign Prostatic Hyperplasia

1.3 Erectile Dysfunction and Benign Prostatic Hyperplasia

1.4 Limitation of Use

2 DOSAGE AND ADMINISTRATION

2.1 Tadalafil Tablets for Use as Needed for Erectile Dysfunction

2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction

2.3 Tadalafil Tablets for Once Daily Use for Benign Prostatic Hyperplasia

2.4 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction and Benign Prostatic

Hyperplasia

2.5 Use with Food

2.6 Use in Specific Populations

2.7 Concomitant Medications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Nitrates

4.2 Hypersensitivity Reactions

4.3 Concomitant Guanylate Cyclase (GC) Stimulators

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular

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

5.3 Prolonged Erection

5.4 Effects on the Eye

5.5 Sudden Hearing Loss

5.6 Alpha-blockers and Antihypertensives

5.7 Renal Impairment

5.8 Hepatic Impairment

5.9 Alcohol

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

5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies

5.12 Effects on Bleeding

5.12 Effects on Bleeding

5.13 Counseling Patients About Sexually Transmitted Diseases

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

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with Tadalafil

7.2 Potential for Other Drugs to Affect Tadalafil

7.3 Potential for Tadalafil to Affect Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Tadalafil Tablets for Use as Needed for ED

14.2 Tadalafil Tablets for Once Daily Use for ED

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

17.1 Nitrates

17.2 Guanylate Cyclase (GC) Stimulators

17.3 Cardiovascular Considerations

17.4 Concomitant Use with Drugs Which Lower Blood Pressure

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

17.6 Priapism

17.7 Sudden Loss of Vision

17.8 Sudden Hearing Loss

17.9 Alcohol

17.10 Sexually Transmitted Disease

17.11 Recommended Administration

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sections or subsections omitted from the full prescribing information are not listed.

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 decreases from 4 weeks until 26 weeks, and

the incremental benefit of tadalafil beyond 26 weeks is unknown [see Clinical Studies (14.3)].

2 DOSAGE AND ADMINISTRATION

Do not split tadalafil tablets; entire dose should be taken.

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 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

Hyperplas ia

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 (5.7) and Use in Specific Populations (8.7)]

Tadalafil Tablets for Once Daily Use

Erectile Dysfunction

Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is

not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].

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 (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 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 are not recommended [see Warnings and

Precautions (5.8)and Use in Specific Populations (8.6)] .

Tadalafil Tablets for Once Daily Use

Mild or moderate (Child Pugh Class A or B): Tadalafil tablets for once daily use has not been

extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if tadalafil

tablets for once daily use is prescribed to these patients.

Severe (Child Pugh Class C): The use of tadalafil tablets are not recommended [see Warnings and

Precautions (5.8) and Use in Specific Populations (8.6)].

2.7 Concomitant Medications

Nitrates

Concomitant use of nitrates in any form is contraindicated [see Contraindications (4.1)].

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

should be initiated at the lowest recommended dose [see Warnings and Precautions (5.6), Drug

Interactions (7.1), and Clinical Pharmacology (12.2)].

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 (7.1), and Clinical

Pharmacology (12.2)].

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 are 10

mg, not to exceed once every 72 hours [see Warnings and Precautions (5.10) and Drug Interactions (7.2)].

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 (5.10) and Drug Interactions (7.2)].

3 DOSAGE FORMS AND STRENGTHS

Four strengths of oval shaped, biconvex beveled edge, film coated tablets are available in different

sizes and different shades of yellow:

Tablet Strength

Tablet Shades

Tablet D ebossing

2.5 mg

light-orange yellow colored

"A9" on one side and "2.5" on other side

5 mg

yellow colored

"B1" on one side and "5" on other side

10 mg

yellow colored

"A15" on one side and "10" on other side

20 mg

yellow colored

"A16" on one side and "20" on other side

4 CONTRAINDICATIONS

4.1 Nitrates

Administration of tadalafil to patients who are using any form of organic nitrate, either regularly and/or

intermittently, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the

hypotensive effect of nitrates [see Clinical Pharmacology (12.2)].

4.2 Hypersensitivity Reactions

Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil (Tadalafil

tablets 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 in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors,

including tadalafil, may potentiate the hypotensive effects of GC stimulators.

5 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.

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 to 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 use in these patients is not recommended.

5.5 Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including tadalafil, 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. 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 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, 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:

Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who

demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of

symptomatic hypotension with concomitant use of PDE5 inhibitors.

In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the

lowest recommended dose.

In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should

be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with

further lowering of blood pressure when taking a PDE5 inhibitor.

Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables,

including intravascular volume depletion and other antihypertensive drugs. [see Dosage and

Administration (2.7) and Drug Interactions (7.1)] .

The efficacy of the coadministration of an alpha-blocker and tadalafil for the treatment of BPH has

not been adequately studied, and due to the potential vasodilatory effects of combined use resulting

in blood pressure lowering, the combination of tadalafil and alpha-blockers is not recommended for

the treatment of BPH. [seeDosage and Administration (2.7), Drug Interactions (7.1), and Clinical

Pharmacology (12.2.)] .

Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day

prior to starting tadalafil tablets for once daily use for the treatment of BPH.

5.7 Renal Impairment

Tadalafil Tablets for Use as Needed

Tadalafil tablets should be limited to 5 mg not more than once in every 72 hours in patients with

creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose

of tadalafil tablets in patients with creatinine clearance 30 to 50 mL/min should be 5 mg not more than

once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours.

[see Use in Specific Populations (8.7)].

Tadalafil Tablets for Once Daily Use

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to

influence clearance by dialysis, tadalafil tablets for once daily use is not recommended in patients with

creatinine clearance less than 30 mL/min [see Use in Specific Populations (8.7)].

BPH and ED/BPH

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to

influence clearance by dialysis, tadalafil tablets for once daily use is not recommended in patients with

creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start

dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response

[see Dosage and Administration (2.6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

5.8 Hepatic Impairment

Tadalafil Tablets for Use as Needed

In patients with mild or moderate hepatic impairment, the dose of tadalafil tablets should not exceed 10

mg. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil

tablets in this group are not recommended [see Use in Specific Populations (8.6)].

Tadalafil Tablets for Once Daily Use

Tadalafil tablets for once daily use has not been extensively evaluated in patients with mild or moderate

hepatic impairment. Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to

these patients. Because of insufficient information in patients with severe hepatic impairment, use of

tadalafil tablets in this group are not recommended [see Use in Specific Populations (8.6)].

5.9 Alcohol

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

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

Tadalafil is 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 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 ADVERSE REACTIONS

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 9,000 men during clinical trials worldwide. In trials of tadalafil

tablets for once daily use, a total of 1,434, 905, and 115 were treated for at least 6 months, 1 year, and 2

years, respectively. For tadalafil tablets for use as needed, over 1,300 and 1,000 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

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

Dyspepsia

Back pain

Myalgia

Nasal congestion

Flus hing

Pain in limb

Tadalafil Tablets for Once Daily Use for ED

a

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 3Studies of 12 weeks Treatment Duration

(Including a Study in Patients with Diabetes) for Tadalafil Tablets for Once DailyUse for ED

Adverse Reaction

Placebo

(N=248)

Tadalafil 2.5 mg

(N=196)

Tadalafil 5 mg (N=304)

Headache

Dyspepsia

Nasopharyngitis

Back pain

Upper respiratory tract infection

Flushing

Myalgia

Cough

Diarrhea

Nasal congestion

Pain in extremity

Urinary tract infection

Gastroesophageal reflux disease

Abdominal pain

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 WeeksTreatment 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

Gastroenteritis

Back pain

Upper respiratory tract infection

Dyspepsia

Gastroesophageal reflux disease

Myalgia

Hypertension

Nasal congestion

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 WeeksTreatment 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 are 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 function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP

increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease,

hemorrhoidal hemorrhage, rectal hemorrhage

Musculoskeletal — arthralgia, neck pain

Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo

Renal and Urinary — renal impairment

Respiratory — dyspnea, epistaxis, pharyngitis

Skin and Appendages — pruritus, rash, sweating

Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival

hyperemia), eye pain, lacrimation increase, swelling of eyelids

Otologic — sudden decrease or loss of hearing, tinnitus

Urogenital — erection increased, spontaneous penile erection

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

post-marketing 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. 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. 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 DRUG INTERACTIONS

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

tablets 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, 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 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

[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 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 C

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 C

by 15%, relative to the values for tadalafil 10 mg alone [see

Dosage and Administration (2.7)].

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 C

, 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 C

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

(2.7)].

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 C

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 tablets 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Tadalafil tablets are not indicated for use in females.

There are no data with the use of tadalafil in pregnant women to inform any drug-associated risks for

adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects

were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at

exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day (see Data).

Data.

Animal Data

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity

when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum

recommended human dose (MRHD) of 20 mg/day during organogenesis. In a perinatal/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 1,000 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

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.

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 for use as needed for ED, diarrhea

was reported more frequently in patients 65 years of age and older who were treated with tadalafil

(2.5% of patients) [see Adverse Reactions (6.1)]. 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

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)].

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.

11 DESCRIPTION

Tadalafil USP is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific

phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C

H N O representing a

molecular weight of 389.40. 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 crystalline solid that is practically

insoluble in water, freely soluble in dimethylsulfoxide and slightly soluble in methylene chloride.

Tadalafil tablets USP are available as oval shaped, biconvex beveled edge, film coated tablets for

oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil USP and the following inactive

ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, Opadry

II Yellow, and sodium lauryl sulfate.

The color coating material contains following ingredients.

Strength

Coating material

Ingredients

2.5 mg

Opadry

II Yellow

HPMC 2910 / Hypromellose, Iron oxide red, Iron

oxide yellow, Lactose monohydrate, Talc, Titanium

dioxide, Triacetin.

5 mg

Opadry

II Yellow

HPMC 2910 / Hypromellose, Iron oxide yellow,

Lactose monohydrate, Talc, Titanium dioxide,

T riacetin.

10 mg

20 mg

12 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

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 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

Pres s ure

Placebo-subtracted mean maximal decrease in

systolic blood pressure (mm Hg)

Tadalafil 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, either 4 or 8 mg daily. The study (N=72 subjects) was conducted in three

parts, each a 3-period crossover.

In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a.m. Tadalafil was

administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.

In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m. Tadalafil was

administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.

In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m. In this part,

tadalafil or placebo were administered at either 8 a.m. or 8 p.m.

The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour

period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 6 and

Figure 3.

Table 6: Doxazosin (8 mg/day) Study 2 (Part C): Mean Maximal Decrease in Systolic Blood

Pres s ure

Placebo-subtracted mean maximal

decrease in

systolic blood pressure (mm Hg)

Tadalafil 20 mg at 8 a.m.

Tadalafil 20 mg at 8 p.m.

Ambulatory Blood - Pressure

Monitoring (ABPM)

Figure 3: Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic

Blood Pressure

Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or

placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings of <85

mm Hg were recorded or one or more decreases in systolic blood pressure of >30 mm Hg from a time-

matched baseline occurred during the analysis interval.

Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of

tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after

8 a.m. dosing of tadalafil or placebo. Of these, 5 and 2 were outliers due to systolic BP <85 mm Hg,

while 15 and 4 were outliers due to a decrease from baseline in systolic BP of >30 mm Hg following

tadalafil and placebo, respectively.

During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following

administration of tadalafil and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers

due to systolic BP <85 mm Hg, while 15 and 5 subjects were outliers due to a decrease from baseline in

systolic BP of >30 mm Hg, following tadalafil and placebo, respectively.

Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the

period beyond 24 hours.

Severe adverse events potentially related to blood-pressure effects were assessed. In the study

(N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic

hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and

dizziness in another subject that began 11 hours after dosing and lasted 2 minutes). No such events were

reported following placebo. In the period prior to tadalafil dosing, one severe event (dizziness) was

reported in a subject during the doxazosin run-in phase.

In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of

once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. After 7 days,

doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days

on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin). The results are shown in Table 7.

Table 7: Doxazosin Study 3: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure

Placebo-subtracted mean maximal decrease in systolic blood pressure

Tadalafil 5 mg

Day 1 of 4 mg Doxazosin

Supine

2.4 (-0.4, 5.2)

Standing

-0.5 (-4.0, 3.1)

Day 7 of 4 mg Doxazosin

Supine

2.8 (-0.1, 5.7)

Standing

1.1 (-2.9, 5.0)

Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1,

2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4

mg), as well as on the seventh day of 4 mg doxazosin administration.

Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier

on placebo due to a decrease from baseline in standing systolic BP of >30 mm Hg.

There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2

mg due to a decrease from baseline in standing systolic BP of >30 mm Hg.

There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4

mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There was one outlier on

tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic

BP <85 mm Hg. Following the seventh day of doxazosin 4 mg, there were no outliers on tadalafil 5 mg,

one subject on placebo had a decrease >30 mm Hg in standing systolic blood pressure, and one subject

on placebo had standing systolic blood pressure <85 mm Hg. All adverse events potentially related to

blood pressure effects were rated as mild or moderate. There were two episodes of syncope in this

study, one subject following a dose of tadalafil 5 mg alone, and another subject following

coadministration of tadalafil 5 mg and doxazosin 4 mg.

Tamsulosin — In the first tamsulosin study, a single oral dose of tadalafil 10, 20 mg, or placebo

was administered in a 3 period, crossover design to healthy subjects taking 0.4 mg once per day

tamsulosin, a selective alpha[1A]- adrenergic blocker (N=18 subjects). Tadalafil or placebo was

administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.

Table 8: Tamsulosin (0.4 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood

Pres s ure

Placebo-subtracted mean maximal decrease in

systolic blood pressure (mm Hg)

Tadalafil 10 mg

Tadalafil 20 mg

Supine

3.2 (-2.3, 8.6)

3.2 (-2.3, 8.7)

Standing

1.7 (-4.7, 8.1)

2.3 (-4.1, 8.7)

Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or

placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing

systolic blood pressure of >30 mm Hg at one or more time points) following administration of tadalafil

10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood

pressure <85 mm Hg. No severe adverse events potentially related to blood-pressure effects were

reported. No syncope was reported.

In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days

of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of

tamsulosin 0.4 mg was added for the last seven days of each period.

Table 9: Tamsulosin Study 2: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure

Placebo-subtracted mean maximal decrease in systolic blood pressure

Tadalafil 5 mg

Day 1 of 0.4 mg Tamsulosin

Supine

-0.1 (-2.2, 1.9)

Standing

0.9 (-1.4, 3.2)

Day 7 of 0.4 mg Tamsulosin

Supine

1.2 (-1.2, 3.6)

Standing

1.2 (-1.0, 3.5)

Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at

1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin

administration. There were no outliers (subjects with a decrease from baseline in standing systolic

blood pressure of >30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day

7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure <85 mm Hg.

No severe adverse events potentially related to blood pressure were reported. No syncope was

reported.

Alfuzosin — A single oral dose of tadalafil 20 mg or placebo was administered in a 2-period,

crossover design to healthy subjects taking once-daily alfuzosin HCl 10 mg extended-release tablets, an

alpha[1]-adrenergic blocker (N=17 completed subjects). Tadalafil or placebo was administered 4 hours

after alfuzosin following a minimum of seven days of alfuzosin dosing.

Table 10: Alfuzosin (10 mg/day) Study: Mean Maximal Decrease (95% CI) in Systolic Blood

Pres s ure

Placebo-subtracted mean maximal decrease in systolic blood

pressure (mm Hg)

Tadalafil 20 mg

Supine

2.2 (-0.9, -5.2)

Standing

4.4 (-0.2, 8.9)

Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or

placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure <85 mm Hg)

following administration of tadalafil 20 mg. There were no subjects with a decrease from baseline in

standing systolic blood pressure of >30 mm Hg at one or more time points. No severe adverse events

potentially related to blood pressure effects were reported. No syncope was reported.

Effects on Blood Pressure When Administered with Antihypertensives

Amlodipine — A study was conducted to assess the interaction of amlodipine (5 mg daily) and

tadalafil 10 mg. There was no effect of tadalafil on amlodipine blood levels and no effect of amlodipine

on tadalafil blood levels. The mean reduction in supine systolic/diastolic blood pressure due to tadalafil

10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using

tadalafil 20 mg, there were no clinically significant differences between tadalafil and placebo in

subjects taking amlodipine.

Angiotensin II receptor blockers (with and without other antihypertensives) — A study was conducted

to assess the interaction of angiotensin II receptor blockers and tadalafil 20 mg. Subjects in the study

were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination

product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements

of blood pressure revealed differences between tadalafil and placebo of 8/4 mm Hg in

systolic/diastolic blood pressure.

Bendrofluazide — A study was conducted to assess the interaction of bendrofluazide (2.5 mg daily)

and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure

due to tadalafil 10 mg in subjects taking bendrofluazide was 6/4 mm Hg, compared to placebo.

Enalapril — A study was conducted to assess the interaction of enalapril (10 to 20 mg daily) and

tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to

tadalafil 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.

Metoprolol — A study was conducted to assess the interaction of sustained-release metoprolol (25

to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic

blood pressure due to tadalafil 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to

placebo.

Effects on Blood Pressure When Administered with Alcohol

Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of

tadalafil with alcohol was evaluated in 3 clinical pharmacology studies. In 2 of these, alcohol was

administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in

an 80-kg male, and tadalafil was administered at a dose of 10 mg in one study and 20 mg in another. In

both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of

these two studies, blood alcohol levels of 0.08% were confirmed. In these two studies, more patients

had clinically significant decreases in blood pressure on the combination of tadalafil and alcohol as

compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was

observed in some subjects. When tadalafil 20 mg was administered with a lower dose of alcohol (0.6

g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10

minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to

alcohol alone, and the hypotensive effects of alcohol were not potentiated.

Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma

concentrations.

Effects on Exercise Stress Testing

The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were

investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with

stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The

primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3

seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference.

Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to

ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual

nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were

observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of

nitrates.

Effects on Vision

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related

impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak

effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6,

which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of

tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or

pupilometry. Across all clinical studies with tadalafil tablets, reports of changes in color vision were

rare (<0.1% of patients).

Effects on Sperm Characteristics

Three studies were conducted in men to assess the potential effect on sperm characteristics of

tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily.

There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In

the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a

decrease in mean sperm concentrations relative to placebo, although these differences were not

clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In

addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone,

luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to

placebo.

Effects on Cardiac Electrophysiology

The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of

peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)

-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QT

(Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90%

CI=1.9, 5.1). The mean change in QT (Individual QT correction) for tadalafil, relative to placebo, was

2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of tadalafil (5 times the highest

recommended dose) was chosen because this dose yields exposures covering those observed upon

coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In

this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to

placebo was 3.1 beats per minute.

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

Absorption — After single oral-dose administration, the maximum observed plasma concentration

) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute

bioavailability of tadalafil following oral dosing has not been determined.

The rate and extent of absorption of tadalafil are not influenced by food; thus tadalafil tablets may be

taken with or without food.

Distribution — The mean apparent volume of distribution following oral administration is

approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations,

94% of tadalafil in plasma is bound to proteins.

Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The

catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol

and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the

methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide

concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at

observed metabolite concentrations.

Excretion — The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5

hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces

(approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).

Geriatric — Healthy male elderly subjects (65 years or over) had a lower oral clearance of

tadalafil, resulting in 25% higher exposure (AUC) with no effect on C

relative to that observed in

healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However,

greater sensitivity to medications in some older individuals should be considered [see Use in Specific

Populations (8.5)].

Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil

dose, exposure (AUC) was reduced approximately 19% and C

was 5% lower than that observed in

healthy subjects. No dose adjustment is warranted.

Patients with BPH — In patients with BPH following single and multiple-doses of 20 mg

tadalafil, no statistically significant differences in exposure (AUC and C

) were observed between

elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment is warranted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2

years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound

tadalafil, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats,

respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20

Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward

mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal

aberration test in human lymphocytes or the in vivo rat micronucleus assays.

Impairment of Fertility — There were no effects on fertility, reproductive performance or

reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400

mg/kg/day, a dose producing AUCs for unbound tadalafil of 14-fold for males or 26-fold for females

the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given tadalafil daily

for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the

seminiferous tubular epithelium in the testes in 20 to 100% of the dogs that resulted in a decrease in

spermatogenesis in 40 to 75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on

AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar

to that expected in humans at the MRHD of 20 mg.

There were no treatment-related testicular findings in rats or mice treated with doses up to 400

mg/kg/day for 2 years.

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 CLINICAL STUDIES

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 4,000 patients. Tadalafil tablets, when taken as

needed up to once per day, was shown to be effective in improving erectile function in men with

erectile dysfunction (ED).

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.

Results in ED Population in US Trials — The 2 primary US efficacy and safety trials included a total of

402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population

was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of

various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions,

including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>90%) patients

reported ED of at least 1-year duration. Study A was conducted primarily in academic centers. Study B

was conducted primarily in community-based urology practices. In each of these 2 trials, tadalafil

tablets 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary

efficacy variables (see Table 11). The treatment effect of tadalafil tablets did not diminish over time.

Table 11: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the

Two Primary US Trials

Study A

Study B

Placebo

T adalafil

Tablets

20 mg

Placebo

T adalafil

Tablets

20 mg

(N=49)

(N=146)

p-value

(N=48)

(N=159)

p-value

EF Domain Score

Endpoint

13.5

19.5

13.6

22.5

Change from baseline

-0.2

<.001

<.001

Insertion of Penis (SEP2)

Endpoint

Change from baseline

<.001

<.001

Maintenance of Erection (SEP3)

Endpoint

Change from baseline

<.001

<.001

Results in General ED Population in Trials Outside the US — The 5 primary efficacy and safety

studies conducted in the general ED population outside the US included 1,112 patients, with a mean age

of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20%

of other ethnicities, and included patients with ED of various severities, etiologies (organic,

psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension,

and other cardiovascular disease. Most (90%) patients reported ED of at least 1-year duration. In these

5 trials, tadalafil tablets 5, 10, and 20 mg showed clinically meaningful and statistically significant

improvements in all 3 primary efficacy variables (see Tables 12, 13 and 14). The treatment effect of

tadalafil tablets did not diminish over time.

Table 12: Mean Endpoint and Change from Baseline for the EF Domain of the IIEF in the General

ED Population in Five Primary Trials Outside the US

Placebo

T adalafil

Tablets

5 mg

T adalafil

Tablets

10 mg

T adalafil

Tablets

20 mg

Study C

Endpoint [Change from baseline]

15.0 [0.7]

17.9 [4.0]

20.0 [5.6]

p=.006

p<.001

Study D

Endpoint [Change from baseline]

14.4 [1.1]

17.5 [5.1]

20.6 [6.0]

p=.002

p<.001

Study E

Endpoint [Change from baseline]

18.1 [2.6]

22.6 [8.1]

25.0 [8.0]

p<.001

p<.001

Study F

Endpoint [Change from baseline]

12.7 [-1.6]

22.8 [6.8]

p<.001

Study G

Endpoint [Change from baseline]

14.5 [-0.9]

21.2 [6.6]

23.3 [8.0]

p<.001

p<.001

a

Treatment duration in Study F was 6 months

Table 13: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 2

("Were you able to insert your penis into the partner's vagina?") in the General ED Population in

Five Pivotal Trials Outside the US

Treatment duration in Study F was 6 months

Placebo

T adalafil

Tablets

5 mg

T adalafil

Tablets

10 mg

T adalafil

Tablets

20 mg

Study C

Endpoint [Change from baseline]

49% [6%]

57% [15%]

73% [29%]

p=.063

p<.001

Study D

Endpoint [Change from baseline]

46% [2%]

56% [18%]

68% [15%]

p=.008

p<.001

Study E

Endpoint [Change from baseline]

55% [10%]

77% [35%]

85% [35%]

p<.001

p<.001

Study F

Endpoint [Change from baseline]

42% [-8%]

81% [27%]

p<.001

Study G

Endpoint [Change from baseline]

45% [-6%]

73% [21%]

76% [21%]

p<.001

p<.001

Table 14: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 3 ("Did

your erection last long enough for you to have successful intercourse?") in the General ED

Population in Five Pivotal Trials Outside the US

Treatment duration in Study F was 6 months

Placebo

T adalafil

Tablets

5 mg

T adalafil

Tablets

10 mg

T adalafil

Tablets

20 mg

Study C

Endpoint [Change from baseline]

26% [4%]

38% [19%]

58% [32%]

p=.040

p<.001

Study D

Endpoint [Change from baseline]

28% [4%]

42% [24%]

51% [26%]

p<.001

p<.001

Study E

Endpoint [Change from baseline]

43% [15%]

70% [48%]

78% [50%]

p<.001

p<.001

Study F

Endpoint [Change from baseline]

27% [1%]

74% [40%]

p<.001

Study G

Endpoint [Change from baseline]

32% [5%]

57% [33%]

62% [29%]

p<.001

p<.001

In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2

a

a

and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease

severity while taking tadalafil tablets, compared to patients on placebo.

Therefore, in all 7 primary efficacy and safety studies, tadalafil tablets showed statistically

significant improvement in patients' ability to achieve an erection sufficient for vaginal penetration and

to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire

and by SEP diaries.

Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil tablets were shown to be

effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in all 7

primary efficacy studies in the general ED population (N=235) and in one study that specifically

assessed tadalafil tablets in ED patients with type 1 or type 2 diabetes (N=216). In this randomized,

placebo-controlled, double-blinded, parallel-arm design prospective trial, tadalafil tablets demonstrated

clinically meaningful and statistically significant improvement in erectile function, as measured by the

EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 15).

Table 15: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study

in ED Patients with Diabetes

Placebo

T adalafil

Tablets

10 mg

T adalafil

Tablets

20 mg

(N=71)

(N=73)

(N=72)

p-value

EF Domain Score

Endpoint [Change from baseline]

12.2 [0.1]

19.3 [6.4]

18.7 [7.3]

<.001

Insertion of Penis (SEP2)

Endpoint [Change from baseline]

30% [-4%]

57% [22%]

54% [23%]

<.001

Maintenance of Erection (SEP3)

Endpoint [Change from baseline]

20% [2%]

48% [28%]

42% [29%]

<.001

Efficacy Results in ED Patients following Radical Prostatectomy — Tadalafil tablets were

shown to be effective in treating patients who developed ED following bilateral nerve-sparing radical

prostatectomy. In 1 randomized, placebo-controlled, double-blinded, parallel-arm design prospective

trial in this population (N=303), tadalafil tablets demonstrated clinically meaningful and statistically

significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and

Questions 2 and 3 of the SEP diary (see Table 16).

Table 16: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study

in Patients who Developed ED Following Bilateral Nerve-Sparing Radical Prostatectomy

Placebo

Tadalafil Tablets

20 mg

(N=102)

(N=201)

p-value

EF Domain Score

Endpoint [Change from baseline]

13.3 [1.1]

17.7 [5.3]

<.001

Insertion of Penis (SEP2)

Endpoint [Change from baseline]

32% [2%]

54% [22%]

<.001

Maintenance of Erection (SEP3)

Endpoint [Change from baseline]

19% [4%]

41% [23%]

<.001

Results in Studies to Determine the Optimal Use of Tadalafil — Several studies were conducted

with the objective of determining the optimal use of tadalafil in the treatment of ED. In one of these

studies, the percentage of patients reporting successful erections within 30 minutes of dosing was

determined. In this randomized, placebo-controlled, double-blinded trial, 223 patients were randomized

to placebo, tadalafil tablets 10, or 20 mg. Using a stopwatch, patients recorded the time following

dosing at which a successful erection was obtained. A successful erection was defined as at least 1

erection in 4 attempts that led to successful intercourse. At or prior to 30 minutes, 35% (26/74), 38%

(28/74), and 52% (39/75) of patients in the placebo, 10-, and 20-mg groups, respectively, reported

successful erections as defined above.

Two studies were conducted to assess the efficacy of tadalafil tablets at a given time point after

dosing, specifically at 24 hours and at 36 hours after dosing.

In the first of these studies, 348 patients with ED were randomized to placebo or tadalafil tablets 20

mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24

hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The

results demonstrated a difference between the placebo group and the tadalafil group at each of the pre-

specified time points. At the 24-hour time point, (more specifically, 22 to 26 hours), 53/144 (37%)

patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the

tadalafil tablets 20-mg group. At the 36-hour time point (more specifically, 33 to 39 hours), 49/133

(37%) of patients reported at least 1 successful intercourse in the placebo group versus 88/137 (64%)

in the tadalafil tablets 20-mg group.

In the second of these studies, a total of 483 patients were evenly randomized to 1 of 6 groups: 3

different dosing groups (placebo, tadalafil tablets 10, or 20 mg) that were instructed to attempt

intercourse at 2 different times (24 and 36 hours post-dosing). Patients were encouraged to make 4

separate attempts at their assigned dose and assigned time point. In this study, the results demonstrated a

statistically significant difference between the placebo group and the tadalafil groups at each of the

pre-specified time points. At the 24-hour time point, the mean, per patient percentage of attempts

resulting in successful intercourse were 42, 56, and 67% for the placebo, tadalafil tablets 10-, and 20-

mg groups, respectively. At the 36-hour time point, the mean, per-patient percentage of attempts

resulting in successful intercourse were 33, 56, and 62% for placebo, tadalafil tablets 10-, and 20-mg

groups, respectively.

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, was 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.

Results in General ED Population — The primary US efficacy and safety trial included a total of

287 patients, with a mean age of 59 years (range 25 to 82 years). The population was 86% White, 6%

Black, 6% Hispanic, and 2% of other ethnicities, and included patients with ED of various severities,

etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes

mellitus, hypertension, and other cardiovascular disease. Most (>96%) patients reported ED of at least

1-year duration.

The primary efficacy and safety study conducted outside the US included 268 patients, with a mean

age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0.4% Hispanic, and

10% of other ethnicities, and included patients with ED of various severities, etiologies (organic,

psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension,

and other cardiovascular disease. Ninety-three percent of patients reported ED of at least 1-year

duration.

In each of these trials, conducted without regard to the timing of dose and sexual intercourse,

tadalafil tablets demonstrated clinically meaningful and statistically significant improvement in erectile

function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary

(see Table 17). When taken as directed, tadalafil tablets were effective at improving erectile function.

In the 6 month double-blind study, the treatment effect of tadalafil tablets did not diminish over time..

Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two

Tadalafil Tablets for Once Daily Use Studies

Twenty-four-week study conducted in the US.

Twelve-week study conducted outside the US.

Statistically significantly different from placebo.

Study H

Study I

Placebo

T adalafil

Tablets

2.5 mg

Tadalafil Tablets

5 mg

Placebo

T adalafil

Tablets

5 mg

(N=94)

(N=96)

(N=97)

p-value

(N=54)

(N=109)

p-

value

EF Domain Score

Endpoint

14.6

19.1

20.8

15.0

22.8

Change from baseline

<.001

<.001

Insertion of Penis (SEP2)

Endpoint

Change from baseline

<.001

<.001

Maintenance of Erection (SEP3)

Endpoint

Change from baseline

<.001

<.001

Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil tablets for once daily use

was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were

included in both studies in the general ED population (N=79). A third randomized, multicenter, double-

blinded, placebo-controlled, parallel-arm design trial included only ED patients with type 1 or type 2

diabetes (N=298). In this third trial, tadalafil tablets demonstrated clinically meaningful and statistically

significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and

Questions 2 and 3 of the SEP diary (see Table 18).

Table 18: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a

Tadalafil Tablets for Once Daily Use Study in ED Patients with Diabetes

Placebo

T adalafil

Tablets

2.5 mg

T adalafil

Tablets

5 mg

(N=100)

(N=100)

(N=98)

p-value

EF Domain Score

Endpoint

14.7

18.3

17.2

Change from baseline

<.001

Insertion of Penis (SEP2)

Endpoint

Change from baseline

<.001

Maintenance of Erection (SEP3)

Endpoint

a

b

Statistically significantly different from placebo.

Change from baseline

<.001

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

), 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.

Table 19: Mean IPSS Changes in BPH Patients in Two Tadalafil Tablets for Once Daily Use

Studies

Study J

Study K

Placebo

T adalafil

Tablets

5 mg

Placebo

T adalafil

Tablets

5 mg

(N=205)

(N=205)

p-value

(N=164)

(N=160)

p-value

Total Symptom Score (IPSS)

Baseline

17.1

17.3

16.6

17.1

Change from Baseline to

Week 12

-2.2

-4.8

<.001

-3.6

-5.6

.004

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

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

In Study J, the effect of tadalafil tablets 5 mg once daily on maximum urinary flow rate (Q

) was

evaluated as a secondary efficacy endpoint. Mean Q

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

was evaluated as a safety endpoint.

Mean Q

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 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 to 86). Patients with multiple co-morbid conditions such as erectile

dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.

Tadalafil 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 -4.0, placebo -2.3: p<.001) and the score

remained decreased through 26 weeks (tadalafil -5.5, placebo -4.5; p=.022). However, the magnitude of

the treatment difference between placebo/finasteride and tadalafil/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 beyond 26 weeks is unknown.

Table 20: Mean Total IPSS Changes in BPH Patients in a Tadalafil Tablets for Once Daily Use Study

Together with Finasteride

Overall ITT population.

Mixed model for repeated measurements.

Unadjusted mean.

Placebo and

finasteride

5 mg

Tadalafil Tablets

5mg and finasteride

5 mg

Treatment

difference

n

(N=350)

n

(N=345)

p-value

Total Symptom Score (IPSS)

Baseline

17.4

17.1

Change from Baseline to

Week 4

-2.3

-4.0

-1.7

<.001

Change from Baseline to

Week 12

-3.8

-5.2

-1.4

.001

Change from Baseline to

Week 26

-4.5

-5.5

-1.0

.022

a

b

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 with

finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant

improvement from baseline (tadalafil/finasteride 13.7, placebo/finasteride 15.1) was observed at week 4

(tadalafil/finasteride 3.7, placebo/finasteride -1.1; p<.001), week 12 (tadalafil/finasteride 4.7,

placebo/finasteride 0.6; p<.001), and week 26 (tadalafil/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

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.

Table 21: Mean IPSS and IIEF EF Domain Changes in the Tadalafil Tablets 5 mg for Once Daily

Use Study in Patients with ED and BPH

Placebo

Tadalafil Tablets 5

mg

p-value

Total Symptom Score (IPSS)

(N=193)

(N=206)

Baseline

18.2

18.5

Change from Baseline to Week 12

-3.8

-6.1

<.001

EF Domain Score (IIEF EF)

(N=188)

(N=202)

Baseline

15.6

16.5

Endpoint

17.6

22.9

Change from Baseline to Week 12

<.001

Table 22: Mean SEP Question 3 Changes in the Tadalafil Tablets 5 mg for Once Daily Use Study

in Patients with ED and BPH

Placebo

Tadalafil Tablets 5

mg

(N=187)

(N=199)

p-value

Maintenance of Erection (SEP3)

Baseline

Endpoint

Change from Baseline to Week 12

<.001

Tadalafil tablets for once daily use resulted in improvement in the IPSS total score at the first scheduled

observation (week 2) and throughout the 12 weeks of treatment (see 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

was evaluated as a safety

endpoint. Mean Q

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 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Tadalafil tablets USP 2.5 mg are light-orange yellow colored, oval shaped, biconvex beveled edge,

film coated tablets with debossing "A9" on one side and "2.5" on other side.

Bottles of 30 13668-565-30

Bottles of 500 13668-565-05

Carton of 100 (10x10) Unit dose Tablets 13668-565-74

Tadalafil tablets USP 5 mg are yellow colored, oval shaped, biconvex beveled edge, film coated tablets

with debossing "B1" on one side and "5" on other side.

Bottles of 30 13668-566-30

Bottles of 500 13668-566-05

Carton of 100 (10x10) Unit dose Tablets 13668-566-74

Tadalafil tablets USP 10 mg are yellow colored, oval shaped, biconvex beveled edge, film coated

tablets with debossing "A15" on one side and "10" on other side.

Bottles of 30 13668-567-30

Bottles of 500 13668-567-05

Carton of 100 (10x10) Unit dose Tablets 13668-567-74

Tadalafil tablets USP 20 mg are yellow colored, oval shaped, biconvex beveled edge, film coated

tablets with debossing "A16" on one side and "20" on other side.

Bottles of 30 13668-568-30

Bottles of 500 13668-568-05

Carton of 100 (10x10) Unit dose Tablets 13668-568-74

16.2 Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP

Controlled Room Temperature]. Keep this and all medication out of the reach of children.

17 PATIENT COUNSELING INFORMATION

"See FDA-approved patient labeling (Patient Information)"

17.1 Nitrates

Physicians should discuss with patients the contraindication of tadalafil with regular and/or

intermittent use of organic nitrates. Patients should be counseled that concomitant use of tadalafil 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 with any use of a GC

stimulator, such as riociguat, for pulmonary arterial hypertension. Patients should be counseled that the

concomitant use of tadalafil 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 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, 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 in individuals who have already experienced NAION in one eye. Physicians should also

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, 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, 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. 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, 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 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.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

For:

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

8067873 Revised December 2018

PATIENT INFORMATION

Tadalafil (tah-DA-la-fil) tablets USP

Read this important information before you start taking tadalafil tablets and each time you get a refill.

There may be new information. You may also find it helpful to share this information with your partner.

This information does not take the place of talking with your healthcare provider. You and your

healthcare provider should talk about tadalafil tablets when you start taking it and at regular checkups. If

you do not understand the information, or have questions, talk with your healthcare provider or

pharmacist.

What Is The Most Important Information I Should Know About Tadalafil tablets?

Tadalafil tablets can cause your blood pressure to drop suddenly to an unsafe level if it is taken

with certain other medicines. You could get dizzy, faint, or have a heart attack or stroke. Never take

tadalafil tablets with any nitrate or guanylate cyclase stimulator medicines.

Do not take tadalafil tablets if you take any medicines called "nitrates." Nitrates are commonly used

to treat angina. Angina is a symptom of heart disease and can cause pain in your chest, jaw, or down your

arm.

Medicines called nitrates include nitroglycerin that is found in tablets, sprays, ointments, pastes, or

patches. Nitrates can also be found in other medicines such as isosorbide dinitrate or isosorbide

mononitrate. Some recreational drugs called "poppers" also contain nitrates, such as amyl nitrite and

butyl nitrite.

Do not take tadalafil tablets if you take medicines called guanylate cyclase stimulators which include:

Riociguat (Adempas

) a medicine that treats pulmonary arterial hypertension and chronic-

thromboembolic pulmonary hypertension.

Ask your healthcare provider or pharmacist if you are not sure if any of your medicines are nitrates or

guanylate cyclase stimulators, such as riociguat.

(See "Who Should Not Take Tadalafil Tablets?")

Tell all of your healthcare providers that you take tadalafil tablets. If you need emergency medical care

for a heart problem, it will be important for your healthcare provider to know when you last took

tadalafil tablets.

After taking a single tablet, some of the active ingredient of tadalafil tablets remains in your body

for more than 2 days. The active ingredient can remain longer if you have problems with your kidneys

or liver, or you are taking certain other medications (see "Can Other Medicines Affect Tadalafil

T ablets ?").

Stop sexual activity and get medical help right away if you get symptoms such as chest pain,dizziness,

or nausea during sex. Sexual activity can put an extra strain on your heart, especially if your heart is

already weak from a heart attack or heart disease.

See also "What Are The Possible Side Effects Of Tadalafil Tablets?"

What Are Tadalafil Tablets?

Tadalafil tablets are a prescription medicine taken by mouth for the treatment of:.

men with erectile dysfunction (ED)

men with symptoms of benign prostatic hyperplasia (BPH)

men with both ED and BPH

Tadalafil Tablets for the Treatment of ED

ED is a condition where the penis does not fill with enough blood to harden and expand when a man is

sexually excited, or when he cannot keep an erection. A man who has trouble getting or keeping an

erection should see his healthcare provider for help if the condition bothers him. Tadalafil tablets helps

increase blood flow to the penis and may help men with ED get and keep an erection satisfactory for

sexual activity. Once a man has completed sexual activity, blood flow to his penis decreases, and his

erection goes away.

Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets.

Tadalafil tablets does not:

cure ED

increase a man's sexual desire

protect a man or his partner from sexually transmitted diseases, including HIV. Speak to your

healthcare provider about ways to guard against sexually transmitted diseases.

serve as a male form of birth control

Tadalafil tablets are only for men over the age of 18, including men with diabetes or who have

undergone prostatectomy.

Tadalafil Tablets for the Treatment of Symptoms of BPH

BPH is a condition that happens in men, where the prostate gland enlarges which can cause urinary

symptoms.

Tadalafil Tablets for the Treatment of ED and Symptoms of BPH

ED and symptoms of BPH may happen in the same person and at the same time. Men who have both ED

and symptoms of BPH may take tadalafil tablets for the treatment of both conditions.

Tadalafil tablets are not for women or children.

Tadalafil tablets must be used only under a healthcare provider's care.

Who Should Not Take Tadalafil Tablets?

Do not take tadalafil tablets if you:

take any medicines called "nitrates".

use recreational drugs called "poppers" like amyl nitrite and butyl nitrite. (See "What Is The

Most Important Information I Should Know About Tadalafil Tablets?" )

take any medicines called guanylate cyclase stimulators, such as riociguat

are allergic to tadalafil tablets or ADCIRCA , or any of its ingredients. See the end of this

leaflet for a complete list of ingredients in tadalafil tablets. Symptoms of an allergic reaction may

include:

®

rash

hives

swelling of the lips, tongue, or throat

difficulty breathing or swallowing

Call your healthcare provider or get help right away if you have any of the symptoms of an allergic

reaction listed above.

What Should I Tell My Healthcare Provider Before Taking Tadalafil Tablets?

Tadalafil tablets are not right for everyone. Only your healthcare provider and you can decide if

tadalafil tablets are right for you. Before taking tadalafil tablets, tell your healthcare provider about all

your medical problems, including if you:

have heart problems such as angina, heart failure, irregular heartbeats, or have had a heart attack.

Ask your healthcare provider if it is safe for you to have sexual activity. You should not take

tadalafil tablets if your healthcare provider has told you not to have sexual activity because of your

health problems.

have pulmonary hypertension

have low blood pressure or have high blood pressure that is not controlled

have had a stroke

have liver problems

have kidney problems or require dialysis

have retinitis pigmentosa, a rare genetic (runs in families) eye disease

have ever had severe vision loss, including a condition called NAION

have stomach ulcers

have a bleeding problem

have a deformed penis shape or Peyronie's disease

have had an erection that lasted more than 4 hours

have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia

Can Other Medicines Affect Tadalafil Tablets?

Tell your healthcare provider about all the medicines you take including prescription and non-

prescription medicines, vitamins, and herbal supplements. Tadalafil tablets and other medicines may

affect each other. Always check with your healthcare provider before starting or stopping any

medicines. Especially tell your healthcare provider if you take any of the following*:

medicines called nitrates (see "What Is The Most Important Information I Should Know About

Tadalafil Tablets?" )

medicines called guanylate cyclase stimulators, such as riociguat (Adempas

), used to treat

pulmonary hypertension

medicines called alpha blockers. These include Hytrin (terazosin HCl), Flomax

(tamsulosin HCl),

Cardura

(doxazosin mesylate), Minipress

(prazosin HCl), Uroxatral

(alfuzosin HCl),

Jalyn (dutasteride and tamsulosin HCl) or Rapaflo

(silodosin). Alpha-blockers are sometimes

prescribed for prostate problems or high blood pressure. If tadalafil tablets are taken with certain

alpha blockers, your blood pressure could suddenly drop. You could get dizzy or faint.

other medicines to treat high blood pressure (hypertension)

medicines called HIV protease inhibitors, such as ritonavir (Norvir

, Kaletra

some types of oral antifungals such as ketoconazole (Nizoral

), itraconazole (Sporanox

some types of antibiotics such as clarithromycin (Biaxin ), telithromycin (Ketek ), erythromycin

(several brand names exist. Please consult your healthcare provider to determine if you are taking

this medicine).

other medicines or treatments for ED.

Tadalafil tablets are also marketed as ADCIRCA for the treatment of pulmonary arterial

hypertension. Do not take both tadalafil tablets and ADCIRCA. Do not take sildenafil citrate

(Revatio

) with tadalafil tablets.

How Should I Take Tadalafil Tablets?

Take tadalafil tablets exactly as your healthcare provider prescribes it. Your healthcare provider

will prescribe the dose that is right for you.

Some men can only take a low dose of tadalafil tablets or may have to take it less often, because of

medical conditions or medicines they take.

Do not change your dose or the way you take tadalafil tablets without talking to your healthcare

provider. Your healthcare provider may lower or raise your dose, depending on how your body

reacts to tadalafil tablets and your health condition.

Tadalafil tablets may be taken with or without meals.

If you take too much tadalafil tablets, call your healthcare provider or emergency room right away.

How Should I Take Tadalafil Tablets for Symptoms of BPH?

For symptoms of BPH, tadalafil tablets are taken once daily.

Do not take tadalafil tablets more than one time each day.

Take one tadalafil tablet every day at about the same time of day.

If you miss a dose, you may take it when you remember but do not take more than one dose per day.

How Should I Take Tadalafil Tablets for ED?

For ED, there are two ways to take tadalafil tablets - either for use as needed OR for use once

daily.

Tadalafil tablets for use as needed:

Do not take tadalafil tablets more than one time each day.

Take one tadalafil tablet before you expect to have sexual activity. You may be able to have sexual

activity at 30 minutes after taking tadalafil tablets and up to 36 hours after taking it. You and your

healthcare provider should consider this in deciding when you should take tadalafil tablets before

sexual activity. Some form of sexual stimulation is needed for an erection to happen with tadalafil

tablets.

Your healthcare provider may change your dose of tadalafil tablets depending on how you respond

to the medicine, and on your health condition.

OR

Tadalafil tablets for once daily use is a lower dose you take every day.

Do not take tadalafil tablets more than one time each day.

Take one tadalafil tablet every day at about the same time of day. You may attempt sexual activity at

any time between doses.

If you miss a dose, you may take it when you remember but do not take more than one dose per day.

Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets.

Your healthcare provider may change your dose of tadalafil tablets depending on how you respond

to the medicine, and on your health condition.

How Should I Take Tadalafil Tablets for Both ED and the Symptoms of BPH?

For both ED and the symptoms of BPH, tadalafil tablets are taken once daily.

Do not take tadalafil tablets more than one time each day.

Take one tadalafil tablet every day at about the same time of day. You may attempt sexual activity at

any time between doses.

If you miss a dose, you may take it when you remember but do not take more than one dose per day.

Some form of sexual stimulation is needed for an erection to happen with tadalafil tablets.

What Should I Avoid While Taking Tadalafil Tablets?

Do not use other ED medicines or ED treatments while taking tadalafil tablets.

Do not drink too much alcohol when taking tadalafil tablets (for example, 5 glasses of wine or 5

shots of whiskey). Drinking too much alcohol can increase your chances of getting a headache or

getting dizzy, increasing your heart rate, or lowering your blood pressure.

What Are The Possible Side Effects Of Tadalafil Tablets?

See "What Is The Most Important Information I Should Know About Tadalafil Tablets?"

The most common side effects with tadalafil tablets are: headache, indigestion, back pain, muscle

aches, flushing, and stuffy or runny nose. These side effects usually go away after a few hours. Men

who get back pain and muscle aches usually get it 12 to 24 hours after taking tadalafil tablets. Back pain

and muscle aches usually go away within 2 days.

Call your healthcare provider if you get any side effect that bothers you or one that does not go away.

Uncommon side effects include:

An erection that won't go away (priapism). If you get an erection that lasts more than 4 hours, get

medical help right away. Priapism must be treated as soon as possible or lasting damage can happen to

your penis, including the inability to have erections.

Color vision changes, such as seeing a blue tinge (shade) to objects or having difficulty telling the

difference between the colors blue and green.

In rare instances, men taking PDE5 inhibitors (oral erectile dysfunction medicines, including tadalafil

tablets) reported a sudden decrease or loss of vision in one or both eyes. It is uncertain whether PDE5

inhibitors directly cause the vision loss. If you experience sudden decrease or loss of vision, stop

taking PDE5 inhibitors, including tadalafil tablets, and call a healthcare provider right away.

Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness, has been rarely

reported in people taking PDE5 inhibitors, including tadalafil tablets. It is not possible to determine

whether these events are related directly to the PDE5 inhibitors, to other diseases or medications, to

other factors, or to a combination of factors. If you experience these symptoms, stop taking tadalafil

tablets and contact a healthcare provider right away.

These are not all the possible side effects of tadalafil tablets. For more information, ask your healthcare

provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How Should I Store Tadalafil Tablets?

Store tadalafil tablets USP at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and

86°F).

Keep tadalafil tablets and all medicines out of the reach of children.

General Information About Tadalafil Tablets:

Medicines are sometimes prescribed for conditions other than those described in patient information

leaflets. Do not use tadalafil tablets for a condition for which it was not prescribed. Do not give

tadalafil tablets to other people, even if they have the same symptoms that you have. It may harm them.

This is a summary of the most important information about tadalafil tablets. If you would like more

information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for

information about tadalafil tablets that is written for health providers.

For more information, call Torrent Pharma Inc. at 1-800-912-9561.

What are the ingredients in Tadalafil Tablets USP?

Active ingredient: tadalafil USP

Inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate,

magnesium stearate, microcrystalline cellulose, Opadry

II Yellow and sodium lauryl sulfate.

The color coating material contains following ingredients.

Strength

Coating material

Ingredients

2.5 mg

Opadry

II Yellow

HPMC 2910 / Hypromellose, Iron oxide red, Iron

oxide yellow, Lactose monohydrate, Talc, Titanium

dioxide, Triacetin.

5 mg

Opadry

II Yellow

HPMC 2910 / Hypromellose, Iron oxide yellow,

Lactose monohydrate, Talc, Titanium dioxide,

T riacetin.

10 mg

20 mg

This Patient Information has been approved by the U.S. Food and Drug Administration

*Trademarks are the property of their respective owners.

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured For

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

8067874 Revised December 2018

Repackaging Information

Please reference the How Supplied section listed above for a description of individual tablets. This

drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged

configuration and repackaged in full compliance with all applicable cGMP regulations. The package

configurations available from Aphena are listed below:

Count

20 mg

71610-303-04

71610-303-06

71610-303-12

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-

resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20190716JH

PRINCIPAL DISPLAY PANEL - 20 mg

NDC 71610-303 - Tadalafil, USP 20 mg Tablets - Rx Only

TADALAFIL

tadalafil tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:716 10 -30 3(NDC:136 6 8 -56 8 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

TADALAFIL (UNII: 742SXX0 ICT) (TADALAFIL - UNII:742SXX0 ICT)

TADALAFIL

20 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

HYDRO XYPRO PYL CELLULO SE, UNSPECIFIED (UNII: 9 XZ8 H6 N6 OH)

HYPRO MELLO SE 2 9 10 ( 15 MPA.S) (UNII: 36 SFW2JZ0 W)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

YELLOW (yello w)

S core

no sco re

Aphena Pharma Solutions - Tennessee, LLC

S hap e

OVAL (bico nvex beveled edge)

S iz e

13mm

Flavor

Imprint Code

A16 ;20

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:716 10 -30 3-0 4

4 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/10 /20 19

2

NDC:716 10 -30 3-0 6

6 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/10 /20 19

3

NDC:716 10 -30 3-12

12 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/10 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA2118 39

0 3/26 /20 19

Labeler -

Aphena Pharma Solutions - T ennessee, LLC (128385585)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Aphena Pharma So lutio ns - Tennessee, LLC

128 38 558 5

REPACK(716 10 -30 3)

Revised: 7/2019

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