Rx Drugs Info

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use cialis safely and effectively. See full prescribing information for cialis.
cialis (Tadalafiltablet, film coated for oral use
Initial U.S. Approval: 2003

RECENT MAJOR CHANGES

Dosage and Administration Erectile Dysfunction, Use in Special Populations, Concomitant Medications ( 2.1, 2.3, 2.4)

1/2008

Warnings and Precautions, Renal Insufficiency, Hepatic Impairment ( 5.7, 5.8)

1/2008


INDICATIONS AND USAGE

CIALIS® is a phosphodiesterase 5 (PDE5) inhibitor indicated for erectile dysfunction (ED) ( 1.1).


DOSAGE AND ADMINISTRATION

  • CIALIS for use as needed: Starting dose: 10 mg up to once daily. 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 ( 2.1).
  • CIALIS for once daily use: 2.5 mg taken once daily, without regard to timing of sexual activity. May increase to 5 mg based upon efficacy and tolerability ( 2.1).
  • CIALIS may be taken without regard to food ( 2.2).

DOSAGE FORMS AND STRENGTHS

Tablets (not scored): 2.5 mg, 5 mg, 10 mg, 20 mg ( 3).


CONTRAINDICATIONS

Administration of CIALIS to patients using any form of organic nitrate is contraindicated. CIALIS was shown to potentiate the hypotensive effect of nitrates ( 4.1).


WARNINGS AND PRECAUTIONS

  • Patients should not use CIALIS if sex is inadvisable due to cardiovascular status ( 5.1).
  • Use of CIALIS with alpha blockers, antihypertensives or substantial amounts of alcohol (≥5 units) may lead to hypotension ( 5.6, 5.9).
  • If taking potent inhibitors of CYP3A4, dose should be adjusted: CIALIS for use as needed: ≤10 mg every 72 hours. For once daily use: dose not to exceed 2.5 mg ( 5.10).
  • Patients should seek emergency treatment if an erection lasts >4 hours Use CIALIS with caution in patients predisposed to priapism ( 5.3).
  • Patients should stop CIALIS and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of Non Arteritic Ischemic Optic Neuropathy (NAION). Discuss increased risk of NAION in patients with history of NAION ( 5.4).
  • Patients should stop CIALIS and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5).

ADVERSE REACTIONS

Most common adverse reactions (≥2%) include headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, and pain in limb ( 6.1, 6.2).



To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • CIALIS can potentiate the hypotensive effects of nitrates, alpha blockers, antihypertensives or alcohol ( 7.1).
  • CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) increase CIALIS exposure ( 7.2).
  • CYP3A4 inducers (e.g. rifampin) decrease CIALIS exposure ( 7.2).

USE IN SPECIFIC POPULATIONS

Hepatic Impairment ( 2.3, 5.8, 8.6):

  • Mild or Moderate: Dosage adjustment may be needed ( 2.3).
  • Severe: Use is not recommended ( 2.3).

Renal Insufficiency ( 2.3, 5.7, 8.7):

  • Moderate: For use as needed: Dosage adjustment may be needed. For once daily use: No dose adjustment is needed ( 2.3).
  • Severe: For use as needed: Dose should not exceed 5 mg every 72 hours. Once daily use is not recommended ( 2.3).


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 01/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1 Erectile Dysfunction

2 DOSAGE AND ADMINISTRATION

2.1 Erectile Dysfunction

2.2 Use with Food

2.3 Use in Special Populations

2.4 Concomitant Medications

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Nitrates

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular

5.2 Potential for Drug Interactions When Taking CIALIS for Once Daily Use

5.3 Prolonged Erection

5.4 Eye

5.5 Sudden Hearing Loss

5.6 Alpha blockers and Antihypertensives

5.7 Renal Insufficiency

5.8 Hepatic Impairment

5.9 Alcohol

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

5.11 Combination With Other Erectile Dysfunction Therapies

5.12 Effects on Bleeding

5.13 Counseling Patients About Sexually Transmitted Diseases

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with CIALIS

7.2 Potential for Other Drugs to Affect CIALIS

7.3 Potential for CIALIS to Affect Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Insufficiency

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 CIALIS for Use as Needed

14.2 CIALIS for Once Daily Use

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

17.1 Nitrates

17.2 Cardiovascular Considerations

17.3 Concomitant Use with Drugs Which Lower Blood Pressure

17.4 Potential for Drug Interactions When Taking CIALIS for Once Daily Use

17.5 Priapism

17.6 Vision

17.7 Sudden Hearing Loss

17.8 Alcohol

17.9 Sexually Transmitted Disease

17.10 Recommended Administration


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Erectile Dysfunction

CIALIS is indicated for the treatment of erectile dysfunction.

2 DOSAGE AND ADMINISTRATION

2.1 Erectile Dysfunction

CIALIS for Use as Needed

 CIALIS for Once Daily Use

2.2 Use with Food

CIALIS may be taken without regard to food.

2.3 Use in Special Populations

Renal Insufficiency

CIALIS for Use as Needed

 CIALIS for Once Daily Use

Hepatic Impairment

CIALIS for Use as Needed

CIALIS for Once Daily Use

Geriatrics

2.4 Concomitant Medications

Nitrites

Alpha Blockers

CYP3A4 Inhibitors

CIALIS for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of CIALIS is 10 mg, not to exceed once every 72 hours [see Warnings and Precautions ( 5.10) and Drug Interactions ( 7.2)].

CIALIS for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the dose should not exceed 2.5 mg [see Warnings and Precautions ( 5.10) and Drug Interactions ( 7.2)].

3 DOSAGE FORMS AND STRENGTHS

Four strengths of film-coated, almond-shaped tablets (not scored) are available in different sizes and different shades of yellow:

 
2.5-mg tablets debossed with “C 2 1/2”
 
5-mg tablets debossed with “C 5”
 
10-mg tablets debossed with “C 10”
 
20-mg tablets debossed with “C 20”

4 CONTRAINDICATIONS

4.1 Nitrates

Administration of CIALIS to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates. This is thought to result from the combined effects of nitrates and CIALIS on the nitric oxide/cGMP pathway [see Clinical Pharmacology ( 12.2)].

5 WARNINGS AND PRECAUTIONS

Evaluation of erectile dysfunction should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.

Before prescribing CIALIS, 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 CIALIS, 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 CIALIS. In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS 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 CIALIS 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 CIALIS, and therefore until further information is available, CIALIS is not recommended for the following groups of patients:

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 CIALIS, 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 CIALIS for Once Daily Use

Physicians should be aware that CIALIS 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.

CIALIS 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 Eye

Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS, 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 permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Adverse Reactions ( 6.2)].

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 CIALIS, 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 CIALIS. 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) and ( 6.2)].

5.6 Alpha blockers and Antihypertensives

Physicians should discuss with patients the potential for CIALIS 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 CIALIS, 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 Clinical Pharmacology ( 12.2) and Drug Interactions ( 7.1)], which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

[See Dosage and Administration ( 2.4) and Drug Interactions ( 7.1)].

5.7 Renal Insufficiency

CIALIS for Use as Needed

CIALIS should be limited to 5 mg not more than once in every 72 hours in patients with severe renal insufficiency or end-stage renal disease on hemodialysis. The starting dose of CIALIS in patients with a moderate degree of renal insufficiency 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. No dose adjustment is required in patients with mild renal insufficiency [see Use in Specific Populations ( 8.7)].

 CIALIS for Once Daily Use

 Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, CIALIS for once daily use is not recommended in patients with severe renal insufficiency. No dose adjustment is required in patients with mild or moderate renal insufficiency [see Use in Specific Populations ( 8.7)].

5.8 Hepatic Impairment

CIALIS for Use as Needed

In patients with mild or moderate hepatic impairment, the dose of CIALIS should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended [see Use In Specific Populations ( 8.6)].

 CIALIS for Once Daily Use

 CIALIS for once daily use has not been extensively evaluated in patients with mild or moderate hepatic insufficiency. Therefore, caution is advised if CIALIS for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended [see Use In Specific Populations ( 8.6)].

5.9 Alcohol

Patients should be made aware that both alcohol and CIALIS, 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 CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.2)].

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

CIALIS is metabolized predominantly by CYP3A4 in the liver. The dose of CIALIS 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 CIALIS for once daily use, the dose of CIALIS should not exceed 2.5 mg [see Dosage and Administration ( 2.4)].

5.11 Combination With Other Erectile Dysfunction Therapies

The safety and efficacy of combinations of CIALIS and other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

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. CIALIS has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although CIALIS has 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 CIALIS 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.

6 ADVERSE REACTIONS

6.1 Clinical Studies 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 6550 men during clinical trials worldwide. In trials of CIALIS for once daily use, a total of 716, 389, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For CIALIS for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.

CIALIS for Use as Needed

In eight primary placebo-controlled Phase 3 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 events were reported (see Table 1) for CIALIS for use as needed:

Table 1: Treatment-Emergent Adverse Events Reported by ≥2% of Patients Treated with CIALIS (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Phase 3 Studies (Including a Study in Patients with Diabetes) for CIALIS for Use as Needed

a The term flushing includes: facial flushing and flushing

Adverse Event Placebo
(N=476)
Tadalafil 5 mg
(N=151)
Tadalafil 10 mg
(N=394)
Tadalafil 20 mg
(N=635)
Headache 5% 11% 11% 15%
Dyspepsia 1% 4% 8% 10%
Back pain 3% 3% 5% 6%
Myalgia 1% 1% 4% 3%
Nasal congestion 1% 2% 3% 3%
Flushinga 1% 2% 3% 3%
Pain in limb 1% 1% 3% 3%

CIALIS for Once Daily Use

In three placebo-controlled Phase 3 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 events were reported (see Table 2) in clinical trials of 12 weeks duration:

Table 2: Treatment-Emergent Adverse Events Reported by ≥2% of Patients Treated with CIALIS for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies at 12 weeks (Including a Study in Patients with Diabetes) for CIALIS for Once Daily Use
Adverse Event Placebo
(N=248)
Tadalafil 2.5 mg
(N=196)
Tadalafil 5 mg
(N=304)
Headache 5% 3% 6%
Dyspepsia 2% 3% 5%
Nasopharyngitis 4% 4% 3%
Back pain 1% 3% 3%
Upper respiratory tract infection 1% 3% 3%
Flushing 1% 1% 3%
Influenza 2% 3% 2%
Myalgia 1% 2% 2%
Cough 0% 4% 2%
Diarrhea 0% 1% 2%
Nasal congestion 0% 2% 2%
Pain in extremity 0% 1% 2%
Bronchitis 1% 2% 0%
Urinary tract infection 0% 2% 0%
Gastroesophageal reflux 0% 2% 1%
Abdominal pain 0% 2% 1%

The following adverse events were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled Phase 3 clinical study:

Table 3: Treatment-Emergent Adverse Events Reported by ≥2% of Patients Treated with CIALIS for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Phase 3 Study of 24 Weeks Treatment Duration for CIALIS for Once Daily Use
Adverse Event Placebo
(N=94)
Tadalafil 2.5 mg
(N=96)
Tadalafil 5 mg
(N=97)
Nasopharyngitis 5% 6% 6%
Gastroenteritis viral 2% 3% 5%
Influenza 3% 5% 3%
Back Pain 3% 5% 2%
Upper Respiratory Tract Infection 0% 3% 4%
Dyspepsia 1% 4% 1%
Gastroesophageal Reflux Disease 0% 3% 2%
Myalgia 2% 4% 1%
Hypertension 0% 1% 3%
Nasal Congestion 0% 0% 4%

Back pain or myalgia was reported at incidence rates described in Tables 1 and 2. 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 recumbancy. 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 CIALIS 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 CIALIS for once daily use are described in Table 2. In studies of CIALIS for once daily use, events of back pain and myalgia were generally mild or moderate with a discontinuation rate of 0.3%.

Across all studies with any CIALIS 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 CIALIS for once daily use or use as needed. A causal relationship of these events to CIALIS is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:

Body as a whole — asthenia, face edema, fatigue, pain

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

Musculoskeletal — arthralgia, neck pain

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

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 CIALIS. 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. 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. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section.

Cardiovascular and cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of CIALIS without sexual activity. Others were reported to have occurred hours to days after the use of CIALIS and sexual activity. It is not possible to determine whether these events are related directly to CIALIS, 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

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 phosphodiesterase type 5 (PDE5) inhibitors, including CIALIS. 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors [see Warnings and Precautions ( 5.4) and Patient Counseling Information ( 17.6)].

Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including CIALIS. 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 CIALIS, 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) and Patient Counseling Information ( 17.7)].

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

7 DRUG INTERACTIONS

7.1 Potential for Pharmacodynamic Interactions with CIALIS

Nitrates — Administration of CIALIS to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken CIALIS, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS 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), Dosage and Administration ( 2.4) and Clinical Pharmacology ( 12.2)].

Alpha Blockers — Caution is advised when PDE5 inhibitors are coadministered with alpha blockers. PDE5 inhibitors, including CIALIS, 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 or tamsulosin [see Warnings and Precautions ( 5.6), Dosage and Administration ( 2.4) 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 CIALIS 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 CIALIS

[See Dosage and Administration ( 2.4) 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.

H2Antagonists (e.g. Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

Cytochrome P450 Inhibitors — CIALIS is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.

CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone [see Dosage and Administration ( 2.4)].

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see Dosage and Administration ( 2.4)].

Cytochrome P450 Inducers — Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.

CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of CIALIS for once daily use; the magnitude of decreased efficacy is unknown.

7.3 Potential for CIALIS to Affect Other Drugs

Aspirin — Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Cytochrome P450 Substrates — CIALIS 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

Pregnancy Category B — CIALIS (tadalafil) is not indicated for use in women. There are no adequate and well controlled studies of CIALIS use in pregnant women. Animal reproduction studies in rats and mice revealed no evidence of fetal harm.

Non-teratogenic effects — Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies 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. (See Animal Toxicology and/or Pharmacology Section 13.2)

8.3 Nursing Mothers

CIALIS is not indicated for use in women. It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk.

8.4 Pediatric Use

CIALIS is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of tadalafil, approximately 25 percent were 65 and over, while approximately 3 percent were 75 and over. No overall differences in efficacy or safety were observed between subjects over 65 years of age compared to younger subjects, therefore 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 ( 2.3) and Warnings and Precautions ( 5.8)].

8.7 Renal Insufficiency

In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal insufficiency. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-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 moderate renal impairment. 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 ( 2.3) 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

CIALIS (tadalafil), an oral treatment for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is:

Image from Drug Label Content

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 and very slightly soluble in ethanol.

CIALIS is available as film-coated, almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

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.

Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, 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. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.

12.2 Pharmacodynamics

Effects on Blood Pressure

Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.

Effects on Blood Pressure When Administered with Nitrates

In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of CIALIS 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).

Image from Drug Label Content

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, CIALIS administration with nitrates is contraindicated. In a patient who has taken CIALIS, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS 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 ( 2.4) 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) oral alpha blocker. In two studies, 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 4 and Figure 2).

Table 4: Doxazosin Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
 Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg
Supine 3.6 (-1.5, 8.8)
Standing 9.8 (4.1, 15.5)
Image from Drug Label Content

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 5 and Figure 3.

Table 5: Doxazosin Study 2 (Part C): Mean Maximal Decrease in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg at 8 a.m. Tadalafil 20 mg at 8 p.m.
Ambulatory Blood-Pressure Monitoring (ABPM) 7 8
Image from Drug Label Content

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 6.

Table 6: 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 7: Tamsulosin Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 10 mg Tadalafil 20 mg
Supine 3.2 (-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 8: 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 Tamsulosin Supine -0.1 (-2.2, 1.9)
Standing 0.9 (-1.4, 3.2)
Day 7 of 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 9: Alfuzosin Study: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg
Supine 2.2 (-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 CIALIS, 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 QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (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.

Image from Drug Label Content

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 (Cmax) 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 CIALIS 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.

Elimination — 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 Cmax 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)].

Pediatric — Tadalafil has not been evaluated in individuals less than 18 years old [see Use in Specific Populations ( 8.4)].

Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 mg.

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.

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 20-100% of the dogs that resulted in a decrease in spermatogenesis in 40-75% 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 upon removal of the drug.

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg and have revealed no evidence of impaired fertility or harm to the fetus due to tadalafil. In addition, there was no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the MRHD during the period of major organ development.

In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.

14 CLINICAL STUDIES

14.1 CIALIS for Use as Needed

The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24-weeks duration, involving over 4000 patients. CIALIS, when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

CIALIS was 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, CIALIS was 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 CIALIS 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 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, CIALIS 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Table 10). The treatment effect of CIALIS did not diminish over time.

Table 10: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US Trials
Study A Study B
Placebo CIALIS
20 mg
Placebo CIALIS
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 6.9 <.001 0.3 9.3 <.001
Insertion of Penis (SEP2)
   Endpoint 39% 62% 43% 77%
   Change from baseline 2% 26% <.001 2% 32% <.001
Maintenance of Erection
  (SEP3)
   Endpoint 25% 50% 23% 64%
   Change from baseline 5% 34% <.001 4% 44% <.001

Results in General ED Population in Trials Outside the US — The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 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, CIALIS 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 11, 12 and 13). The treatment effect of CIALIS did not diminish over time.

Table 11: 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

a Treatment duration in Study F was 6 months

Placebo CIALIS
5 mg
CIALIS
10 mg
CIALIS
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 Fa
   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
Table 12: 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

a Treatment duration in Study F was 6 months

Placebo CIALIS
5 mg
CIALIS
10 mg
CIALIS
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 Fa
   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 13: 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

a Treatment duration in Study F was 6 months

Placebo CIALIS
5 mg
CIALIS
10 mg
CIALIS
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 Fa
   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 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking CIALIS, compared to patients on placebo.

Therefore, in all 7 primary efficacy and safety studies, CIALIS 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 — CIALIS was 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 CIALIS in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial, CIALIS 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 14).

Table 14: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in ED Patients with Diabetes
Placebo CIALIS
10 mg
CIALIS
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 — CIALIS was 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), CIALIS 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 Patients who Developed ED Following Bilateral Nerve-Sparing Radical Prostatectomy
Placebo CIALIS
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 CIALIS — Several studies were conducted with the objective of determining the optimal use of CIALIS 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, CIALIS 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 CIALIS at a given timepoint 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 CIALIS 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 CIALIS group at each of the pre-specified timepoints. At the 24-hour timepoint, (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 CIALIS 20-mg group. At the 36-hour timepoint (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 CIALIS 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, CIALIS 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 timepoint. In this study, the results demonstrated a statistically significant difference between the placebo group and the CIALIS groups at each of the pre-specified timepoints. At the 24-hour timepoint, the mean, per patient percentage of attempts resulting in successful intercourse were 42, 56, and 67% for the placebo, CIALIS 10-, and 20-mg groups, respectively. At the 36-hour timepoint, the mean, per-patient percentage of attempts resulting in successful intercourse were 33, 56, and 62% for placebo, CIALIS 10-, and 20-mg groups, respectively.

14.2 CIALIS for Once Daily Use

The efficacy and safety of CIALIS 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. CIALIS, when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

CIALIS was 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. CIALIS was 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 Cialis.

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, CIALIS 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). When taken as directed, CIALIS was effective at improving erectile function.

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

Table 16: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two CIALIS for Once Daily Use Studies

a Twenty-four-week study conducted in the US.

b Twelve-week study conducted outside the US.

c Statistically significantly different from placebo

Study Ha Study Ib
Placebo CIALIS CIALIS Placebo CIALIS
2.5 mg 5 mg 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 1.2 6.1c 7.0c <.001 0.9 9.7c <.001
Insertion of Penis (SEP2)
   Endpoint 51% 65% 71% 52% 79%
   Change from baseline 5% 24%c 26%c <.001 11% 37%c <.001
Maintenance of Erection (SEP3)
   Endpoint 31% 50% 57% 37% 67%
   Change from baseline 10% 31%c 35%c <.001 13% 46%c <.001

Efficacy Results in ED Patients with Diabetes Mellitus — CIALIS 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, CIALIS 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).

Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a CIALIS for Once Daily Use Study in ED Patients with Diabetes

a Statistically significantly different from placebo

Placebo CIALIS
2.5 mg
CIALIS
5 mg
(N=100) (N=100) (N=98) p-value
EF Domain Score
   Endpoint 14.7 18.3 17.2
   Change from baseline 1.3 4.8a 4.5a <.001
Insertion of Penis (SEP2)
   Endpoint 43% 62% 61%
   Change from baseline 5% 21%a 29%a <.001
Maintenance of Erection (SEP3)
   Endpoint 28% 46% 41%
   Change from baseline 8% 26%a 25%a <.001
   

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

CIALIS (tadalafil) is supplied as follows:

Four strengths of film-coated, almond-shaped tablets (not scored) are available in different sizes and different shades of yellow, and supplied in the following package sizes:

2.5 mg tablets debossed with “C 2 1/2”
   Blisters of 2 x 15 NDC 0002-4465-34
5-mg tablets debossed with “C 5”
   Bottles of 30 NDC 0002-4462-30
   Blisters of 2 x 15 NDC 0002-4462-34
10-mg tablets debossed with “C 10”
   Bottles of 30 NDC 0002-4463-30
20-mg tablets debossed with “C 20”
   Bottles of 30 NDC 0002-4464-30

16.2 Storage

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

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA approved Patient Labeling

17.1 Nitrates

Physicians should discuss with patients the contraindication of CIALIS with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of CIALIS 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 CIALIS. In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of CIALIS 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 CIALIS should seek immediate medical attention [see Contraindications ( 4.1) and Warnings and Precautions ( 5.1)].

17.2 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)].

17.3 Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should discuss with patients the potential for CIALIS 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)].

17.4 Potential for Drug Interactions When Taking CIALIS for Once Daily Use

Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing CIALIS 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.

17.5 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.

17.6 Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS, 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 permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Clinical Studies ( 6.2)].

17.7 Sudden Hearing Loss

Physicians should advise patients to stop taking PDE5 inhibitors, including CIALIS, 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 CIALIS. 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) and ( 6.2)].

17.8 Alcohol

Patients should be made aware that both alcohol and CIALIS, 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 CIALIS 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)].

17.9 Sexually Transmitted Disease

The use of CIALIS 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.

17.10 Recommended Administration

CIALIS is available in two dosing regimens; therefore, physicians should instruct patients on the appropriate administration to allow optimal use.

For CIALIS for use as needed, 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 CIALIS for once daily use, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity. Cialis is effective at improving erectile function over the course of therapy

Literature revised January 7, 2008

Eli Lilly and Company
Indianapolis, IN 46285, USA
www.cialis.com
Copyright © 2003, 2008, Eli Lilly and Company. All rights reserved.
PV 5217 AMP

Patient Information

CIALIS®(See-AL-iss)
(tadalafil) tablets

Read this important information before you start taking CIALIS 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 CIALIS 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 CIALIS?

CIALIS 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.

Do not take CIALIS 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.

Tell all of your healthcare providers that you take CIALIS. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took CIALIS.

After taking a single tablet, some of the active ingredient of CIALIS 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 CIALIS?”).

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 CIALIS?”

What Is CIALIS?

CIALIS is a prescription medicine taken by mouth for the treatment of erectile dysfunction (ED) in men.

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. CIALIS 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 CIALIS.

CIALIS does not:

CIALIS is only for men over the age of 18 who have ED, including men with diabetes or who have undergone prostatectomy

CIALIS is not for women or children.

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

Who Should Not Take CIALIS?

Do not take CIALIS if you:

What Should I Tell My Healthcare Provider Before Taking CIALIS?

CIALIS is not right for everyone. Only your healthcare provider and you can decide if CIALIS is right for you. Before taking CIALIS, tell your healthcare provider about all your medical problems, including if you:

Can Other Medicines Affect CIALIS?

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. CIALIS 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:*

How Should I Take CIALIS?

There are two ways to take CIALIS:

CIALIS for use as needed:

OR

CIALIS for once daily use:

What Should I Avoid While Taking CIALIS?

What Are The Possible Side Effects Of CIALIS?

See “What Is The Most Important Information I Should Know About CIALIS?”

The most common side effects with CIALIS 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 CIALIS. 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 CIALIS) reported a sudden decrease or loss of vision in one or both eyes. It is not possible to determine whether these events are related directly to these medicines, to other factors such as high blood pressure or diabetes, or to a combination of these. If you experience sudden decrease or loss of vision, stop taking PDE5 inhibitors, including CIALIS, 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 CIALIS. 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 CIALIS and contact a healthcare provider right away.

These are not all the possible side effects of CIALIS. For more information, ask your healthcare provider or pharmacist.

How Should I Store CIALIS?

Store CIALIS at room temperature between 59° and 86°F (15° and 30°C).

Keep CIALIS and all medicines out of the reach of children.

General Information About CIALIS:

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use CIALIS for a condition for which it was not prescribed. Do not give CIALIS 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 CIALIS. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CIALIS that is written for health providers. For more information you can also visit www.cialis.com, or call 1-877-CIALIS1 (1-877-242-5471).

What Are The Ingredients In CIALIS?

Active Ingredient: tadalafil

Inactive Ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

Rx only

CIALIS® (tadalafil) is a registered trademark of Eli Lilly and Company.

*The brands listed are trademarks of their respective owners and are not trademarks of Eli Lilly and Company. The makers of these brands are not affiliated with and do not endorse Eli Lilly and Company or its products.

Literature revised January 7, 2008

Eli Lilly and Company
Indianapolis, IN 46285, USA
www.cialis.com
Copyright © 2003, 2008, Eli Lilly and Company. All rights reserved.
PV 5225 AMP

Cialis (Tadalafil)
PRODUCT INFO
Product Code 0002-4465 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Tadalafil (Tadalafil) Active 2.5 MILLIGRAM  In 1 TABLET
Hydroxypropyl cellulose Inactive  
Hypromellose Inactive  
Iron oxide Inactive  
Lactose monohydrate Inactive  
Magnesium stearate Inactive  
Cellulose microcrystalline Inactive  
Sodium lauryl sulfate Inactive  
Talc Inactive  
Titanium dioxide Inactive  
Croscarmellose sodium Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color yellow Score 1
Shape OVAL (almond) Symbol false
Imprint Code C;2;1/2 Coating true
Size 9mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0002-4465-34 2 BLISTER PACK In 1 CARTON contains a BLISTER PACK
1 15 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0002-4465-34)

Cialis (Tadalafil)
PRODUCT INFO
Product Code 0002-4462 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Tadalafil (Tadalafil) Active 5 MILLIGRAM  In 1 TABLET
Hydroxypropyl cellulose Inactive  
Hypromellose Inactive  
Iron oxide Inactive  
Lactose monohydrate Inactive  
Magnesium stearate Inactive  
Cellulose microcrystalline Inactive  
Sodium lauryl sulfate Inactive  
Talc Inactive  
Titanium dioxide Inactive  
Croscarmellose sodium Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color yellow Score 1
Shape OVAL (almond) Symbol false
Imprint Code C;5 Coating true
Size 10mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0002-4462-30 30 TABLET In 1 BOTTLE None
2 0002-4462-34 2 BLISTER PACK In 1 CARTON contains a BLISTER PACK
2 15 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0002-4462-34)

Cialis (Tadalafil)
PRODUCT INFO
Product Code 0002-4463 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Tadalafil (Tadalafil) Active 10 MILLIGRAM  In 1 TABLET
Hydroxypropyl cellulose Inactive  
Hypromellose Inactive  
Iron oxide Inactive  
Lactose monohydrate Inactive  
Magnesium stearate Inactive  
Cellulose microcrystalline Inactive  
Sodium lauryl sulfate Inactive  
Talc Inactive  
Titanium dioxide Inactive  
Croscarmellose sodium Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color yellow Score 1
Shape OVAL (almond) Symbol false
Imprint Code C;10 Coating true
Size 11mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0002-4463-30 30 TABLET In 1 BOTTLE None

Cialis (Tadalafil)
PRODUCT INFO
Product Code 0002-4464 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Tadalafil (Tadalafil) Active 20 MILLIGRAM  In 1 TABLET
Hydroxypropyl cellulose Inactive  
Hypromellose Inactive  
Iron oxide Inactive  
Lactose monohydrate Inactive  
Magnesium stearate Inactive  
Cellulose microcrystalline Inactive  
Sodium lauryl sulfate Inactive  
Talc Inactive  
Titanium dioxide Inactive  
Croscarmellose sodium Inactive  
Triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color yellow Score 1
Shape OVAL (almond) Symbol false
Imprint Code C;20 Coating true
Size 12mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 0002-4464-30 30 TABLET In 1 BOTTLE None

Revised: 01/2008Eli Lilly and Company

Data are from FDA and U.S. National Library of Medicine.