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Tadalafil Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Tadalafil 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:

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.

For the treatment of erectile dysfunction: Tadalafil 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.

For the treatment of pulmonary arterial hypertension: Tadalafil is available as orange, film–coated, almond–shaped tablets for oral administration. Each tablet contains 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.

2. INDICATIONS AND USAGE

2.1 Erectile Dysfunction

Tadalafil is indicated for the trea tment of erectile dysfunction (ED).

2.2 Benign Prostatic Hyperplasia

Tadalafil is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

2.3 Erectile Dysfunction and Benign Prostatic Hyperplasia

Tadalafil is indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).

3. DOSAGE AND ADMINISTRATION

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

3.1 Tadalafil (CIALIS) for Use as Needed for Erectile Dysfunction

• The recommended starting dose of tadalafil for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.

• The dose may be increased to 20 mg or decreased to 5 mg, based o n individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.

• Tadalafil for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of tadalafil, this should be taken into consideration.

3.2 Tadalafil (CIALIS) for Once Daily Use for Erectile Dysfunction

• The recommended starting dose of tadalafil for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

• The tadalafil dose for once daily use may be increased to 5 mg , based on individual efficacy and tolerability.

3.3 Tadalafil (CIALIS) for Once Daily Use for Benign Prostatic Hyperplasia

The recommended dose of tadalafil for once daily use is 5 mg, taken at approximately the same time every day.

3.4 Tadalafil (CIALIS) for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia

The recommended dose of tadalafil for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

3.5 Use with Food

Tadalafil may be taken without regard to food.

3.6 Use in Specific Populations

Renal Impairment

Tadalafil for Use as Needed

• Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.

• Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions and Use in Specific Populations].

Tadalafil for Once Daily Use

Erectile Dysfunction

• Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil for once daily use is not recommended [see Warnings and Precautions and Use in Specific Populations].

Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia

• Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response.

• Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil for once daily use is not recommended [see Warnings and Precautions and Use in Specific Populations].

Hepatic Impairment

Tadalafil for Use as Needed

• Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of tadalafil once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.

• Severe (Child Pugh Class C): The use of tadalafil is not recommended [see Warnings and Precautions and Use in Specific Populations].

Tadalafil for Once Daily Use

• Mild or moderate (Child Pugh Class A or B): Tadalafil for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if tadalafil for once daily use is prescribed to these patients.

• Severe (Child Pugh Class C): The use of tadalafil is not recommended [see Warnings and Precautions and Use in Specific Populations].

3.7 Concomitant Medications

Nitrates

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

Alpha Blockers

ED — When tadalafil is coadministered with an alpha blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and tadalafil should be initiated at the lowest recommended dose [see Warnings and Precautions, Drug Interactions].

BPH — Tadalafil is not recommended for use in combination with alpha blockers for the treatment of BPH [see Warnings and Precautions, Drug Interactions].

CYP3A4 Inhibitors

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

Tadalafil for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg [see Warnings and Precautions and Drug Interactions].

3.8 Pulmonary Arterial Hypertension (ADCIRCA Usage)

The recommended dose of tadalafil is 40 mg (two 20 mg tablets) taken once daily with or without food. Dividing the dose (40 mg) over the course of the day is not recommended.

Use in Special Populations

Renal Impairment

• Mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min): Start dosing at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

• Severe (creatinine clearance <30 mL/min and on hemodialysis): Avoid use of tadalafil because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Warnings and Precautions and Use In Specific Populations].

Hepatic Impairment

• Mild or moderate (Child Pugh Class A or B): Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once per day.

• Severe (Child Pugh Class C): Patients with severe hepatic cirrhosis have not been studied. Avoid use of tadalafil [see Warnings and Precautions and Use in Specific Populations].

Geriatric Patients

• No dose adjustment is required in patients >65 years of age without renal impairment or hepatic impairment.

Use with Ritonavir

Co-administration of Tadalafil in Patients on Ritonavir

In patients receiving ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Warnings and Precautions, Drug Interactions].

Co-administration of Ritonavir in Patients on Tadalafil

Avoid use of tadalafil during the initiation of ritonavir. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Warnings and Precautions, Drug Interactions].

4. CONTRAINDICATIONS

4.1 Nitrates

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

4.2 Hypersensitivity Reactions

Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil. Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions].

5. MECHANISM OF ACTION

5.1 Erectile Dysfunction

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.

5.2 Pulmonary Arterial Hypertension

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

Erectile Dysfunction: Tadalafil is not indicated for use in women. There are no adequate and well-controlled studies of tadalafil in pregnant women.

Pulmonary Arterial Hypertension: Animal reproduction studies in rats and mice revealed no evidence of fetal harm. There are, however, no adequate and well-controlled studies of tadalafil in pregnant women. Because animal reproduction studies are not always predictive of human response, tadalafil should be used during pregnancy only if clearly needed.

Non–teratogenic effects

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at unbound tadalafil exposures up to 7 times the maximum recommended human dose (MRHD) of 40 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to unbound tadalafil concentrations greater than 5 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 8 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance.

6.2 Nursing Mothers

It is not known if tadalafil and/or its metabolites is excreted in human breast milk. Use of tadalafil in nursing mothers is not recommended.

6.3 Pediatric Use

Safety and effectiveness of tadalafil in pediatric patients have not been established.

6.4 Geriatric Use

No overall difference in the efficacy or safety of this drug was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.

7. WARNINGS AND PRECAUTIONS

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

Before prescribing tadalafil, it is important to note the following:

7.1 Cardiovascular

Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including tadalafil, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.

Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of tadalafil. In such a patient, who has taken tadalafil, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking tadalafil should seek immediate medical attention.

Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.

The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for tadalafil, and therefore until further information is available, tadalafil is not recommended for the following groups of patients:

• myocardial infarction within the last 90 days

• unstable angina or angina occurring during sexual intercourse

• New York Heart Association Class 2 or greater heart failure in the last 6 months

• uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension (>170/100 mm Hg)

• stroke within the last 6 months.

As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects. While this effect should not be of consequence in most patients, prior to prescribing tadalafil, 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.

7.2 Potential for Drug Interactions When Taking Tadalafil for Once Daily Use

Physicians should be aware that tadalafil 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].

7.3 Prolonged Erection

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.

Tadalafil 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).

7.4 Eye

Physicians should advise patients to stop use of all PDE5 inhibitors, including tadalafil, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including 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].

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.

7.5 Sudden Hearing Loss

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

7.6 Alpha blockers and Antihypertensives

Physicians should discuss with patients the potential for tadalafil to augment the blood-pressure-lowering effect of alpha blockers and antihypertensive medications [see Drug Interactions].

Caution is advised when PDE5 inhibitors are coadministered with alpha blockers. PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions], which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:

ED

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.

• In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.

• Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs. [See Dosage and Administration and Drug Interactions].

BPH

• The efficacy of the co-administration of an alpha-blocker and tadalafil for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of tadalafil and alpha-blockers is not recommended for the treatment of BPH. [See Dosage and Administration, Drug Interactions].

• Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting tadalafil for once daily use for the treatment of BPH.

7.7 Renal Insufficiency

Tadalafil for Use as Needed

Tadalafil should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of tadalafil in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. [See Use in Specific Populations].

Tadalafil for Once Daily Use

ED

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations].

BPH and ED/BPH

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response [see Dosage and Administration, Use in Specific Populations].

7.8 Hepatic Impairment

Tadalafil for Use as Needed

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

Tadalafil for Once Daily Use

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

7.9 Alcohol

Patients should be made aware that both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Dosage and Administration].

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

Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of tadalafil 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]. In patients taking potent inhibitors of CYP3A4 and tadalafil for once daily use, the dose of tadalafil should not exceed 2.5 mg [see Dosage and Administration].

7.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

7.12 Effects on Bleeding

Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Tadalafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil 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.

7.13 Counseling Patients About Sexually Transmitted Diseases

The use of tadalafil 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.

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

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

8. ADVERSE REACTIONS

8.1 Erectile Dysfunction

The following are treatment-emergent adverse events reported by ≥2% of patients treated with tadalafil (10 or 20 mg) and more frequent on drug than placebo in clinical trials: Headache, Dyspepsia, Back pain, Myalgia, Nasal congestion, Flushing, Pain in limb.

Postmarketing surveillance

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

Other adverse events: The following list includes other adverse events that have been identified during postmarketing use of tadalafil. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. 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 were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole: hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis.

Nervous: migraine.

Ophthalmologic: visual field defect, retinal vein occlusion, retinal artery occlusion.

Urogenital: priapism.

8.2 Pulmonary Arterial Hypertension

Tadalafil was administered to 398 patients with PAH during clinical trials worldwide. In trials of tadalafil, a total of 311 and 251 subjects have been treated for at least 182 days and 360 days, respectively. The overall rates of discontinuation because of an adverse event (AE) in the placebo-controlled trial were 9% for tadalafil 40 mg and 15% for placebo. The rates of discontinuation because of AEs, other than those related to worsening of PAH, in patients treated with tadalafil 40 mg was 4% compared to 5% in placebotreated patients.

In the placebo-controlled study, the most common AEs were generally transient and mild to moderate in intensity. Table 1 presents treatment-emergent adverse events reported by ≥ 9% of patients in the tadalafil 40 mg group and occurring more frequently than with placebo.

TABLE 1: Treatment-Emergent Adverse Events Reported by ≥ 9% of Patients in Tadalafil and More Frequent than Placebo by 2%

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tadalafil. These events have been chosen for inclusion either because of 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 estimate reliably 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 tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of tadalafil and sexual activity. It is not possible to determine whether these events are related directly to tadalafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [see Warnings and Precautions].

Body as a whole — Hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis.

Nervous — Migraine, seizure and seizure recurrence, and transient global amnesia.

Ophthalmologic — Visual field defect, retinal vein occlusion, and retinal artery occlusion.

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

Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions].

Urogenital — Priapism [see Warnings and Precautions].

9. 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.

10. DRUG INTERACTIONS

10.1 Potential for Pharmacodynamic Interactions with Tadalafil

Nitrates — Administration of tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications, Dosage and Administration].

Alpha Blockers — Caution is advised when PDE5 inhibitors are coadministered with alpha blockers. PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin or tamsulosin [see Warnings and Precautions, Dosage and Administration].

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].

Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [See Warnings and Precautions].

10.2 Potential for Other Drugs to Affect Tadalafil

[See Dosage and Administration and Warnings and Precautions].

Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

H2 Antagonists (e.g. Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

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

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

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].

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

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

10.3 Potential for Tadalafil to Affect Other Drugs

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

Cytochrome P450 Substrates — Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

CYP1A2 (e.g. Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

CYP2C9 (e.g. Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

CYP3A4 (e.g. Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.

P-glycoprotein (e.g. Digoxin) — Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.

11. 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.

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 tadalafil 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].

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

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.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names:

Erectile Dysfunction: CIALIS, by ELI LILLY.

Pulmonary Arterial Hypertension: ADCIRCA, by ELI LILLY CO.

b) Generic drugs: None.

2) 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 10 NDC 0002-4462-10

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

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ADCIRCA (tadalafil) is supplied as follows:

20 mg orange, film–coated, almond–shaped tablets (not scored), debossed with “4467”

Bottles of 60 NDC 66302-467-60

3) Storage:

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep out of reach of children.

Rx only

Rev 10/11