Adcirca

tadalafil

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

Indications and Usage for Adcirca

Pulmonary Arterial Hypertension

Adcirca® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class II - III symptoms and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (23%).

Adcirca Dosage and Administration

Pulmonary Arterial Hypertension

The recommended dose of Adcirca 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 Adcirca because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Warnings and Precautions (5.3) and Use In Specific Populations (8.6)].

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 Adcirca [see Warnings and Precautions (5.4) and Use in Specific Populations (8.7)].

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 Adcirca in Patients on Ritonavir

In patients receiving ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Warnings and Precautions (5.2), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Co-administration of Ritonavir in Patients on Adcirca

Avoid use of Adcirca during the initiation of ritonavir. Stop Adcirca at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Warnings and Precautions (5.2), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

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

Contraindications

Concomitant Organic Nitrates

Do not use Adcirca in patients who are using any form of organic nitrate, either regularly or intermittently. Adcirca potentiates the hypotensive effect of nitrates. This potentiation is thought to result from the combined effects of nitrates and Adcirca on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2)].

Hypersensitivity Reactions

Adcirca is contraindicated in patients with a known serious hypersensitivity to tadalafil (Adcirca or CIALIS). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions (6.2)].

Warnings and Precautions

Cardiovascular Effects

Discuss with patients the appropriate action to take in the event that they experience anginal chest pain requiring nitroglycerin following intake of Adcirca. At least 48 hours should elapse after the last dose of Adcirca before taking nitrates. If a patient has taken Adcirca within 48 hours, administer nitrates under close medical supervision with appropriate hemodynamic monitoring. Patients who experience anginal chest pain after taking Adcirca should seek immediate medical attention.

PDE5 inhibitors, including tadalafil, have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Prior to prescribing Adcirca, carefully consider whether patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure or with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of Adcirca to patients with veno-occlusive disease, administration of Adcirca to such patients is not recommended. Should signs of pulmonary edema occur when Adcirca is administered, the possibility of associated PVOD should be considered.

There is a lack of data on safety and efficacy in the following groups who were specifically excluded from the PAH clinical trials:

• Patients with clinically significant aortic and mitral valve disease


• Patients with pericardial constriction


• Patients with restrictive or congestive cardiomyopathy


• Patients with significant left ventricular dysfunction


• Patients with life-threatening arrhythmias


• Patients with symptomatic coronary artery disease


• Patients with hypotension (<90/50 mm Hg) or uncontrolled hypertension

Use with Alpha Blockers and Antihypertensives

PDE5 inhibitors, including Adcirca, and alpha–adrenergic blocking agents are 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). Safety of combined use of PDE5 inhibitors and alpha blockers may be affected by other variables, including intravascular volume depletion and use of other antihypertensive drugs [see Drug Interactions (7.1)].

Use with Alcohol

Both alcohol and tadalafil are mild vasodilators. When mild vasodilators are taken in combination, blood pressure-lowering effects are increased [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].

Use with Potent CYP3A Inhibitors or Inducers

Co-administration of Adcirca in Patients on Ritonavir

In patients receiving ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.3), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Co-administration of Ritonavir in Patients on Adcirca

Avoid use of Adcirca during the initiation of ritonavir. Stop Adcirca at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.3), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Other Potent Inhibitors of CYP3A

Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole and itraconazole, avoid use of Adcirca [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Potent Inducers of CYP3A

For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of Adcirca [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Use in Renal Impairment

In patients with mild or moderate renal impairment

Start dosing at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

In patients with severe renal impairment

Avoid use of Adcirca because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Use in Hepatic Impairment

In patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B)

Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis, consider a starting dose of 20 mg once daily Adcirca [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

In patients with severe hepatic cirrhosis (Child-Pugh Class C)

Patients with severe hepatic cirrhosis have not been studied. Avoid use of Adcirca [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Effects on the Eye

Physicians should advise patients to seek immediate 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.

Hearing Impairment

Physicians should advise patients to seek immediate 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 Adcirca. 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 (6.2)].

Combination with Other PDE5 Inhibitors

Tadalafil is also marketed as CIALIS. The safety and efficacy of taking Adcirca together with CIALIS or other PDE5 inhibitors have not been studied. Inform patients taking Adcirca not to take CIALIS or other PDE5 inhibitors.

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.

Adcirca 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).

Effects on Bleeding

PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Adcirca has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Adcirca 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.

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

• Hypotension [see Warnings and Precautions (5.1)]


• Vision loss [see Warnings and Precautions (5.5)]


• Hearing loss [see Warnings and Precautions (5.6)]


• Priapism [see Warnings and Precautions (5.8)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tadalafil was administered to 398 patients with PAH during clinical trials worldwide. In trials of Adcirca, 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 Adcirca 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 Adcirca 40 mg was 4% compared to 5% in placebo-treated 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 Adcirca 40 mg group and occurring more frequently than with placebo.

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

EVENT	Placebo (%) (N=82)	Adcirca 20 mg (%) (N=82)	Adcirca 40 mg (%) (N=79)
Headache	15	32	42
Myalgia	4	9	14
Nasopharyngitis	7	2	13
Flushing	2	6	13
Respiratory Tract Infection (Upper and Lower)	6	7	13
Pain in Extremity	2	5	11
Nausea	6	10	11
Back Pain	6	12	10
Dyspepsia	2	13	10
Nasal Congestion (Including sinus congestion)	1	0	9

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 (5.1)].

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 (5.5) and Patient Counseling Information (17)].

Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.6) and Patient Counseling Information (17)].

Urogenital — Priapism [see Warnings and Precautions (5.8)].

Drug Interactions

Potential for Pharmacodynamic Interactions with Adcirca

Nitrates

Do not use Adcirca in patients who are using any form of organic nitrate [see Contraindications (4.1)]. In clinical pharmacology studies Adcirca potentiated the hypotensive effect of nitrates [see Clinical Pharmacology (12.2)]. In a patient who has taken Adcirca, where nitrate administration is deemed medically necessary in a life–threatening situation, at least 48 hours should elapse after the last dose of Adcirca before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.

Alpha-Blockers

PDE5 inhibitors, including Adcirca, 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, alfuzosin or tamsulosin [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

Antihypertensives

PDE5 inhibitors, including Adcirca, 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, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo [see Warnings and Precautions (5.1) 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 Adcirca can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

Potential for Other Drugs to Affect Adcirca

Ritonavir

Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir [see Dosage and Administration (2.3), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)].

Other Potent Inhibitors of CYP3A

Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of Adcirca [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Potent Inducers of CYP3A

For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of Adcirca [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Potential for Adcirca to Affect Other Drugs

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 (e.g., theophylline, warfarin, midazolam, lovastatin, bosentan) [see Clinical Pharmacology (12.3)].

Aspirin

Tadalafil (10 mg and 20 mg once daily) does not potentiate the increase in bleeding time caused by aspirin [see Clinical Pharmacology (12.3)].

P-glycoprotein (e.g., digoxin)

Coadministration of tadalafil (40 mg once daily) for 10 days did not significantly alter digoxin pharmacokinetics in healthy subjects [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

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 [see Nonclinical Toxicology (13.3)].

Nursing Mothers

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. Because many drugs are excreted in human milk, caution should be exercised when Adcirca is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in the clinical study of tadalafil for pulmonary arterial hypertension, 28 percent were 65 and over, while 8 percent were 75 and over. No overall differences in safety were observed between subjects over 65 years of age compared to younger subjects or those over 75 years of age. No dose adjustment is warranted based on age alone; however, a greater sensitivity to medications in some older individuals should be considered. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Renal Impairment

For patients with mild or moderate renal impairment, start Adcirca at 20 mg once daily. Increase the dose to 40 mg once daily based upon individual tolerability [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

In patients with severe renal impairment, avoid use of Adcirca because of increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Hepatic Impairment

Because of limited clinical experience in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A or B), consider a starting dose of Adcirca 20 mg once daily. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied, thus avoid use of Adcirca in such patients [see Dosage and Administration (2.2), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Overdosage

Single doses up to 500 mg have been given to healthy male subjects, and multiple daily doses up to 100 mg have been given to male patients with erectile dysfunction. Adverse reactions were similar to those seen at lower doses. Doses greater than 40 mg have not been studied in patients with pulmonary arterial hypertension. In cases of overdose, standard supportive measures should be adopted as needed. Hemodialysis contributes negligibly to tadalafil elimination.

Adcirca Description

Adcirca (tadalafil), an oral treatment for pulmonary arterial hypertension, 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.

Adcirca 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.

Adcirca - Clinical Pharmacology

Mechanism of Action

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.

Pharmacodynamics

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. Do not use Adcirca in patients taking any form of nitrates [see Contraindications (4.1)].

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) assessed the interaction between nitroglycerin and tadalafil. Subjects received daily doses of tadalafil 20 mg or matching placebo for 7 days and then were given 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). 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 effects at this timepoint. After 48 hours, the interaction was not detectable. [See Contraindications (4.1) and Warnings and Precautions (5.1)].

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 Antihypertensives

Amlodipine — A study assessed the interaction between 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 because of 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 assessed the interaction between 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.

Bendroflumethiazide — A study assessed the interaction between bendroflumethiazide (2.5 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of tadalafil 10 mg in subjects taking bendroflumethiazide was 6/4 mm Hg, compared to placebo.

Enalapril — A study assessed the interaction between enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of tadalafil 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.

Metoprolol — A study assessed the interaction between sustained–release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure because of 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 three clinical pharmacology studies. In two 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 Blood Pressure When Administered with Alpha-Blockers

Alpha-blockers and PDE5 inhibitors, including tadalafil, are systemic vasodilators. In subjects receiving concomitant tadalafil (20 mg single dose) and doxazosin (8 mg daily), an alpha-1 adrenergic receptor blocker, there was an augmentation of the blood pressure–lowering effect of doxazosin. This effect was still present at 12 hours postdose and had generally disappeared at 24 hours. The number of subjects with potentially clinically significant standing–blood–pressure decreases was greater for the combination.

An additional study was performed with tadalafil (20 mg single dose) and doxazosin (4 and 8 mg daily) using ambulatory blood pressure monitoring. The augmentation appeared unrelated to dosing times and resulted in a greater number of outliers for the combination than had been observed in the previous study. Both of these studies had some symptomatology associated with these blood pressure changes.

A further study was carried out with doxazosin (up to 4 mg daily) added to tadalafil (5 mg daily) and there was again an augmentation of response. In this clinical pharmacology study there were symptoms associated with the decrease in blood pressure, including syncope.

An interaction study with tadalafil (20 mg single dose) and alfuzosin, also an alpha-1 adrenergic receptor blocker, showed no clinically significant effect on blood pressure.

In two clinical pharmacology studies in healthy volunteers, tadalafil (5 mg daily, and 10 mg and 20 mg single dose) had no clinically significant effect on blood pressure changes because of tamsulosin, a selective alpha-1a adrenergic receptor blocking agent.

Effects on Cardiac Electrophysiology

The effect of a single 100 mg dose of tadalafil (2.5 times the recommended dose) on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double–blinded, placebo, and active–controlled (intravenous ibutilide) 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). 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.

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 similar 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 PDE 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 pupillometry. Across all clinical studies with tadalafil, 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.

Dose-Response Relationship

Dose-response relationships, between 20 mg and 40 mg, were not observed for 6-minute walk distance or pulmonary vascular resistance (PVR) in subjects with PAH in the placebo-controlled study. Median change from baseline in 6-minute walk distance was 32 meters and 35 meters at 16 weeks in subjects receiving 20 mg and 40 mg daily, respectively. Mean change from baseline PVR was -254 dynes*sec*cm-5 and -209 dynes*sec*cm-5 at 16 weeks in patients receiving 20 mg and 40 mg daily, respectively.

Pharmacokinetics

Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. In PAH patients administered between 20 and 40 mg of tadalafil, an approximately 1.5-fold greater AUC was observed indicating a less than proportional increase in exposure over the entire dose range of 2.5 to 40 mg. During tadalafil 20 and 40 mg once daily dosing, steady-state plasma concentrations were attained within 5 days, and exposure was approximately 1.3-fold higher than after a single dose.

Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 2 and 8 hours (median time of 4 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 Adcirca may be taken with or without food.

Distribution — The mean apparent volume of distribution following oral administration is approximately 77 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.

Metabolism — Tadalafil is predominantly metabolized by CYP3A 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 — Following 40 mg, the mean oral clearance for tadalafil is 3.4 L/hr and the mean terminal half-life is 15 hours in healthy subjects. In patients with pulmonary hypertension not receiving concomitant bosentan, the mean oral clearance for tadalafil is 1.6 L/hr, and the mean terminal half-life is 35 hours. 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).

Population pharmacokinetics — In patients with pulmonary hypertension not receiving concomitant bosentan, the average tadalafil exposure at steady-state following 40 mg was 26% higher when compared to those of healthy volunteers. The results suggest a lower clearance of tadalafil in patients with pulmonary hypertension compared to healthy volunteers.

Geriatric patients

In healthy male elderly subjects (65 years or over) after a 10 mg dose, a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax was observed relative to that in healthy subjects 19 to 45 years of age.

Renal impairment

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 cleara