Adcirca

Name: Adcirca

Why is this medication prescribed?

Tadalafil (Cialis) is used to treat erectile dysfunction (ED, impotence; inability to get or keep an erection), and the symptoms of benign prostatic hyperplasia (BPH; an enlarged prostate) which include difficulty urinating (hesitation, dribbling, weak stream, and incomplete bladder emptying), painful urination, and urinary frequency and urgency in adult men. Tadalafil (Adcirca) is used to improve the ability to exercise in people with pulmonary arterial hypertension (PAH; high blood pressure in the vessels carrying blood to the lungs, causing shortness of breath, dizziness, and tiredness). Tadalafil is in a class of medications called phosphodiesterase (PDE) inhibitors. It works to treat erectile dysfunction by increasing blood flow to the penis during sexual stimulation. This increased blood flow can cause an erection. Tadalafil treats PAH by relaxing the blood vessels in the lungs to allow blood to flow more easily.

If you are taking tadalafil to treat erectile dysfunction, you should know that it does not cure erectile dysfunction or increase sexual desire. Tadalafil does not prevent pregnancy or the spread of sexually transmitted diseases such as human immunodeficiency virus (HIV).

How should this medicine be used?

Tadalafil comes as a tablet to take by mouth. It may be taken with or without food.

If you are taking tadalafil to treat erectile dysfunction, follow your doctor's directions and the guidelines in this paragraph. There are two different ways to take tadalafil, either daily or on an as needed basis. Talk to your doctor about which dosing schedule is right for you. Tadalafil is sometimes taken as needed, usually at least 30 minutes before sexual activity and not more often than once every 24 hours. Your doctor will help you decide the best time for you to take tadalafil before sexual activity. Tadalafil is also sometimes taken once a day every day without regard to timing of sexual activity. You may attempt sexual activity at any time between doses. If you are taking tadalafil on a regular schedule, take it at around the same time every day. If you have certain health conditions or are taking certain medications, your doctor may tell you to take tadalafil less often or may prescribe a lower dose to be taken once a day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take tadalafil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking tadalafil to treat PAH or BPH, follow your doctor's directions and the guidelines in this paragraph. You should take tadalafil one time a day. Take all of the tablets for your daily dose at one time each day; do not divide the tablets to take as separate doses. Take tadalafil at around the same time every day. If you are already taking medication to treat BPH, your doctor may tell you to stop taking your other medication at least one day before starting treatment with tadalafil. Follow your doctor's directions carefully, and ask your doctor or pharmacist to explain any part you do not understand.

If you are taking tadalafil for erectile dysfunction, your doctor will probably start you on an average dose of tadalafil and increase or decrease your dose depending on your response to the medication. Tell your doctor if tadalafil is not working well or if you are experiencing side effects.

If you are taking tadalafil for PAH, you should know that tadalafil controls PAH but does not cure it. Continue to take tadalafil even if you feel well. Do not stop taking tadalafil without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

What special dietary instructions should I follow?

Talk to your doctor about eating grapefruit and drinking grapefruit juice while taking this medicine.

What should I do if I forget a dose?

If you are taking tadalafil for erectile dysfunction on a regular schedule, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose or more than one dose per day to make up for a missed one.

If you are taking tadalafil for PAH or BPH, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Brand names

  • Adcirca®
  • Cialis®

Commonly used brand name(s)

In the U.S.

  • Adcirca
  • Cialis

Available Dosage Forms:

  • Tablet

Therapeutic Class: Erectile Dysfunction Agent

Pharmacologic Class: Phosphodiesterase Type 5 Inhibitor

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”.

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 clearance 31 to 50 mL/min) renal impairment. 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, respectively. 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 [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

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 (2.2) and Warnings and Precautions (5.4)].

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.

Race

Pharmacokinetic studies have included subjects from different ethnic groups, and no differences in the typical exposure to tadalafil have been identified. No dose adjustment is warranted.

Gender

In healthy female and male subjects following single and multiple-doses of tadalafil, no clinically relevant differences in exposure (AUC and Cmax) were observed. No dose adjustment is warranted.

Drug interaction studies

Tadalafil is a substrate of and predominantly metabolized by CYP3A. Drugs that inhibit CYP3A can increase tadalafil exposure.

Ritonavir

Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A, 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. Ritonavir inhibits and induces CYP3A, the enzyme involved in the metabolism of tadalafil, in a time-dependent manner. The results suggest the initial inhibitory effect of ritonavir on CYP3A may be mitigated by a more slowly evolving induction effect so that after about 1 week of ritonavir twice daily, the exposure of tadalafil is similar in the presence of and absence of ritonavir [see Dosage and Administration (2.3), Warnings and Precautions (5.2), and Drug Interactions (7.2)]. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.

Other Cytochrome P450 inhibitors

CYP3A (e.g., ketoconazole) Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A, 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.

Although specific interactions have not been studied, other CYP3A inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

Cytochrome P450 inducers

CYP3A (e.g., rifampin, bosentan) Rifampin (600 mg daily), a CYP3A inducer, reduced tadalafil 10 mg single–dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone.

Bosentan (125 mg twice daily), a substrate of CYP2C9 and CYP3A and a moderate inducer of CYP3A, CYP2C9 and possibly CYP2C19, reduced tadalafil (40 mg once per day) systemic exposure by 42% and Cmax by 27% following multiple-dose co-administration.

Although specific interactions have not been studied, other CYP3A inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure.

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.

CYP1A2 (e.g., theophylline) Tadalafil (10 mg once per day) 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 (10 mg and 20 mg once per day) had no significant effect on exposure (AUC) to S–warfarin or R–warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

CYP3A (e.g., midazolam, lovastatin or bosentan) Tadalafil (10 mg and 20 mg once per day) had no significant effect on exposure (AUC) to midazolam or lovastatin. Tadalafil (40 mg once per day) had no clinically significant effect on exposure (AUC and Cmax) of bosentan, a substrate of CYP2C9 and CYP3A, or its metabolites.

Aspirin Tadalafil (10 mg and 20 mg once per day) did not potentiate the increase in bleeding time caused by aspirin.

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.

Combined oral contraceptives At steady-state, tadalafil (40 mg once per day) increased ethinyl estradiol exposure (AUC) by 26% and Cmax by 70% relative to oral contraceptive administered with placebo. There was no significant effect of tadalafil on levonorgestrel.

Antacids Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil (10 mg) 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 tadalafil (10 mg) pharmacokinetics.

Clinical Studies

Adcirca for Pulmonary Arterial Hypertension

A randomized, double-blind, 16 week placebo-controlled study was conducted in 405 patients with pulmonary arterial hypertension, defined as a resting mean pulmonary artery pressure (mPAP) ≥25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg, and pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. Allowed background therapy included bosentan (maintenance dosing up to 125 mg twice daily) and chronic anticoagulation. The use of prostacyclin or analogue, L–arginine, phosphodiesterase inhibitor, or other chronic PAH medications were not permitted.

Subjects were randomly assigned to 1 of 5 treatment groups (tadalafil 2.5, 10, 20, 40 mg, or placebo) in a 1:1:1:1:1 ratio. Subjects had to be at least 12 years of age and had a diagnosis of PAH that was idiopathic, heritable, related to connective tissue disease, anorexigen use, human immunodeficiency virus (HIV) infection, associated with an atrial-septal defect, or associated with surgical repair of a congenital systemic-to-pulmonary shunt of least 1 year in duration (for example, ventricular septal defect, patent ductus arteriosus). Patients with a history of left-sided heart disease, severe renal insufficiency, or pulmonary hypertension related to conditions other than specified in the inclusion criteria were not eligible for enrollment.

The mean age of all subjects was 54 years (range 14 - 90 years) with the majority of subjects being Caucasian (81%) and female (78%). PAH etiologies were predominantly idiopathic or heritable PAH (61%) and related to connective tissue disease (23%). More than half (53%) of the subjects in the study were receiving concomitant bosentan therapy. The majority of subjects had a World Health Organization (WHO) Functional Class III (65%) or II (32%). The mean baseline 6-minute walk distance (6-MWD) was 343 meters. Of the 405 subjects, 341 completed the study.

The primary efficacy endpoint was the change from baseline at week 16 in 6-MWD (see Figure 1). In the Adcirca 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD was 33 meters (95% C.I. 15-50 meters; p=0.0004). The improvement in 6-MWD was apparent at 8 weeks of treatment and then maintained at week 12 and week 16.

Figure 1: 6-Minute Walk Distance (meters) Mean Change from Baseline, with 95% Confidence Intervals

Placebo-adjusted changes in 6-MWD at 16 weeks were evaluated in subgroups (see Figure 2). In patients taking only Adcirca 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean change in 6-MWD was 44 meters. In patients taking Adcirca 40 mg and concomitant bosentan therapy, the placebo adjusted mean change in 6-MWD was 23 meters.

Figure 2: Placebo-adjusted Mean Change in 6-Minute Walk Distance (meters) of Adcirca 40 mg, with 95% Confidence Intervals

There was less clinical worsening (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, initiation of new PAH therapy [prostacyclin or analog, endothelin receptor antagonist, PDE5 inhibitor], or worsening WHO functional class) in the Adcirca 40 mg group compared to the placebo group and the groups that used lower doses of Adcirca.

Table 2: Number (percent) with Clinical Worseninga

a Subjects may be counted in more than one category

Adcirca
Placebo
N=82
2.5 mg
N=82
10 mg
N=80
20 mg
N=82
40 mg
N=79
Total with clinical worsening 13 (16) 10 (12) 7 (9) 8 (10) 4 (5)
     Death 1 0 1 0 0
     Hospitalization for worsening PAH 2 2 3 0 1
     New PAH therapy 0 1 0 2 1
     Worsening WHO class 11 10 6 6 3

The Kaplan-Meier plot of times to clinical worsening is shown below in Figure 3.

Figure 3: Kaplan-Meier Plot of Time to Clinical Worsening

Long-Term Treatment of Pulmonary Arterial Hypertension

Patients (N=357) from the placebo-controlled study entered a long-term extension study. Of these, 311 patients have been treated with tadalafil for at least 6 months and 182 for 1 year (median exposure 356 days; range 2 days to 415 days). The survival rate in the extension study was 96.5 per 100 patient years. Without a control group, these data must be interpreted cautiously.

Patient Counseling Information

See FDA-Approved Patient Labeling (Patient Information)

  • Inform patients of contraindication of Adcirca with any use of organic nitrates or GC stimulators.
  • Inform patients that tadalafil is also marketed as CIALIS for erectile dysfunction (ED) and for the signs and symptoms of benign prostatic hyperplasia (BPH). Advise patients taking Adcirca not to take CIALIS or other PDE5 inhibitors.
  • Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking Adcirca. Such an event may be a sign of NAION.
  • Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking Adcirca. These events may be accompanied by tinnitus and dizziness.

Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285, USA

Marketed by: United Therapeutics Corporation

Copyright © 2009, 2017, Eli Lilly and Company. All rights reserved.

ADC-0004-USPI-20170801

PATIENT INFORMATION

Adcirca® (Ad-sur-kuh)

(tadalafil) tablets

Read this patient information before you start taking Adcirca and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Adcirca?

Never take Adcirca with any nitrate or guanylate cyclase stimulator medicines:

  • Your blood pressure could drop quickly to an unsafe level
  • You could get dizzy, faint and even have a heart attack or stroke.

Nitrates include:

  • Medicines that treat chest pain (angina)
  • Nitroglycerin in any form including tablets, patches, sprays, and ointments
  • Other nitrate medicines (isosorbide mononitrate or dinitrate)
  • Street drugs that are inhaled, called “poppers” (amyl nitrate, butyl nitrate or nitrite)

Guanylate cyclase stimulators include:

  • Riociguat (Adempas®) a medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension

Ask your healthcare provider or pharmacist if you are not sure if you take a nitrate or guanylate cyclase stimulator medicine.

What is Adcirca?

Adcirca is a prescription medicine used to treat pulmonary arterial hypertension (PAH, high blood pressure in your lungs) to improve your ability to exercise.

It is not known if Adcirca is safe or effective in children.

Who should not take Adcirca?

Do not take Adcirca if you

  • take any medicines called nitrates.
  • use recreational drugs called “poppers” like amyl nitrate, butyl nitrate or nitrite.
  • take any medicines called guanylate cyclase stimulators
  • are allergic to tadalafil or any other ingredient in Adcirca. See “What are the ingredients in Adcirca?” at the end of this leaflet.

See “What is the most important information I should know about Adcirca?”

What should I tell my healthcare provider before taking Adcirca?

Before taking Adcirca, tell your healthcare provider about all of your medical conditions, including if you:

  • are allergic to Adcirca or Cialis or any of its ingredients. See the end of this leaflet for a complete list of ingredients in Adcirca.
  • have pulmonary veno-occlusive disease (PVOD)
  • have heart problems such as angina (chest pain), heart failure, irregular heartbeats, or have had a heart attack
  • have low blood pressure or high blood pressure that is not controlled
  • have had a stroke
  • have liver problems
  • have kidney problems or get dialysis
  • have stomach ulcers
  • have retinitis pigmentosa, a rare genetic eye disease
  • have ever had any sudden vision loss, including any damage to your optic nerve or NAION.
  • have ever had hearing problems such as ringing in the ears, dizziness, or loss of hearing
  • have a deformed penis shape or Peyronie's disease
  • have had an erection that lasted more than 4 hours
  • have blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia
  • are pregnant or planning to become pregnant. It is not known if Adcirca will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
  • are breastfeeding or plan to breast feed. It is not known if Adcirca passes into your breast milk. You and your healthcare provider should decide if you will take Adcirca or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Adcirca and other medicines may affect each other.

Especially tell your healthcare provider if you take any of these medicines*:

  • nitrates or guanylate cyclase stimulators (see “What is the most important information I should know about Adcirca?”)
  • anti-hypertensives, used to treat high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint.
  • alpha blockers, used to treat prostate disease and high blood pressure. Your blood pressure could suddenly drop. You could get dizzy or faint.
  • protease inhibitors, used to treat HIV infection, such as ritonavir (Norvir®, Kaletra®)
  • ketoconazole (Extina®, Xolegel®, Ketozole®, Nizoral A-D®, Nizoral®) itraconazole (Sporanox®)
  • erythromycin (several brand names exist. Please consult your healthcare provider to determine if you are taking this medicine)
  • rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®)
  • bosentan (Tracleer®)
  • phenobarbital, phenytoin (Dilantin®), carbamazepine (Tegretol®)
  • CIALIS® or other medicines or treatments for erectile dysfunction (impotence).
  • Adcirca is also marketed as CIALIS for the treatment of male erectile dysfunction (ED, impotence) and for the signs and symptoms of benign prostatic hyperplasia (BPH, enlarged prostate). Do not take both Adcirca and CIALIS. Do not take Adcirca and other medicines or treatments for erectile dysfunction.

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Adcirca?

  • Take Adcirca exactly as your healthcare provider tells you.
  • Take Adcirca tablets at the same time every day. You should take both tablets at the same time, one after the other, every day. Do not split your dose.
  • Adcirca can be taken with or without food.
  • Do not change your dose or stop taking Adcirca without speaking to your healthcare provider.
  • If you take too much Adcirca, call your healthcare provider or go to an emergency department right away.

What should I avoid while taking Adcirca?

Do not have more than 4 alcohol-containing drinks in a short period of time while you take Adcirca. Drinking too much alcohol can lower your blood pressure. You could get dizzy or faint.

What are the possible side effects of Adcirca?

The following side effects were reported rarely in patients taking tadalafil:

  • Decreased eyesight or loss of vision in one or both eyes (NAION). If you notice a sudden decrease or loss of vision in one or both eyes, contact a healthcare provider right away.
  • Sudden decrease or loss of hearing, sometimes with ringing in the ears and dizziness. If you notice a sudden decrease or loss of hearing, contact a healthcare provider right away.
  • In men, an erection that lasts more than 4 hours (with or without pain). Talk to your healthcare provider or go to the emergency department right away. An erection that lasts more than 4 hours must be treated as soon as possible or you can have lasting damage to your penis, including the inability to have erections.

See “What is the most important information I should know about Adcirca?”

The most common side effects with Adcirca include:

  • headache
  • muscle pain
  • getting red or hot in the face (flushing)
  • nausea
  • pain in the arms, legs, or back
  • upset stomach
  • stuffy or congested nose

Tell your healthcare provider about any side effect that bothers you or does not go away.

These are not all the possible side effects of Adcirca. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How Should I Store Adcirca?

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

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

General Information about the safe and effective use of Adcirca

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Adcirca for a condition for which it was not prescribed. Do not give Adcirca to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about Adcirca. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Adcirca that is written for healthcare professionals. For more information, go to www.Adcirca.com or call 1-800-LILLYRX (1-800-545-5979).

What Are The Ingredients In Adcirca?

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

Adcirca® (tadalafil) is a 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.

Revised 08/2017

Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285, USA

Marketed by: United Therapeutics Corporation

Copyright © 2009, 2017, Eli Lilly and Company. All rights reserved.

ADC-0003-PPI-20170801

Administration

Instructions

Erectile dysfunction (PRN use): Take before anticipated sexual activity

Erectile dysfunction (once-daily use): Take at approximately same time each day without regard to timing of sexual activity

Adcirca dosing information

Usual Adult Dose for Pulmonary Hypertension:

- 40 mg orally once a day

Comment: Dividing the 40 mg dose over the course of the day is not recommended.

What other drugs will affect Adcirca?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • medicines to treat erectile dysfunction or pulmonary arterial hypertension;

  • an antibiotic or antifungal medicine;

  • antiviral medicine to treat hepatitis C or HIV/AIDS;

  • drugs to treat high blood pressure or a prostate disorder; or

  • seizure medicine.

This list is not complete. Other drugs may interact with tadalafil, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

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