Tadalafil 20 mg Tablet, Film Coated, 60-count — NDC 69097-526-03 (Billing 69097-0526-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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 tadalafil tablets 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 ) Effects on Blood Pressure The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1. a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination.

Some patients had symptoms associated with the decrease in blood pressure including syncope. Figur… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 (C max ) 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 tadalafil tablets 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

3.4L/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

1.6L/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 C max 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 C max 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 ).

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 wit… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 tadalafil tablets 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 ) Effects on Blood Pressure The effects of tadalafil on blood pressure alone and administered with antihypertensives, alcohol, and alpha-blockers is shown in Figure 1. a In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed, and dizziness occurred at a similar frequency to alcohol alone. b In studies of tadalafil co-administration with doxazosin, the number of subjects with potentially clinically significant standing blood pressure decreases was greater for the combination.

Some patients had symptoms associated with the decrease in blood pressure including syncope. Figure 1: Effects of Tadalafil on Blood Pressure 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 i… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Tadalafil Tablets 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 4). In the tadalafil 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 4: 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 5).

In patients taking only tadalafil 40 mg (i.e., without concomitant bosentan), the placebo-adjusted mean change in 6-MWD was 44 meters. In patients taking tadalafil 40 mg and concomitant bosentan therapy, the placebo adjusted mean change in 6-MWD was 23 meters. Figure 5: Placebo-adjusted Mean Change in 6-Minute Walk Distance (meters) of Tadalafil Tablets 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 tadalafil 40 mg group compared to the placebo group and the groups that used lower doses of tadalafil.

Table 2: Number (percent) with Clinical Worsening Subjects may be counted in more than one category Tadalafil 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 6. Figure 6: Kaplan-Meier Plot of Time to Clinical Worsening

14.2Long-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 m… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg. Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells.

Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays. Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥10 mg/kg/day.

Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg. There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

13.2Animal Toxicology and/or Pharmacology Animal studies showed vascular inflammation in tadalafil–treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1– to 17–fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1– and 6-month studies at unbound tadalafil exposure of 0.5– to 38–fold the human exposure (AUC) at the MRHD of 40 mg.

In a 12–month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4– to 10–fold the human exposure at the MRHD of 40 mg. The abnormal blood–cell findings were reversible within 2 weeks upon removal of the drug.