CLINICAL PHARMACOLOGY
Mechanism of Action
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
Pharmacodynamics
Effects on Blood Pressure
Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.
Effects on Blood Pressure When Administered with Nitrates
In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of CIALIS in patients taking any form of nitrates is contraindicated [see Contraindications (4.1)].
A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable (see Figure 1).
 Figure 1: Mean Maximal Change in Blood Pressure (Tadalafil Minus Placebo, Point Estimate with 90% CI) in Response to Sublingual Nitroglycerin at 2 (Supine Only), 4, 8, 24, 48, 72, and 96 Hours after the Last Dose of Tadalafil 20 mg or Placebo
Therefore, CIALIS administration with nitrates is contraindicated. In a patient who has taken CIALIS, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of CIALIS before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications (4.1)].
Effect on Blood Pressure When Administered With Alpha Blockers
Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)]. In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) oral alpha blocker. In two studies, daily oral alpha blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil.
Doxazosin — Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha[1]-adrenergic blocker.
In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects). Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing (see Table 4 and Figure 2).
Table 4: Doxazosin Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) | Tadalafil 20 mg |
| Supine | 3.6 (-1.5, 8.8) |
| Standing | 9.8 (4.1, 15.5) |
 Figure 2: Doxazosin Study 1: Mean Change from Baseline in Systolic Blood Pressure
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Outliers were defined as subjects with a standing systolic blood pressure of <85 mm Hg or a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. No such events were reported following placebo. Two such events were reported following administration of tadalafil. Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days. This subject previously experienced a mild episode of vertigo on doxazosin and placebo. Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day. No syncope was reported.
In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily. The study (N=72 subjects) was conducted in three parts, each a 3-period crossover.
In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m. In this part, tadalafil or placebo were administered at either 8 a.m. or 8 p.m.
The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 5 and Figure 3.
Table 5: Doxazosin Study 2 (Part C): Mean Maximal Decrease in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) | Tadalafil 20 mg at 8 a.m. | Tadalafil 20 mg at 8 p.m. |
| Ambulatory Blood-Pressure Monitoring (ABPM) | 7 | 8 |
 Figure 3: Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic Blood Pressure
Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings of <85 mm Hg were recorded or one or more decreases in systolic blood pressure of >30 mm Hg from a time-matched baseline occurred during the analysis interval.
Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of tadalafil or placebo. Of these, 5 and 2 were outliers due to systolic BP <85 mm Hg, while 15 and 4 were outliers due to a decrease from baseline in systolic BP of >30 mm Hg following tadalafil and placebo, respectively.
During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of tadalafil and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP <85 mm Hg, while 15 and 5 subjects were outliers due to a decrease from baseline in systolic BP of >30 mm Hg, following tadalafil and placebo, respectively.
Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the period beyond 24 hours.
Severe adverse events potentially related to blood-pressure effects were assessed. In the study (N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and dizziness in another subject that began 11 hours after dosing and lasted 2 minutes). No such events were reported following placebo. In the period prior to tadalafil dosing, one severe event (dizziness) was reported in a subject during the doxazosin run-in phase.
In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. After 7 days, doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin). The results are shown in Table 6.
Table 6: Doxazosin Study 3: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure | Tadalafil 5 mg |
| Day 1 of 4 mg Doxazosin | Supine | 2.4 (-0.4, 5.2) |
| Standing | -0.5 (-4.0, 3.1) |
| Day 7 of 4 mg Doxazosin | Supine | 2.8 (-0.1, 5.7) |
| Standing | 1.1 (-2.9, 5.0) |
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4 mg), as well as on the seventh day of 4 mg doxazosin administration.
Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier on placebo due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There was one outlier on tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP <85 mm Hg. Following the seventh day of doxazosin 4 mg, there were no outliers on tadalafil 5 mg, one subject on placebo had a decrease >30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure <85 mm Hg. All adverse events potentially related to blood pressure effects were rated as mild or moderate. There were two episodes of syncope in this study, one subject following a dose of tadalafil 5 mg alone, and another subject following coadministration of tadalafil 5 mg and doxazosin 4 mg.
Tamsulosin — In the first tamsulosin study, a single oral dose of tadalafil 10, 20 mg, or placebo was administered in a 3 period, crossover design to healthy subjects taking 0.4 mg once per day tamsulosin, a selective alpha[1A]-adrenergic blocker (N=18 subjects). Tadalafil or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Table 7: Tamsulosin Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) | Tadalafil 10 mg | Tadalafil 20 mg |
| Supine | 3.2 (-2.3, 8.6) | 3.2 (-2.3, 8.7) |
| Standing | 1.7 (-4.7, 8.1) | 2.3 (-4.1, 8.7) |
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points) following administration of tadalafil 10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood-pressure effects were reported. No syncope was reported.
In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of tamsulosin 0.4 mg was added for the last seven days of each period.
Table 8: Tamsulosin Study 2: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure | Tadalafil 5 mg |
| Day 1 of Tamsulosin | Supine | -0.1 (-2.2, 1.9) |
| Standing | 0.9 (-1.4, 3.2) |
| Day 7 of Tamsulosin | Supine | 1.2 (-1.2, 3.6) |
| Standing | 1.2 (-1.0, 3.5) |
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin administration. There were no outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day 7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood pressure were reported. No syncope was reported.
Alfuzosin — A single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking once-daily alfuzosin HCl 10 mg extended-release tablets, an alpha[1]-adrenergic blocker (N=17 completed subjects). Tadalafil or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Table 9: Alfuzosin Study: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure | Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) | Tadalafil 20 mg |
| Supine | 2.2 (-0.9,-5.2) |
| Standing | 4.4 (-0.2, 8.9) |
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure <85 mm Hg) following administration of tadalafil 20 mg. There were no subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. No severe adverse events potentially related to blood pressure effects were reported. No syncope was reported.
Effects on Blood Pressure When Administered with Antihypertensives
Amlodipine — A study was conducted to assess the interaction of amlodipine (5 mg daily) and tadalafil 10 mg. There was no effect of tadalafil on amlodipine blood levels and no effect of amlodipine on tadalafil blood levels. The mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using tadalafil 20 mg, there were no clinically significant differences between tadalafil and placebo in subjects taking amlodipine.
Angiotensin II receptor blockers (with and without other antihypertensives) — A study was conducted to assess the interaction of angiotensin II receptor blockers and tadalafil 20 mg. Subjects in the study were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.
Bendrofluazide — A study was conducted to assess the interaction of bendrofluazide (2.5 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking bendrofluazide was 6/4 mm Hg, compared to placebo.
Enalapril — A study was conducted to assess the interaction of enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.
Metoprolol — A study was conducted to assess the interaction of sustained-release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to placebo.
Effects on Blood Pressure When Administered with Alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of tadalafil with alcohol was evaluated in 3 clinical pharmacology studies. In 2 of these, alcohol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in one study and 20 mg in another. In both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of these two studies, blood alcohol levels of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of alcohol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to alcohol alone, and the hypotensive effects of alcohol were not potentiated.
Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Effects on Exercise Stress Testing
The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.
Effects on Vision
Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupilometry. Across all clinical studies with CIALIS, reports of changes in color vision were rare (<0.1% of patients).
Effects on Sperm Characteristics
Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Effects on Cardiac Electrophysiology
The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide) -controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.
Pharmacokinetics
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1.6-fold greater than after a single dose. Mean tadalafil concentrations measured after the administration of a single oral dose of 20 mg and single and once daily multiple doses of 5 mg, from a separate study, (see Figure 4) to healthy male subjects are depicted in Figure 4.
 Figure 4: Plasma tadalafil concentrations (mean ± SD) following a single 20-mg tadalafil dose and single and once daily multiple doses of 5 mg
Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food; thus CIALIS may be taken with or without food.
Distribution — The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Elimination — The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Geriatric — Healthy male elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered [see Use in Specific Populations (8.5)].
Pediatric — Tadalafil has not been evaluated in individuals less than 18 years old [see Use in Specific Populations (8.4)].
Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats, respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20 mg.
Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.
There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 14-fold for males or 26-fold for females the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20-100% of the dogs that resulted in a decrease in spermatogenesis in 40-75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 20 mg.
There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
Animal Toxicology and/or Pharmacology
Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks upon removal of the drug.
Reproductive Toxicology Studies
Reproduction studies have been performed in rats and mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg and have revealed no evidence of impaired fertility or harm to the fetus due to tadalafil. In addition, there was no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the MRHD during the period of major organ development.
In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.
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