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Cialis

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Cialis

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.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The mechanism for reducing BPH symptoms has not been established.

Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, 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 (e.g., adrenal cortex). 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].

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

Mean Maximal Change in Blood Pressure - Illustration

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].

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 and WARNINGS AND PRECAUTIONS]. In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alpha-blocker. In two studies, a 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 5 and Figure 2).

Table 5: Doxazosin (8 mg/day) 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

Doxazosin Study 1: Mean Change from Baseline in Systolic Blood Pressure - Illustration

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 6 and Figure 3.

Table 6: Doxazosin (8 mg/day) 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

Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic Blood Pressure - Illustration

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 7.

Table 7: 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 8: Tamsulosin (0.4 mg/day) 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 9: 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 0.4 mg Tamsulosin Supine -0.1 (-2.2, 1.9) 
Standing 0.9 (-1.4, 3.2) 
Day 7 of 0.4 mg 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 10: Alfuzosin (10 mg/day) 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 QT c (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QT c (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

Plasma tadalafil concentrations - Illustration

Absorption

After single oral-dose administration, the maximum observed plasma concentration (C max ) 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.

Excretion

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 C max relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered [see Use In Specific Populations].

Pediatric

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

Patients with Diabetes Mellitus

In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and C max was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.

Patients with BPH

In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and C max ) were observed between elderly (70 to 85 years) and younger (&le60 years of age) subjects. No dose adjustment is warranted.

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 after stopping treatment.

Clinical Studies

CIALIS For Use As Needed For ED

The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24-weeks duration, involving over 4000 patients. CIALIS, when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

CIALIS was studied in the general ED population in 7 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the US. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve-sparing radical prostatectomy.

In these 7 trials, CIALIS was taken as needed, at doses ranging from 2.5 to 20 mg, up to once per day. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.

Several assessment tools were used to evaluate the effect of CIALIS on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at the end of a treatment-free baseline period and subsequently at follow-up visits after randomization. The IIEF EF domain has a 30point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into the partner's vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.

Results in ED Population in US Trials

The 2 primary US efficacy and safety trials included a total of 402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most ( > 90%) patients reported ED of at least 1-year duration. Study A was conducted primarily in academic centers. Study B was conducted primarily in community-based urology practices. In each of these 2 trials, CIALIS 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Table 11). The treatment effect of CIALIS did not diminish over time.

Table 11: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US Trials

Study A Study B
Placebo 
(N=49)
CIALIS 20 mg 
(N=146)
p-value Placebo
 (N=48)
CIALIS 20 mg 
(N=159)
p-value
EF Domain Score 
  Endpoint 13.5 19.5 13.6 22.5
  Change from baseline -0.2 6.9 < .001  0.3 9.3 < .001 
Insertion of Penis (SEP2) 
  Endpoint 39% 62% 43% 77%
  Change from baseline 2% 26% < .001  2% 32% < .001 
Maintenance of Erection (SEP3) 
  Endpoint 25% 50% 23% 64%
  Change from baseline 5% 34% < .001  4% 44% < .001 

Results in General ED Population in Trials Outside the US

The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 patients, with a mean age of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (90%) patients reported ED of at least 1-year duration. In these 5 trials, CIALIS 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 12, 13 and 14). The treatment effect of CIALIS did not diminish over time.

Table 12: Mean Endpoint and Change from Baseline for the EF Domain of the IIEF in the General ED Population in Five Primary Trials Outside the US

Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 20 mg
Study C 
Endpoint [Change from baseline] 15.0[0.7] 17.9 [4.0] 
p=.006  
20.0 [5.6] 
p < .001 
Study D 
Endpoint [Change from baseline] 14.4[1.1]  17.5 [5.1] 
p=.002 
20.6 [6.0] 
p < .001 
Study E 
Endpoint [Change from baseline] 18.1[2.6]  22.6 [8.1] 
p < .001 
25.0 [8.0] 
p < .001 
Study F
Endpoint [Change from baseline] 12.7 [-1.6]  22.8 [6.8] 
p < .001 
Study G 
Endpoint [Change from baseline] 14.5[-0.9]  21.2 [6.6] 
p < .001 
23.3 [8.0] 
p < .001 
aTreatment duration in Study F was 6 months

Table 13: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 2 (“Were you able to insert your penis into the partner's vagina?”) in the General ED Population in Five Pivotal Trials Outside the US

Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 20 mg
Study C 
  Endpoint [Change from baseline] 49% [6%] 

57% [15%] 
p=.063 

73% [29%] 
p < .001 
Study D 
  Endpoint [Change from baseline] 46% [2%]  56% [18%] 
p=.008 
68% [15%] 
p < .001 
Study E 
  Endpoint [Change from baseline] 55% [10%]  77% [35%] 
p < .001 
85% [35%] 
p < .001 
Study Fa 
  Endpoint [Change from baseline] 42% [-8%]  81% [27%] 
p < .001 
Study G 
  Endpoint [Change from baseline] 45% [-6%]  73% [21%] 
p < .001 
76% [21%] 
p < .001 
aTreatment duration in Study F was 6 months

Table 14: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 3 (“Did your erection last long enough for you to have successful intercourse?”) in the General ED Population in Five Pivotal Trials Outside the US

Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 20 mg
Study C 
  Endpoint [Change from baseline] 26%[4%]  38% [19%] 
p=.040 
58% [32%]
p < .001  
Study D 
  Endpoint [Change from baseline] 28%[4%]  42% [24%] 
p < .001 
51% [26%]
p < .001  
Study E 
  Endpoint [Change from baseline] 43%[15%]  70% [48%] 
p < .001 
78% [50%]
p < .001  
Study Fa 
  Endpoint [Change from baseline] 27% [1%]  74% [40%] 
p < .001 
Study G 
  Endpoint [Change from baseline] 32% [5%]  57% [33%]
p < .001  
62% [29%] 
p < .001 
aTreatment duration in Study F was 6 months

In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking CIALIS, compared to patients on placebo.

Therefore, in all 7 primary efficacy and safety studies, CIALIS showed statistically significant improvement in patients' ability to achieve an erection sufficient for vaginal penetration and to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire and by SEP diaries.

Efficacy Results in ED Patients with Diabetes Mellitus

CIALIS was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in all 7 primary efficacy studies in the general ED population (N=235) and in one study that specifically assessed CIALIS in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 15).

Table 15: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in ED Patients with Diabetes

Placebo
(N=71)
CIALIS 10 mg
(N=73)
CIALIS 20 mg
(N=72)
p-value
EF Domain Score
  Endpoint [Change from baseline] 12.2 [0.1] 19.3 [6.4] 18.7 [7.3] < .001
Insertion of Penis (SEP2)
  Endpoint [Change from baseline] 30% [-4%] 57% [22%] 54% [23%] < .001
Maintenance of Erection (SEP3)
  Endpoint [Change from baseline] 20% [2%] 48% [28%] 42% [29%] < .001

Efficacy Results in ED Patients following Radical Prostatectomy

CIALIS was shown to be effective in treating patients who developed ED following bilateral nerve-sparing radical prostatectomy. In 1 randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial in this population (N=303), CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 16).

Table 16: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in Patients who Developed ED Following Bilateral Nerve-Sparing Radical Prostatectomy

Placebo
(N=102)
CIALIS 20 mg
(N=201)
p-value
EF Domain Score
  Endpoint [Change from baseline] 13.3 [1.1] 17.7 [5.3] < .001
Insertion of Penis (SEP2)
  Endpoint [Change from baseline] 32% [2%] 54% [22%] < .001
Maintenance of Erection (SEP3)
  Endpoint [Change from baseline] 19% [4%] 41% [23%] < .001

Results in Studies to Determine the Optimal Use of CIALIS

Several studies were conducted with the objective of determining the optimal use of CIALIS in the treatment of ED. In one of these studies, the percentage of patients reporting successful erections within 30 minutes of dosing was determined. In this randomized, placebo-controlled, double-blinded trial, 223 patients were randomized to placebo, CIALIS 10, or 20 mg. Using a stopwatch, patients recorded the time following dosing at which a successful erection was obtained. A successful erection was defined as at least 1 erection in 4 attempts that led to successful intercourse. At or prior to 30 minutes, 35% (26/74), 38% (28/74), and 52% (39/75) of patients in the placebo, 10-, and 20-mg groups, respectively, reported successful erections as defined above.

Two studies were conducted to assess the efficacy of CIALIS at a given timepoint after dosing, specifically at 24 hours and at 36 hours after dosing.

In the first of these studies, 348 patients with ED were randomized to placebo or CIALIS 20 mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24 hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The results demonstrated a difference between the placebo group and the CIALIS group at each of the pre-specified timepoints. At the 24-hour timepoint, (more specifically, 22 to 26 hours), 53/144 (37%) patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the CIALIS 20-mg group. At the 36-hour timepoint (more specifically, 33 to 39 hours), 49/133 (37%) of patients reported at least 1 successful intercourse in the placebo group versus 88/137 (64%) in the CIALIS 20-mg group.

In the second of these studies, a total of 483 patients were evenly randomized to 1 of 6 groups: 3 different dosing groups (placebo, CIALIS 10, or 20 mg) that were instructed to attempt intercourse at 2 different times (24 and 36 hours post-dosing). Patients were encouraged to make 4 separate attempts at their assigned dose and assigned timepoint. In this study, the results demonstrated a statistically significant difference between the placebo group and the CIALIS groups at each of the pre-specified timepoints. At the 24-hour timepoint, the mean, per patient percentage of attempts resulting in successful intercourse were 42, 56, and 67% for the placebo, CIALIS 10-, and 20-mg groups, respectively. At the 36-hour timepoint, the mean, per-patient percentage of attempts resulting in successful intercourse were 33, 56, and 62% for placebo, CIALIS 10-, and 20-mg groups, respectively.

CIALIS For Once Daily Use For ED

The efficacy and safety of CIALIS for once daily use in the treatment of erectile dysfunction has been evaluated in 2 clinical trials of 12-weeks duration and 1 clinical trial of 24-weeks duration, involving a total of 853 patients. CIALIS, when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

CIALIS was studied in the general ED population in 2 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-and 24-weeks duration, respectively. One of these studies was conducted in the United States and one was conducted in centers outside the US. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. CIALIS was taken once daily at doses ranging from 2.5 to 10 mg. Food and alcohol intake were not restricted. Timing of sexual activity was not restricted relative to when patients took Cialis.

Results in General ED Population

The primary US efficacy and safety trial included a total of 287 patients, with a mean age of 59 years (range 25 to 82 years). The population was 86% W hite, 6% Black, 6% Hispanic, and 2% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most ( > 96%) patients reported ED of at least 1-year duration.

The primary efficacy and safety study conducted outside the US included 268 patients, with a mean age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0.4% Hispanic, and 10% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Ninety-three percent of patients reported ED of at least 1-year duration.

In each of these trials, conducted without regard to the timing of dose and sexual intercourse, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 17). When taken as directed, CIALIS was effective at improving erectile function.

In the 6 month double-blind study, the treatment effect of CIALIS did not diminish over time.

Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two CIALIS for Once Daily Use Studies

Study Ha Study Ib
Placebo
(N=94)
CIALIS 2.5 mg
(N=96)
CIALIS 5 mg
(N=97)
p-value Placebo
(N=54)
CIALIS 5 mg
(N=109)
p-value
EF Domain Score
  Endpoint 14.6 19.1 20.8 15.0 22.8
  Change from baseline 1.2 6.1c 7.0c < .001 0.9 9.7c < .001
Insertion of Penis (SEP2)
  Endpoint 51% 65% 71% 52% 79%
  Change from baseline 5% 24%c 26%c < .001 11% 37%c < .001
Maintenance of Erection (SEP3)
  Endpoint 31% 50% 57% 37% 67%
  Change from baseline 10% 31%c 35%c < .001 13% 46%c < .001
aTwenty-four-week study conducted in the US.
bTwelve-week study conducted outside the US.
cStatistically significantly different from placebo.

Efficacy Results in ED Patients with Diabetes Mellitus

CIALIS for once daily use was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in both studies in the general ED population (N=79). A third randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design trial included only ED patients with type 1 or type 2 diabetes (N=298). In this third trial, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 18).

Table 18: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a CIALIS for Once Daily Use Study in ED Patients with Diabetes

Placebo
(N=100)
CIALIS 2.5 mg
(N=100)
CIALIS 5 mg
(N=98)
p-value
EF Domain Score
  Endpoint 14.7 18.3 17.2
  Change from baseline 1.3 4.8a 4.5a < .001
Insertion of Penis (SEP2)
  Endpoint 43% 62% 61%
  Change from baseline 5% 21%a 29%a < .001
Maintenance of Erection (SEP3)
  Endpoint 28% 46% 41%
  Change from baseline 8% 26%a 25%a < .001
aStatistically significantly different from placebo.

CIALIS 5 mg For Once Daily Use For Benign Prostatic Hyperplasia (BPH)

The efficacy and safety of CIALIS for once daily use for the treatment of the signs and symptoms of BPH was evaluated in 3 randomized, multinational, double-blinded, placebo-controlled, parallel-design, efficacy and safety studies of 12 weeks duration. Two of these studies were in men with BPH and one study was specific to men with both ED and BPH [see Clinical Studies]. The first study (Study J) randomized 1058 patients to receive either CIALIS 2.5 mg, 5 mg, 10 mg or 20 mg for once daily use or placebo. The second study (Study K) randomized 325 patients to receive either CIALIS 5 mg for once daily use or placebo. The full study population was 87% W hite, 2% Black, 11% other races; 15% was of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.

The primary efficacy endpoint in the two studies that evaluated the effect of CIALIS for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Q max ), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study J and as a safety endpoint in Study K.

The results for BPH patients with moderate to severe symptoms and a mean age of 63.2 years (range 44 to 87) who received either CIALIS 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively.

In each of these 2 trials, CIALIS 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks.

Table 19: Mean IPSS Changes in BPH Patients in Two CIALIS for Once Daily Use Studies

Study J Study K
Placebo
(N=205)
CIALIS 5 mg
(N=205)
p-value Placebo
(N=164)
CIALIS 5 mg
(N=160)
p-value
Total Symptom Score (IPSS)
  Baseline 17.1 17.3 16.6 17.1
  Change from Baseline to Week 12 -2.2 -4.8 < .001 -3.6 -5.6 .004

Figure 5: Mean IPSS Changes in BPH Patients by Visit in Study J

Mean IPSS Changes in BPH Patients by Visit in Study J - Illustration

Figure 6: Mean IPSS Changes in BPH Patients by Visit in Study K

Mean IPSS Changes in BPH Patients by Visit in Study K - Illustration

In Study J, the effect of CIALIS 5 mg once daily on maximum urinary flow rate (Q max ) was evaluated as a secondary efficacy endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (CIALIS 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.

In Study K, the effect of CIALIS 5 mg once daily on Q max was evaluated as a safety endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (CIALIS 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.

Efficacy Results in Patients with BPH initiating CIALIS and Finasteride

CIALIS for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate ( > 30 cc) for up to 26 weeks. This additional double-blinded, parallel-design study of 26 weeks duration randomized 696 men to initiate either CIALIS 5 mg with finasteride 5 mg or placebo with finasteride 5 mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as erectile dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.

CIALIS with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see Table 20). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at week 4 (CIALIS -4.0, placebo -2.3: p < .001) and the score remained decreased through 26 weeks (CIALIS -5.5, placebo -4.5; p=.022). However, the magnitude of the treatment difference between placebo/finasteride and CIALIS/finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in Table 20 and in Figure 7. The incremental benefit of CIALIS beyond 26 weeks is unknown.

Table 20: Mean Total IPSS Changes in BPH Patients in a CIALIS for Once Daily Use Study Together with Finasteride

n Placebo and finasteride 5 mg
(N=350)a
n CIALIS 5mg and finasteride 5 mg
(N=345)a
Treatment difference p-valueb
Total Symptom Score (IPSS)
  Baselinec 349 17.4 344 17.1
  Change from Baseline to Week 4b 340 -2.3 330 -4.0 -1.7 < .001
  Change from Baseline to Week 12b 318 -3.8 317 -5.2 -1.4 .001
  Change from Baseline to Week 26b 295 -4.5 308 -5.5 -1.0 .022
aOverall ITT population.
bMixed model for repeated measurements.
cUnadjusted mean.

Figure 7: Mean Total IPSS Changes By Visit in BPH Patients Taking CIALIS for Once Daily Use Together With Finasteride

Mean Total IPSS Changes By Visit in BPH Patients - Illustration

In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. CIALIS with finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (CIALIS/finasteride 13.7, placebo/finasteride 15.1) was observed at week 4 (CIALIS/finasteride 3.7, placebo/finasteride -1.1; p < .001), week 12 (CIALIS/finasteride 4.7, placebo/finasteride 0.6; p < .001), and week 26 (CIALIS/finasteride 4.7, placebo/finasteride 0.0; p < .001).

CIALIS 5 mg For Once Daily Use For ED And BPH

The efficacy and safety of CIALIS for once daily use for the treatment of ED, and the signs and symptoms of BPH, in patients with both conditions was evaluated in one placebo-controlled, multinational, double-blind, parallel-arm study which randomized 606 patients to receive either CIALIS 2.5 mg, 5 mg, for once daily use or placebo. ED severity ranged from mild to severe and BPH severity ranged from moderate to severe. The full study population had a mean age of 63 years (range 45 to 83) and was 93% White, 4% Black, 3% other races; 16% were of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.

In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). Timing of sexual activity was not restricted relative to when patients took CIALIS.

The efficacy results for patients with both ED and BPH, who received either CIALIS 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8.

CIALIS 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. CIALIS 5 mg for once daily use also resulted in statistically significant improvement in SEP3. CIALIS 2.5 mg did not result in statistically significant improvement in the total IPSS.

Table 21: Mean IPSS and IIEF EF Domain Changes in the CIALIS 5 mg for Once Daily Use Study in Patients with ED and BPH

Placebo CIALIS 5 mg p-value
Total Symptom Score (IPSS)
(N=193) (N=206)
  Baseline 18.2 18.5
  Change from Baseline to Week 12 -3.8 -6.1 < .001
EF Domain Score (IIEF EF)
(N=188) (N=202)
  Baseline 15.6 16.5
  Endpoint 17.6 22.9
  Change from Baseline to Week 12 1.9 6.5 < .001

Table 22: Mean SEP Question 3 Changes in the CIALIS 5 mg for Once Daily Use Study in Patients with ED and BPH

Placebo
(N=187)
CIALIS 5 mg
(N=199)
p-value
Maintenance of Erection (SEP3)
Baseline 36% 43%
Endpoint 48% 72%
Change from Baseline to Week 12 12% 32% < .001

CIALIS for once daily use resulted in improvement in the IPSS total score at the first scheduled observation (week 2) and throughout the 12 weeks of treatment (see Figure 8).

Figure 8: Mean IPSS Changes in ED/BPH Patients by Visit in Study L

Mean IPSS Changes in ED/BPH Patients by Visit in Study L - Illustration

In this study, the effect of CIALIS 5 mg once daily on Q max was evaluated as a safety endpoint. Mean Q max increased from baseline in both the treatment and placebo groups (CIALIS 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.

Last reviewed on RxList: 5/19/2014
This monograph has been modified to include the generic and brand name in many instances.

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