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. CIALIS inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by CIALIS has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that CIALIS 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 CIALIS is more potent on PDE5 than on other phosphodiesterases. These studies have shown that CIALIS 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. CIALIS is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, CIALIS is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. CIALIS is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. CIALIS 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, CIALIS 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
CIALIS 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, CIALIS (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.
A study was conducted to assess the degree of interaction between nitroglycerin and CIALIS, should nitroglycerin be required in an emergency situation after CIALIS 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 CIALIS 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 CIALIS (2, 4, 8, 24, 48, 72, and 96 hours after CIALIS). The objective of the study was to determine when, after CIALIS dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between CIALIS and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between CIALIS and NTG was not observed, although a few more CIALIS subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable
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
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 CIALIS with alpha-blocker agents in healthy male subjects
In four studies, a single oral dose of CIALIS 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 CIALIS.
Doxazosin — Three clinical pharmacology studies were conducted with CIALIS and doxazosin, an alpha[1]-adrenergic blocker.
In the first doxazosin study, a single oral dose of CIALIS 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 CIALIS or placebo after a minimum of seven days of doxazosin dosing
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after CIALIS or placebo administration.
Outliers were defined as subjects with a standing systolic blood pressure of 30 mm Hg at one or more time points. There were nine and three outliers following administration of CIALIS 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 CIALIS 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 CIALIS.
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 CIALIS 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily.
Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after CIALIS or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings 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 CIALIS and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of CIALIS or placebo. Of these, 5 and 2 were outliers due to systolic BP 30 mm Hg following CIALIS and placebo, respectively.
During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of CIALIS and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP 30 mm Hg, following CIALIS and placebo, respectively.
Some additional subjects in both the CIALIS 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 CIALIS (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 CIALIS 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 CIALIS 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).
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 CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP 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 CIALIS 5 mg alone, and another subject following coadministration of CIALIS 5 mg and doxazosin 4 mg.
Tamsulosin — In the first tamsulosin study, a single oral dose of CIALIS 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). CIALIS or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after CIALIS 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 CIALIS 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 CIALIS 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.
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 CIALIS 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 CIALIS 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).
CIALIS or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after CIALIS or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure 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 CIALIS 10 mg. There was no effect of CIALIS on amlodipine blood levels and no effect of amlodipine on CIALIS blood levels. The mean reduction in supine systolic/diastolic blood pressure due to CIALIS 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using CIALIS 20 mg, there were no clinically significant differences between CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 10 mg.
Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS, are mild systemic vasodilators. The interaction of CIALIS 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 CIALIS 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 CIALIS and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects.
When CIALIS 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.
CIALIS did not affect alcohol plasma concentrations and alcohol did not affect CIALIS plasma concentrations.
Effects on Exercise Stress Testing
The effects of CIALIS 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 (CIALIS 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that CIALIS was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received CIALIS followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by CIALIS 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 CIALIS 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 CIALIS 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 CIALIS for 6 months and the study of 20 mg CIALIS 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 CIALIS 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 CIALIS compared to placebo.
Effects on Cardiac Electrophysiology
The effect of a single 100-mg dose of CIALIS on the QT interval was evaluated at the time of peak CIALIS 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 CIALIS, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for CIALIS, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of CIALIS (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of CIALIS 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 CIALIS compared to placebo was 3.1 beats per minute.
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. CIALIS inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by CIALIS has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that CIALIS 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 CIALIS is more potent on PDE5 than on other phosphodiesterases. These studies have shown that CIALIS 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. CIALIS is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, CIALIS is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. CIALIS is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. CIALIS 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, CIALIS 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
CIALIS 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, CIALIS (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.
A study was conducted to assess the degree of interaction between nitroglycerin and CIALIS, should nitroglycerin be required in an emergency situation after CIALIS 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 CIALIS 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 CIALIS (2, 4, 8, 24, 48, 72, and 96 hours after CIALIS). The objective of the study was to determine when, after CIALIS dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between CIALIS and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between CIALIS and NTG was not observed, although a few more CIALIS subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable
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
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 CIALIS with alpha-blocker agents in healthy male subjects
In four studies, a single oral dose of CIALIS 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 CIALIS.
Doxazosin — Three clinical pharmacology studies were conducted with CIALIS and doxazosin, an alpha[1]-adrenergic blocker.
In the first doxazosin study, a single oral dose of CIALIS 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 CIALIS or placebo after a minimum of seven days of doxazosin dosing
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after CIALIS or placebo administration.
Outliers were defined as subjects with a standing systolic blood pressure of 30 mm Hg at one or more time points. There were nine and three outliers following administration of CIALIS 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 CIALIS 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 CIALIS.
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 CIALIS 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily.
Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after CIALIS or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings 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 CIALIS and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of CIALIS or placebo. Of these, 5 and 2 were outliers due to systolic BP 30 mm Hg following CIALIS and placebo, respectively.
During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of CIALIS and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP 30 mm Hg, following CIALIS and placebo, respectively.
Some additional subjects in both the CIALIS 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 CIALIS (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 CIALIS 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 CIALIS 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).
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 CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP 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 CIALIS 5 mg alone, and another subject following coadministration of CIALIS 5 mg and doxazosin 4 mg.
Tamsulosin — In the first tamsulosin study, a single oral dose of CIALIS 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). CIALIS or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after CIALIS 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 CIALIS 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 CIALIS 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.
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 CIALIS 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 CIALIS 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).
CIALIS or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after CIALIS or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure 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 CIALIS 10 mg. There was no effect of CIALIS on amlodipine blood levels and no effect of amlodipine on CIALIS blood levels. The mean reduction in supine systolic/diastolic blood pressure due to CIALIS 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using CIALIS 20 mg, there were no clinically significant differences between CIALIS 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 CIALIS 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 CIALIS 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 CIALIS 10 mg.
Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to CIALIS 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 CIALIS, are mild systemic vasodilators. The interaction of CIALIS 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 CIALIS 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 CIALIS and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects.
When CIALIS 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.
CIALIS did not affect alcohol plasma concentrations and alcohol did not affect CIALIS plasma concentrations.
Effects on Exercise Stress Testing
The effects of CIALIS 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 (CIALIS 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that CIALIS was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received CIALIS followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by CIALIS 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 CIALIS 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 CIALIS 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 CIALIS for 6 months and the study of 20 mg CIALIS 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 CIALIS 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 CIALIS compared to placebo.
Effects on Cardiac Electrophysiology
The effect of a single 100-mg dose of CIALIS on the QT interval was evaluated at the time of peak CIALIS 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 CIALIS, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for CIALIS, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of CIALIS (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of CIALIS 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 CIALIS compared to placebo was 3.1 beats per minute.
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