Cialis

[tadalafil]

Effects on Blood Pressure when CIALIS is 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.

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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 2).

Figure 2: 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).

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

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Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N= 59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with CIALIS, reports of changes in color vision were rare (< 0.1% of patients).

Effects on Sperm Characteristics —

There were no clinically relevant effects on sperm concentration, sperm count, motility, or morphology in humans in placebo-controlled studies of daily doses of tadalafil 10 mg (N= 204) or 20 mg (N= 217) for 6 months. In addition, tadalafil had no effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone.

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.

Clinical Studies

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 daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

Study Design —

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 daily. 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 30-point 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 your 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.

Study Results —

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 1). The treatment effect of CIALIS did not diminish over time.

Table 1: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US Trials
Study A Study B Placebo CIALIS Placebo CIALIS

20 mg 20 mg (N= 49) (N= 146) p-value (N= 48) (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

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 2, 3, and 4).
The treatment effect of CIALIS did not diminish over time.

Table 2: 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 CIALIS CIALIS 5 mg 10 mg 20 mg

Study C Endpoint [Change from baseline] 15.0 [0.7] 17.9 [4.0] 20.0 [5.6]
p=. 006 p<. 001 Study D
Endpoint [Change from baseline] 14.4 [1.1] 17.5 [5.1] 20.6 [6.0] p=. 002 p<. 001
Study E Endpoint [Change from baseline] 18.1 [2.6] 22.6 [8.1] 25.0 [8.0]
p<. 001 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] 23.3 [8.0]
p<. 001 p<. 001 * Treatment duration in Study F was 6 months

Table 3: 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 CIALIS CIALIS

5 mg 10 mg 20 mg Study C
Endpoint [Change from baseline] 49% [6%] 57% [15%] 73% [29%] p=. 063 p<. 001
Study D Endpoint [Change from baseline] 46% [2%] 56% [18%] 68% [15%]
p=. 008 p<. 001 Study E
Endpoint [Change from baseline] 55% [10%] 77% [35%] 85% [35%] p<. 001 p<. 001
Study F* Endpoint [Change from baseline] 42% [-8%] 81% [27%]
p<. 001 Study G
Endpoint [Change from baseline] 45% [-6%] 73% [21%] 76% [21%] p<. 001 p<. 001
* Treatment duration in Study F was 6 months

Table 4: 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 CIALIS CIALIS

5 mg 10 mg 20 mg Study C
Endpoint [Change from baseline] 26% [4%] 38% [19%] 58% [32%] p=. 040 p<. 001
Study D Endpoint [Change from baseline] 28% [4%] 42% [24%] 51% [26%]
p<. 001 p<. 001 Study E
Endpoint [Change from baseline] 43% [15%] 70% [48%] 78% [50%] p<. 001 p<. 001
Study F* Endpoint [Change from baseline] 27% [1%] 74% [40%]
p<. 001 Study G
Endpoint [Change from baseline] 32% [5%] 57% [33%] 62% [29%] p<. 001 p<. 001
* Treatment 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 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 1 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 5).

Table 5: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in ED Patients with Diabetes
Placebo CIALIS CIALIS 10 mg 20 mg

(N= 71) (N= 73) (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 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 6).

Table 6: 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 CIALIS

20 mg (N= 102) (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

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 1 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.

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