DRUG INTERACTIONS
7 CIALIS can potentiate the hypotensive effects of nitrates, alpha blockers, antihypertensives or alcohol ( 7.1 ).
CYP3A4 inhibitors (e.g.
ketoconazole, ritonavir) increase CIALIS exposure.
For concomitant use with potent CYP3A4 inhibitors, dose adjustment may be needed ( 2.7 , 5.10 , 7.2 ).
CYP3A4 inducers (e.g.
rifampin) decrease CIALIS exposure ( 7.2 ).
7.1 Potential for Pharmacodynamic Interactions with CIALIS Nitrates — Administration of CIALIS to patients who are using any form of organic nitrate, is contraindicated.
In clinical pharmacology studies, CIALIS was shown to potentiate the hypotensive effect of nitrates.
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 Dosage and Administration ( 2.7 ), Contraindications ( 4.1 ), and Clinical Pharmacology ( 12.2 )] .
Alpha-Blockers — Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers.
PDE5 inhibitors, including CIALIS, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects.
When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.
Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin.
[See Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( 12.2 )] .
Antihypertensives — PDE5 inhibitors, including tadalafil, are mild systemic vasodilators.
Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol).
Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo.
[See Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.2 )] .
Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators.
When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased.
Substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
[See Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.2 )] .
7.2 Potential for Other Drugs to Affect CIALIS [See Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.10 )] .
Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
H 2 Antagonists (e.g.
Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.
Cytochrome P450 Inhibitors — CIALIS is a substrate of and predominantly metabolized by CYP3A4.
Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.
CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and C max by 22%, relative to the values for tadalafil 20 mg alone.
Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and C max by 15%, relative to the values for tadalafil 10 mg alone [see Dosage and Administration ( 2.7 )] .
Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.
HIV Protease inhibitor — Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in C max , relative to the values for tadalafil 20 mg alone.
Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in C max , relative to the values for tadalafil 20 mg alone.
Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure [see Dosage and Administration ( 2.7 )] .
Cytochrome P450 Inducers — Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.
CYP3A4 (e.g., Rifampin) — Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and C max by 46%, relative to the values for tadalafil 10 mg alone.
Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure.
No dose adjustment is warranted.
The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of CIALIS for once daily use; the magnitude of decreased efficacy is unknown.
7.3 Potential for CIALIS to Affect Other Drugs Aspirin — Tadalafil did not potentiate the increase in bleeding time caused by aspirin.
Cytochrome P450 Substrates — CIALIS is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms.
Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
CYP1A2 (e.g.
Theophylline) — Tadalafil had no significant effect on the pharmacokinetics of theophylline.
When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.
CYP2C9 (e.g.
Warfarin) — Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.
CYP3A4 (e.g.
Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.
P-glycoprotein (e.g.
Digoxin) — Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.
OVERDOSAGE
10 Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients.
Adverse events were similar to those seen at lower doses.
In cases of overdose, standard supportive measures should be adopted as required.
Hemodialysis contributes negligibly to tadalafil elimination.
DESCRIPTION
11 CIALIS (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Tadalafil has the empirical formula C 22 H 19 N 3 O 4 representing a molecular weight of 389.41.
The structural formula is: The chemical designation is pyrazino[1´,2´:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-.
It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
CIALIS is available as almond-shaped tablets for oral administration.
Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
Chemical Structure
CLINICAL STUDIES
14 14.1 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 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 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 CIALIS 20 mg Placebo CIALIS 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 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 a Treatment duration in Study F was 6 months Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 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 a 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 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 a Treatment duration in Study F was 6 months Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 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 a 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 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 a Treatment duration in Study F was 6 months Placebo CIALIS 5 mg CIALIS 10 mg CIALIS 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 a 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 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 CIALIS 10 mg CIALIS 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 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 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 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.
14.2 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% White, 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 a Twenty-four-week study conducted in the US.
b Twelve-week study conducted outside the US.
c Statistically significantly different from placebo.
Study H a Study I b Placebo CIALIS 2.5 mg CIALIS 5 mg Placebo CIALIS 5 mg (N=94) (N=96) (N=97) p-value (N=54) (N=109) p-value EF Domain Score Endpoint 14.6 19.1 20.8 15.0 22.8 Change from baseline 1.2 6.1 c 7.0 c <.001 0.9 9.7 c <.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 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 a Statistically significantly different from placebo.
Placebo CIALIS 2.5 mg CIALIS 5 mg (N=100) (N=100) (N=98) p-value EF Domain Score Endpoint 14.7 18.3 17.2 Change from baseline 1.3 4.8 a 4.5 a <.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 14.3 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 ( 14.4 )] .
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% White, 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 CIALIS 5 mg Placebo CIALIS 5 mg (N=205) (N=205) p-value (N=164) (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 Figure 6: Mean IPSS Changes in BPH Patients by Visit in Study K 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.
Figure 5 Figure 6 14.4 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 20 and 21 and Figure 7 .
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 20: 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 21: Mean SEP Question 3 Changes in the CIALIS 5 mg for Once Daily Use Study in Patients with ED and BPH Placebo CIALIS 5 mg (N=187) (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 7 ).
Figure 7: Mean IPSS Changes in ED/BPH Patients by Visit in Study L 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.
Figure 7
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied CIALIS (tadalafil) is supplied as follows: Strengths of film-coated, almond-shaped tablets (not scored) are available in different sizes and different shades of yellow, and supplied in the following package sizes: 5-mg tablets debossed with “C 5” Bottles of 30 NDC 54868-5956-0 10-mg tablets debossed with “C 10” Bottles of 3 NDC 54868-4665-3 Bottles of 5 NDC 54868-4665-1 Bottles of 6 NDC 54868-4665-4 Bottles of 10 NDC 54868-4665-2 Bottles of 30 NDC 54868-4665-0 20-mg tablets debossed with “C 20” Bottles of 3 NDC 54868-4968-0 Bottles of 4 NDC 54868-4968-6 Bottles of 5 NDC 54868-4968-2 Bottles of 6 NDC 54868-4968-3 Bottles of 10 NDC 54868-4968-5 Bottles of 15 NDC 54868-4968-4 Bottles of 20 NDC 54868-4968-7 Bottles of 30 NDC 54868-4968-1 16.2 Storage Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Keep out of reach of children.
RECENT MAJOR CHANGES
Indications and Usage: Benign Prostatic Hyperplasia ( 1.2 ) 10/2011 Erectile Dysfunction and Benign Prostatic Hyperplasia ( 1.3 ) 10/2011 Dosage and Administration: Dosage and Administration ( 2 ) 10/2011 CIALIS for Once Daily Use for Benign Prostatic Hyperplasia ( 2.3 ) 10/2011 CIALIS for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia ( 2.4 ) 10/2011 Use in Specific Populations ( 2.6 ) 10/2011 Concomitant Medications ( 2.7 ) 10/2011 Warnings and Precautions: Warnings and Precautions ( 5 ) 10/2011 Alpha-blockers and Antihypertensives ( 5.6 ) 10/2011 Renal Impairment ( 5.7 ) 10/2011 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH ( 5.14 ) 10/2011
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects in ED clinical studies of tadalafil, approximately 25 percent were 65 and over, while approximately 3 percent were 75 and over.
Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over.
In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and ≥75 years of age) and younger subjects (≤65 years of age).
Therefore no dose adjustment is warranted based on age alone.
However, a greater sensitivity to medications in some older individuals should be considered.
[See Clinical Pharmacology ( 12.3 )] .
MECHANISM OF ACTION
12.1 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, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases.
These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs.
Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels.
Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction.
Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10.
Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11.
PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues (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.
INDICATIONS AND USAGE
1 CIALIS ® is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of: erectile dysfunction (ED) ( 1.1 ) the signs and symptoms of benign prostatic hyperplasia (BPH) ( 1.2 ) ED and the signs and symptoms of BPH (ED/BPH) ( 1.3 ) 1.1 Erectile Dysfunction CIALIS ® is indicated for the treatment of erectile dysfunction (ED).
1.2 Benign Prostatic Hyperplasia CIALIS is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
1.3 Erectile Dysfunction and Benign Prostatic Hyperplasia CIALIS is indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).
PEDIATRIC USE
8.4 Pediatric Use CIALIS is not indicated for use in pediatric patients.
Safety and efficacy in patients below the age of 18 years has not been established.
PREGNANCY
8.1 Pregnancy Pregnancy Category B — CIALIS (tadalafil) is not indicated for use in women.
There are no adequate and well controlled studies of CIALIS use in pregnant women.
Animal reproduction studies in rats and mice revealed no evidence of fetal harm.
Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis.
In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC.
Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC.
Surviving offspring had normal development and reproductive performance.
In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed.
The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day.
This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg.
Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
NUSRING MOTHERS
8.3 Nursing Mothers CIALIS is not indicated for use in women.
It is not known whether tadalafil is excreted into human milk.
While tadalafil or some metabolite of tadalafil was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk.
Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
Before prescribing CIALIS, it is important to note the following: Patients should not use CIALIS if sex is inadvisable due to cardiovascular status ( 5.1 ).
Use of CIALIS with alpha blockers, antihypertensives or substantial amounts of alcohol (≥5 units) may lead to hypotension ( 5.6 , 5.9 ).
CIALIS is not recommended in combination with alpha blockers for the treatment of BPH because efficacy of the combination has not been adequately studied and because of the risk of blood pressure lowering.
Caution is advised when CIALIS is used as a treatment for ED in men taking alpha blockers.
( 2.7 , 5.6 , 7.1 , 12.2 ) If taking potent inhibitors of CYP3A4, dose should be adjusted: CIALIS for use as needed: ≤10 mg every 72 hours.
For once daily use: dose not to exceed 2.5 mg ( 5.10 ).
Patients should seek emergency treatment if an erection lasts >4 hours.
Use CIALIS with caution in patients predisposed to priapism ( 5.3 ).
Patients should stop CIALIS and seek medical care if a sudden loss of vision occurs in one or both eyes, which could be a sign of Non Arteritic Ischemic Optic Neuropathy (NAION).
Discuss increased risk of NAION in patients with history of NAION ( 5.4 ).
Patients should stop CIALIS and seek prompt medical attention in the event of sudden decrease or loss of hearing ( 5.5 ).
Prior to initiating treatment with CIALIS for BPH, consideration should be given to other urological conditions that may cause similar symptoms ( 5.14 ).
5.1 Cardiovascular Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity.
Therefore, treatments for erectile dysfunction, including CIALIS, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status.
Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of CIALIS.
In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed 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.
Therefore, patients who experience anginal chest pain after taking CIALIS should seek immediate medical attention.
[See Contraindications ( 4.1 ) and Patient Counseling Information ( 17.1 )] .
Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for CIALIS, and therefore until further information is available, CIALIS is not recommended for the following groups of patients: myocardial infarction within the last 90 days unstable angina or angina occurring during sexual intercourse New York Heart Association Class 2 or greater heart failure in the last 6 months uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension stroke within the last 6 months.
As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure.
In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects [see Clinical Pharmacology ( 12.2 )] .
While this effect should not be of consequence in most patients, prior to prescribing CIALIS, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.
Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.
5.2 Potential for Drug Interactions When Taking CIALIS for Once Daily Use Physicians should be aware that CIALIS for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol [see Drug Interactions ( 7.1 , 7.2 , 7.3 )] .
5.3 Prolonged Erection There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds.
Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.
Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
CIALIS should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease).
5.4 Eye Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS, and seek medical attention in the event of a sudden loss of vision in one or both eyes.
Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.
It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors.
Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Adverse Reactions ( 6.2 )] .
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
5.5 Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including CIALIS, and seek prompt medical attention in the event of sudden decrease or loss of hearing.
These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including CIALIS.
It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1 , 6.2 )] .
5.6 Alpha-blockers and Antihypertensives Physicians should discuss with patients the potential for CIALIS to augment the blood-pressure-lowering effect of alpha blockers and antihypertensive medications [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] .
Caution is advised when PDE5 inhibitors are coadministered with alpha blockers.
PDE5 inhibitors, including CIALIS, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects.
When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.
In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] , which may lead to symptomatic hypotension (e.g., fainting).
Consideration should be given to the following: ED Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.
Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.
In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.
Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs.
[See Dosage and Administration ( 2.7 ) and Drug Interactions ( 7.1 )] .
BPH The efficacy of the co-administration of an alpha-blocker and CIALIS for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of CIALIS and alpha-blockers is not recommended for the treatment of BPH.
[See Dosage and Administration ( 2.7 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology (12.2.)] .
Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting CIALIS for once daily use for the treatment of BPH.
5.7 Renal Impairment CIALIS for Use as Needed CIALIS should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis.
The starting dose of CIALIS in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours.
[See Use in Specific Populations ( 8.7 )] .
CIALIS for Once Daily Use ED Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, CIALIS for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations ( 8.7 )] .
BPH and ED/BPH Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, CIALIS for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min.
In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response [see Dosage and Administration ( 2.6 ), Use in Specific Populations ( 8.7 ), and Clinical Pharmacology ( 12.3 )] .
5.8 Hepatic Impairment CIALIS for Use as Needed In patients with mild or moderate hepatic impairment, the dose of CIALIS should not exceed 10 mg.
Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended [see Use in Specific Populations ( 8.6 )] .
CIALIS for Once Daily Use CIALIS for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment.
Therefore, caution is advised if CIALIS for once daily use is prescribed to these patients.
Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended [see Use in Specific Populations ( 8.6 )] .
5.9 Alcohol Patients should be made aware that both alcohol and CIALIS, a PDE5 inhibitor, act as mild vasodilators.
When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased.
Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Clinical Pharmacology ( 12.2 )] .
5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4) CIALIS is metabolized predominantly by CYP3A4 in the liver.
The dose of CIALIS for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole [see Drug Interactions ( 7.2 )] .
In patients taking potent inhibitors of CYP3A4 and CIALIS for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration ( 2.7 )] .
5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies The safety and efficacy of combinations of CIALIS and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied.
Inform patients not to take CIALIS with other PDE5 inhibitors, including ADCIRCA.
5.12 Effects on Bleeding Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5.
PDE5 is found in platelets.
When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone.
CIALIS has not been administered to patients with bleeding disorders or significant active peptic ulceration.
Although CIALIS has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.
5.13 Counseling Patients About Sexually Transmitted Diseases The use of CIALIS offers no protection against sexually transmitted diseases.
Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
5.14 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH Prior to initiating treatment with CIALIS for BPH, consideration should be given to other urological conditions that may cause similar symptoms.
In addition, prostate cancer and BPH may coexist.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION “See FDA-approved Patient Labeling ( Patient Information )” 17.1 Nitrates Physicians should discuss with patients the contraindication of CIALIS with regular and/or intermittent use of organic nitrates.
Patients should be counseled that concomitant use of CIALIS with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of CIALIS.
In such a patient, who has taken CIALIS, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed 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.
Therefore, patients who experience anginal chest pain after taking CIALIS should seek immediate medical attention [see Contraindications ( 4.1 ) and Warnings and Precautions ( 5.1 )] .
17.2 Cardiovascular Considerations Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease.
Physicians should advise patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity and seek immediate medical attention [see Warnings and Precautions ( 5.1 )] .
17.3 Concomitant Use with Drugs Which Lower Blood Pressure Physicians should discuss with patients the potential for CIALIS to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] .
17.4 Potential for Drug Interactions When Taking CIALIS for Once Daily Use Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing CIALIS for once daily use, especially the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of cytochrome P450 3A4) and with substantial consumption of alcohol.
[See Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 , 7.2 ), Clinical Pharmacology ( 12.2 ), and Clinical Studies ( 14.2 )] .
17.5 Priapism There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds.
Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue.
Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
17.6 Vision Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS, and seek medical attention in the event of a sudden loss of vision in one or both eyes.
Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.
It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors.
Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators such as PDE5 inhibitors [see Clinical Studies ( 6.2 )] .
17.7 Sudden Hearing Loss Physicians should advise patients to stop taking PDE5 inhibitors, including CIALIS, and seek prompt medical attention in the event of sudden decrease or loss of hearing.
These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including CIALIS.
It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.1 , 6.2 )] .
17.8 Alcohol Patients should be made aware that both alcohol and CIALIS, a PDE5 inhibitor, act as mild vasodilators.
When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased.
Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] .
17.9 Sexually Transmitted Disease The use of CIALIS offers no protection against sexually transmitted diseases.
Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
17.10 Recommended Administration Physicians should instruct patients on the appropriate administration of CIALIS to allow optimal use.
For CIALIS for use as needed in men with ED, patients should be instructed to take one tablet at least 30 minutes before anticipated sexual activity.
In most patients, the ability to have sexual intercourse is improved for up to 36 hours.
For CIALIS for once daily use in men with ED or ED/BPH, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity.
Cialis is effective at improving erectile function over the course of therapy.
For CIALIS for once daily use in men with BPH, patients should be instructed to take one tablet at approximately the same time every day.
DOSAGE AND ADMINISTRATION
2 Do not split CIALIS tablets; entire dose should be taken.
CIALIS for use as needed: ED: Starting dose: 10 mg as needed prior to sexual activity.
Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability.
Improves erectile function compared to placebo up to 36 hours post dose.
Not to be taken more than once per day ( 2.1 ).
CIALIS for once daily use: ED: 2.5 mg taken once daily, without regard to timing of sexual activity.
May increase to 5 mg based upon efficacy and tolerability ( 2.2 ).
BPH: 5 mg, taken at approximately the same time every day ( 2.3 ) ED and BPH: 5 mg, taken at approximately the same time every day ( 2.3 , 2.4 ) CIALIS may be taken without regard to food ( 2.5 ).
2.1 CIALIS for Use as Needed for Erectile Dysfunction The recommended starting dose of CIALIS for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.
The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability.
The maximum recommended dosing frequency is once per day in most patients.
CIALIS for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing.
Therefore, when advising patients on optimal use of CIALIS, this should be taken into consideration.
2.2 CIALIS for Once Daily Use for Erectile Dysfunction The recommended starting dose of CIALIS for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
The CIALIS dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.
2.3 CIALIS for Once Daily Use for Benign Prostatic Hyperplasia The recommended dose of CIALIS for once daily use is 5 mg, taken at approximately the same time every day.
2.4 CIALIS for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia The recommended dose of CIALIS for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
2.5 Use with Food CIALIS may be taken without regard to food.
2.6 Use in Specific Populations Renal Impairment CIALIS for Use as Needed Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.
Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )] .
CIALIS for Once Daily Use Erectile Dysfunction Creatinine clearance less than 30 mL/min or on hemodialysis: CIALIS for once daily use is not recommended [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )] .
Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended.
An increase to 5 mg may be considered based on individual response.
Creatinine clearance less than 30 mL/min or on hemodialysis: CIALIS for once daily use is not recommended [see Warnings and Precautions ( 5.7 ) and Use in Specific Populations ( 8.7 )] .
Hepatic Impairment CIALIS for Use as Needed Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day.
The use of CIALIS once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.
Severe (Child Pugh Class C): The use of CIALIS is not recommended [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.6 )].
CIALIS for Once Daily Use Mild or moderate (Child Pugh Class A or B): CIALIS for once daily use has not been extensively evaluated in patients with hepatic impairment.
Therefore, caution is advised if CIALIS for once daily use is prescribed to these patients.
Severe (Child Pugh Class C): The use of CIALIS is not recommended [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.6 )].
2.7 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated [see Contraindications ( 4.1 )] .
Alpha Blockers ED — When CIALIS is coadministered with an alpha blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and CIALIS should be initiated at the lowest recommended dose [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] .
BPH — CIALIS is not recommended for use in combination with alpha blockers for the treatment of BPH [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 )] .
CYP3A4 Inhibitors CIALIS for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of CIALIS is 10 mg, not to exceed once every 72 hours [see Warnings and Precautions ( 5.10 ) and Drug Interactions ( 7.2 )] .
CIALIS for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg [see Warnings and Precautions ( 5.10 ) and Drug Interactions ( 7.2 )] .