THE EFFICACY AND SAFETY OF TADALAFIL IN UNITED STATES AND PUERTO RICAN MEN WITH ERECTILE DYSFUNCTION

0022-5347/04/1722-0652/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 172, 652– 657, August 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000132857.39680.ce

THE EFFICACY AND SAFETY OF TADALAFIL IN UNITED STATES AND PUERTO RICAN MEN WITH ERECTILE DYSFUNCTION ALLEN D. SEFTEL,*, † STEVEN K. WILSON,‡ PETER M. KNAPP, JANEY SHIN,§ W. CHRISTINE WANG§ AND SANJEEV AHUJA§ From the University Hospitals, Case Western Reserve University, Cleveland VA Medical Center, Cleveland, Ohio (ADS), University of Arkansas for Medical Sciences, Van Buren, Arkansas (SKW), Indiana University and Urology of Indiana, Indianapolis, Indiana (PMK), and Eli Lilly and Company, Toronto, Ontario, Canada, (JS) and Indianapolis, Indiana (WCW, SA)

ABSTRACT

Purpose: We evaluate the efficacy and safety of tadalafil, taken as needed, in men with mild to severe erectile dysfunction (ED) and assess sexual intercourse attempt patterns. Materials and Methods: In this multicenter, double-blind, placebo controlled, parallel study conducted in the United States and Puerto Rico 207 men with ED were randomized to placebo or 20 mg tadalafil for 12 weeks. The primary efficacy variables were changes from baseline in the mean International Index of Erectile Function erectile function domain score and mean per patient percentage of “yes” responses to Sexual Encounter Profile (SEP) diary questions 2 (successful penetration) and 3 (successful intercourse). The Global Assessment Question was a secondary end point and post hoc analyses on sexual intercourse attempt patterns were conducted. Results: Men treated with tadalafil compared with placebo reported greater mean changes from baseline on the erectile function domain score (9.3 vs 0.3 with placebo, p ⬍0.001) and on the mean per patient percentage of successful penetration (SEP question 2, 31.6% vs 2.3% with placebo, p ⬍0.001) and successful intercourse attempts (SEP question 3, 43.6% vs 3.5% with placebo, p ⬍0.001). The per treatment group percentage of successful intercourse attempts during treatment was higher for tadalafil than placebo (67.6% vs 24.1%, respectively, p ⬍0.001) and most successful intercourse attempts occurred between 4 and 36 hours after taking tadalafil. Of the men treated with tadalafil 82.8% reported improved erections versus 19.6% taking placebo (Global Assessment Question, p ⬍0.001). The most common treatment emergent adverse events were headache (15.7% vs 6.3% with placebo), back pain (8.8% vs 0%), and dyspepsia (7.5% vs 0%). Conclusions: Tadalafil (20 mg) significantly improved erectile function and patients did not closely temporally link sexual intercourse attempts with taking tadalafil. Tadalafil was also well tolerated in both groups of men with mild to severe ED. KEY WORDS: impotence, phosphodiesterase inhibitors, treatment outcome, safety

The first approved orally active phosphodiesterase type 5 (PDE5) inhibitor, sildenafil, altered how clinicians treat erectile dysfunction (ED). Unlike older treatment options, sildenafil was discrete and noninvasive, and it quickly became the preferred treatment choice for patients. Despite these advances, patients report dissatisfaction with sildenafil and early treatment discontinuation rates for the drug range from 14% to as high as 47%.1 A perceived lack of consistent efficacy is the most commonly cited reason for patient dissatisfaction and discontinuation.1 Inadequate dosing or patient failure to follow the dosing instructions may underlie the perceived lack of efficacy.2 For an optimal response to sildenafil, patients should be instructed to attempt sexual intercourse approximately 1 hour or within 30 minutes to 4 hours

after dosing, and be informed that a high-fat meal may delay the effect of the drug.3 Tadalafil is a PDE5 inhibitor approved for the treatment of ED in Europe and in the United States. Tadalafil and other PDE5 inhibitors enhance the nitric oxide signaling pathway by inhibiting hydrolysis of cyclic guanosine monophosphate which ultimately results in cavernosal smooth muscle relaxation needed for an erection.4 However, the pharmacokinetic properties of tadalafil differ significantly from sildenafil. It has a 17.5-hour half-life that allows patients to have successful sexual intercourse up to 36 hours after dosing and tadalafil may be taken without food restrictions.5 In past clinical trials of tadalafil patients were informed of the extended period of drug effectiveness but were not made aware of its dosing implications, namely the flexibility in the time between taking tadalafil and initiating sexual activity.6 In this study we presented to patients possible scenarios for taking tadalafil, which demonstrated that tadalafil could be taken well in advance of potential sexual activity. We evaluated the efficacy and safety of tadalafil in United States and Puerto Rican men with mild to severe ED of broad-spectrum etiology. Because patients were made explicitly aware of the flexibility of dose timing for tadalafil relative to attempting sexual intercourse, we also assessed the sexual intercourse attempt patterns of the patients.

Accepted for publication March 19, 2004. Supported by Lilly ICOS LLC (Bothell, Washington and Indianapolis, Indiana). Study received ethical review board approval. * Correspondence: Department of Urology, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, Ohio 44106-5046 (telephone: 216-844-7632; FAX: 216-844-4846; e-mail: [email protected]). † Financial interest and/or other relationship with Pfizer, Bayer, Lilly, ICOS, Sanofi, QLT and Auxilium. ‡ Financial interest and/or other relationship with American Medical Systems, ICOS, Mentor and AMT. § Financial interest and/or other relationship with Eli Lilly and Company. 652

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EFFICACY AND SAFETY OF TADALAFIL MATERIALS AND METHODS

Study design. This double-blind, randomized, parallel, placebo controlled study was conducted at 21 centers in the United States and Puerto Rico from December 2001 to May 2002. After a 4-week treatment-free run-in period, patients completed the International Index of Erectile Function (IIEF) questionnaire.7 Their score on the erectile function (EF) domain of the IIEF (sum of questions 1 to 5 and 15) determined the baseline ED severity (mild, moderate, severe).8 Within each severity group patients were randomly allocated in a 3:1 ratio to treatment with either 20 mg tadalafil or placebo for 12 weeks. During the treatment phase patients returned for a study visit every 4 weeks until they completed or discontinued the study. Patients were instructed to take 1 tablet of the study drug as needed before sexual intercourse (maximum of once daily) without regard to food. The dosing instructions also highlighted the study period of drug effectiveness (see Appendix). Only the 20 mg dose of tadalafil was dose used in the study. Dosage adjustments were not permitted. The tadalafil and placebo tablets were identical to maintain blinding. Patients, site personnel and sponsor remained blinded to the randomization assignment until the database was locked for analysis. Ethical review boards approved the study protocol and patients provided written informed consent for study participation. Study population. Men 18 years old or older with a minimum 3-month history of ED of broad-spectrum etiology or severity were eligible for study. ED was defined as a consistent change in the quality of erection that adversely affected satisfaction with sexual intercourse. Patients were also in a stable relationship with a female partner, and those who made at least 4 attempts at sexual intercourse during the run-in period were randomly allocated to treatment. Patients with clinically significant penile deformities or penile implants, a recent history of stroke or spinal cord trauma, a history of unstable cardiovascular disease (unstable angina, myocardial infarction or myocardial revascularization within the prior 90 days), systolic blood pressure greater than 170 or less than 90 mm Hg or diastolic blood pressure greater than 100 or less than 50 mm Hg, or clinically significant renal or hepatic insufficiency, and those who failed to achieve any erection following radical prostatectomy or pelvic surgery or who were receiving nitrates, antiandrogens or chemotherapy were excluded from study. Patients who received prior ineffective treatment with sildenafil, in the opinion of the study investigator, were also not eligible for the study. Efficacy measures. The efficacy of tadalafil was measured with the IIEF EF domain (score 26 or greater represents no ED and the maximal score is 30),7 and questions 2 and 3 of the Sexual Encounter Profile (SEP) diary (question 2: Were you able to insert your penis into your partner’s vagina? [yes/no] and question 3: Did your erection last long enough for you to have successful intercourse? [yes/no]). The IIEF was administered after the run-in period (baseline) and at 4-week intervals during treatment (post-baseline). Patients completed the SEP diary after each sexual intercourse attempt throughout the study. Secondary efficacy measures included the intercourse satisfaction and overall satisfaction domains of the IIEF, the percentage of “yes” responses to SEP question 4 (Were you satisfied with the hardness of your erection? [yes/no]), and the Global Assessment Question ([GAQ], Has the treatment you have been taking during this study improved your erections? [yes/no]). Patients answered the GAQ at the end of the study or at the discontinuation visit. Safety. Safety was assessed by evaluating the incidence of adverse events and any changes in laboratory results or vital

signs. At the screening and last study visits a full physical examination and clinical laboratory tests were performed. Additionally at the screening visit a 12-lead electroencephalogram was done. Study personnel recorded concomitant medication use, blood pressure and pulse at every visit. The date of onset or resolution of any adverse event was recorded at each study visit. Treatment emergent adverse events (events that first occurred or worsened after baseline) were summarized by the Medical Dictionary for Regulatory Activities, and severity and possible relationship to study drug were noted. Statistical analyses. The co-primary efficacy variables were mean change from baseline to end point in the IIEF EF domain score and mean changes from baseline to the postbaseline period in the per patient percentage of “yes” responses to SEP questions 2 and 3. The null hypothesis was that tadalafil and placebo did not differ on all 3 co-primary efficacy variables. To reject the null hypothesis a significance of 0.05 was required (2-tailed). A sample size of 210 patients was calculated to give greater than 90% power to detect a significant treatment effect in each of the 3 co-primary efficacy variables at ␣-0.05. All analyses were conducted on an intent-to-treat basis. Efficacy analyses included all patients who had a baseline measurement and at least 1 post-baseline measurement. The scores on the IIEF domains were analyzed using the last observation carried forward convention. For each SEP question the baseline and post-baseline scores were the percentage of “yes” responses relative to the number of sexual encounters during the run-in and treatment periods, respectively. The co-primary efficacy variables (IIEF EF domain, SEP questions 2 and 3), IIEF intercourse satisfaction and overall satisfaction domains, and SEP question 4 were analyzed using analysis of covariance (ANCOVA) models, including terms for baseline efficacy value, treatment group, pooled site and baseline-by-treatment group interaction (if p ⬍0.10). Logistic regression was used to evaluate the GAQ using the same terms as in the ANCOVA model. Only patients who responded to the GAQ were included in the analysis. Additional post hoc efficacy analyses included 1) mean change from baseline in the IIEF EF domain score by baseline ED severity, 2) percentage of patients who attained an EF domain score of 26 or greater at end point by baseline ED severity, 3) post-baseline percentage of “yes” responses to SEP question 3 by treatment group, and 4) mean post-baseline per patient percentage of successful intercourse attempts (SEP question 3) by response to the GAQ and by IIEF EF domain scores 26 or greater (no ED), respectively. Sexual intercourse attempt patterns by treatment group were also investigated, including 1) average number of intercourse attempts per week and the average number of intercourse attempts per dose, 2) percentage of intercourse attempts and percentage of successful intercourse attempts at selected intervals after dosing, and 3) percentage of intercourse attempts occurring between 4 and 36 hours after dosing by each 4-week segment of the treatment phase. Safety analyses included all randomized patients. The incidence of treatment emergent adverse events between treatment groups was compared using Fisher’s exact test. Changes in continuous laboratory analytes or vital signs were evaluated by a ranked ANOVA model with a term for treatment group. RESULTS

Patient demographics. Of the 239 men screened for the study 207 were randomized to treatment (tadalafil 159 and placebo 48). A majority of patients (176 [85.0%]) completed

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EFFICACY AND SAFETY OF TADALAFIL

the study. Of the 8 placebo treated patients who discontinued early 5 discontinued due to a perceived lack of efficacy. In comparison, 23 patients discontinued tadalafil early and the most common reasons for discontinuation were adverse events (8) and loss to followup (5) (fig. 1). The treatment groups were well balanced across all baseline characteristics (table 1). Mean patient age ⫾ SD was 59 ⫾ 10 years and 73% self-reported that they were white. Approximately 43% of patients had severe ED and the mean baseline IIEF EF domain score was 13.2. The most prevalent ED etiology was organic and the most common comorbid conditions were hypertension and benign prostatic hyperplasia. Of the patients 167 (81%) had and 40 (19%) had not taken sildenafil. Efficacy. Patients treated with tadalafil reported a significantly greater change from baseline on the IIEF EF domain score compared to those taking placebo (20 mg tadalafil 9.3, placebo 0.3, p ⬍0.001, table 2). Tadalafil was also significantly superior to placebo in increasing the mean per patient percentage of successful penetration (SEP question 2) and successful intercourse attempts (SEP question 3) between the baseline and post-baseline periods (p ⬍0.001 for both, table 2). On the IIEF intercourse satisfaction and overall satisfaction domains patients treated with tadalafil reported significantly more improvement on both domains compared to

their counterparts treated with placebo (p ⬍0.001 for both, table 2). The change from baseline in the mean per patient percentage of satisfaction with erectile hardness (SEP question 4) was also significantly greater for patients treated with tadalafil (43.8%) compared to placebo (5.6%, p ⬍0.001, table 2). At study end 82.8% of patients treated with tadalafil reported improved erections as measured by the GAQ compared to 19.6% of those treated with placebo (p ⬍0.001, table 2). Patients receiving tadalafil reported improvement from baseline on the IIEF EF domain score, regardless of baseline ED severity. The improvement ranged from a mean change score of 5.6 for patients with mild ED to 11.0 for those with severe ED (fig. 2). Overall, 50% of patients receiving tadalafil attained an IIEF EF domain score of 26 or greater (no ED) at the end of treatment compared to 8.5% of patients receiving placebo. Furthermore, among patients treated with tadalafil 72.1%, 52.4% and 34.3% with mild, moderate and severe ED at baseline, respectively, attained an IIEF EF domain score of 26 or greater at end point (fig. 3). After baseline 67.6% (3,371 of 4,990) of all sexual intercourse attempts were successful for patients receiving tadalafil compared to 24.1% (262 of 1,089) of placebo treated patients (p ⬍0.001). Of the patients who reported improved erections on the GAQ mean per patient percentage of successful intercourse

FIG. 1. Study flow diagram. For patients treated with tadalafil the adverse events resulting in discontinuation of the study were headache (2), back pain (1), herpes zoster (1), chest pain (1), back injury (1), penile disorder (1) and coronary artery disease (1). One placebo treated patient discontinued the study because of headache.

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EFFICACY AND SAFETY OF TADALAFIL TABLE 1. Demographic and baseline characteristics of patients with ED No. Placebo (%)

No. 20 Mg Tadalafil (%)

Total pts 48 159 ED duration 12 mos 47 (97.9) 148 (93.1) or greater ED etiology:* Organic 24 (50.0) 94 (59.1) Psychogenic 4 (8.3) 16 (10.1) Mixed 20 (41.7) 49 (30.8) IIEF erectile function severity: No ED (26–30)† 1 (2.1) 5 (3.1) Mild (17–25) 15 (31.3) 43 (27.0) Moderate (11–16) 12 (25.0) 42 (26.4) Severe (1–10) 20 (41.7) 69 (43.4) Ethnicity: White 36 (75.0) 115 (72.3) African descent 4 (8.3) 22 (13.8) Hispanic 7 (14.6) 19 (11.9) Asian 1 (2.1) 2 (1.3) Other 0 (0) 1 (0.6) Comorbid conditions:‡ Hypertension 18 (37.5) 57 (35.9) Benign prostatic 13 (27.1) 45 (28.3) hyperplasia Diabetes mellitus 7 (14.6) 29 (18.2) Hyperlipidemia 11 (22.9) 26 (16.4) Depression 1 (2.1) 12 (7.6) Coronary artery 3 (6.3) 7 (4.4) disease Peripheral vascular 1 (2.1) 0 (0) disease * The cause of ED was determined by the investigators based on patient history, physical examination findings and any previous diagnostic testing. † Medical history and the investigator assessment of the history and condition took precedence over IIEF EF domain scores and, therefore, patients who scored 26 –30 (normal) on the IIEF EF domain are considered to have mild ED. ‡ Comorbid conditions include patients with either a history or ongoing comorbid conditions when entering the study.

attempts (SEP question 3) was 73.4% for those treated with tadalafil and 47.1% for placebo treated patients (p ⫽ 0.003). Of the patients who attained an IIEF EF domain score of 26 or greater at end point mean per patient percentage of successful intercourse attempts was 86.3% for those receiving tadalafil and 66.1% for placebo treated patients (p ⫽ 0.039). Sexual intercourse attempt patterns. After baseline average number of sexual intercourse attempts per week was 2.8 for patients treated with tadalafil and 2.0 for placebo treated patients (table 3). This difference was marginally significant (p ⫽ 0.053) after controlling for the baseline number of sexual intercourse attempts per week. Average number of attempts per dose was 0.99 for patients treated with tadalafil and 0.86 for those on placebo. Of the patients 64 treated with tadalafil and 12 treated with placebo averaged more than 1 attempt per dose. Average number of attempts was 1.4 per dose for patients treated with tadalafil and 1.3 per dose for placebo treated patients (p ⫽ 0.61, table 3).

FIG. 2. Mean change from baseline IIEF erectile function domain scores by baseline severity. Population summarized consists of those patients having baseline and post-baseline data on IIEF EF domain. Six patients (3%) who scored 26 –30 on baseline IIEF EF domain (no ED) were included in analysis and were considered to have mild ED for this purpose.

FIG. 3. Percent of patients attaining IIEF erectile function domain scores 26 or greater at end point.

Among patients treated with tadalafil 55.2% of intercourse attempts (2,446 of 4,433) occurred between 4 and 36 hours after taking the drug, whereas among patients treated with placebo 34.8% (350 of 1,005) of attempts occurred between this interval after dosing (p ⫽ 0.001). Within each 4-week segment of the treatment phase the percentage of intercourse attempts occurring between 4 and 36 hours after dosing ranged from 54.5% (817 of 1,500) in the first 4 weeks of treatment, 52.5% (723 of 1,376) in the second and 58.2% (906 of 1,557) in the third for patients treated with tadalafil. The respective values for the placebo treated patients were 37.8% (139 of 368), 35.4% (115 of 325) and 30.8% (90 of 312). Of all successful intercourse attempts during the study 57.8% (1,728 of 2,988) and 26.8% (63 of 235) occurred between 4 hours and 36 hours after dosing for patients treated with tadalafil and placebo, respectively (p ⬍0.001). Furthermore, patients treated with tadalafil reported sig-

TABLE 2. Summary of efficacy variables Placebo

Primary efficacy variables: IIEF erectile function domain SEP question 2 (successful penetration)* SEP question 3 (successful intercourse)* Secondary efficacy variables: IIEF intercourse satisfaction domain IIEF overall satisfaction domain SEP question 4 (hardness of erection)* GAQ (improved erections)* * Yes responses.

20 Mg Tadalafil No. Pts

Mean Baseline

Mean End

Mean ⫾ SD Change

p Value

No. Pts

Mean Baseline

Mean End

Mean ⫾ SD Change

48 48 48

13.4 40.5 19.1

13.6 42.8 22.6

0.3 ⫾ 0.9 2.3 ⫾ 5.5 3.5 ⫾ 4.2

157 155 155

13.3 45.2 20.7

22.5 76.8 64.2

9.3 ⫾ 0.6 31.6 ⫾ 2.5 43.6 ⫾ 2.7

⬍0.001 ⬍0.001 ⬍0.001

48 48 48 46

6.5 4.4 4.2 —

7.3 4.5 9.9 9 (19.6)

0.8 ⫾ 0.4 0.0 ⫾ 0.3 5.6 ⫾ 2.7 —

156 157 155 151

6.6 4.2 7.1 —

10.6 7.3 51.0 125 (82.8)

4.0 ⫾ 0.3 3.1 ⫾ 0.2 43.8 ⫾ 2.7 —

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

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EFFICACY AND SAFETY OF TADALAFIL

TABLE 3. Summary of sexual intercourse attempt patterns during treatment p Value

Placebo

20 Mg Tadalafil

2.0

2.8

0.053

1.3

1.4

0.61

34.8

55.2

0.001

26.8

57.8

⬍0.001

Mean No. sexual intercourse attempts/wk Mean No. sexual intercourse attempts/dose among patients who averaged more than 1 attempt/dose % Intercourse attempts between 4–36 hrs after dosing % Successful intercourse attempts between 4–36 hrs after dosing

nificantly more successful intercourse attempts at all selected intervals after dosing compared to placebo treated patients. Percentages of successful intercourse attempts ranged from 61.7% to 74.1% for tadalafil and 0% to 33% for placebo (table 4). Safety. The most common treatment emergent adverse events were headache (15.7% vs 6.3% with placebo), back pain (8.8% vs 0% with placebo) and dyspepsia (7.5% vs 0% with placebo). In general, the adverse events were mild or moderate in severity. Two patients who received 20 mg tadalafil experienced chest pain requiring hospitalization (these adverse events were assessed as serious and possibly related to study drug by the site investigators). No clinically significant treatment related changes in laboratory tests or vital signs were observed. During the study 8 patients (5.0%) treated with tadalafil and 1 on placebo (2.1%) discontinued the drug due to adverse events. We also investigated the safety of tadalafil among Hispanic patients. Headache (tadalafil 6 [32%] and placebo 1 [14%]), back pain (tadalafil 2 [10.5%] and placebo 0) and dyspepsia (tadalafil 1 [5%] and placebo 0) were the most commonly reported adverse events. Because the study was not designed to detect statistical difference between Hispanic and nonHispanic populations we did not have sufficient power to make statistical comparisons. DISCUSSION

Patients treated with 20 mg tadalafil showed significant improvement compared to placebo treated patients on all primary and secondary efficacy end points. Mean change in the IIEF EF domain scores reported by patients taking tadalafil tended to be greater than those of placebo treated patients, irrespective of baseline severity. Furthermore, the change was clinically meaningful.9 Notably, 50.0% of patients receiving tadalafil attained IIEF EF domain scores 26 or greater, representing no ED, at end point. Additionally, 67.6% of post-baseline sexual intercourse

attempts were successful for patients taking tadalafil compared to 24.1% for placebo treated patients. Improvements in erectile function and in the number of successful penetration and intercourse attempts reported by patients treated with tadalafil were further corroborated by improvements in erectile hardness satisfaction, intercourse satisfaction and overall satisfaction. On the GAQ 82.8% of patients taking tadalafil reported improved erections. The robustness of the results for tadalafil was further strengthened by the concordance of the post-baseline mean per patient percentage of successful intercourse attempts (SEP question 3) with the IIEF EF domain score and positive responses to the GAQ. For most ED treatments patients must think about taking a drug and attempting sexual intercourse shortly thereafter, typically within 4 hours. In contrast, tadalafil offers the opportunity to engage in sexual intercourse beyond 4 hours after dosing. Patients must be made aware of the flexibility in the timing of intercourse after taking tadalafil. Our results indicate that a majority of intercourse attempts occurred between 4 and 36 hours after dosing. Furthermore, patients who distanced sexual attempt from dosing experienced successful sexual intercourse. Patients in our sample, who were aware of the flexibility afforded by tadalafil, were receptive and adapted early in the trial to a dosing regimen wherein sexual intercourse was not closely temporally linked to taking the drug. Tadalafil was also well tolerated. The safety and efficacy results observed in our sample of United States and Puerto Rican men were consistent with the results from an integrated analysis of studies of tadalafil.6 This study has limitations. Flexible dosing was not permitted in this study, as patients were required to take a single 20 mg dose of tadalafil. The 10 mg dose of tadalafil, which is effective and safe for many patients with ED, was not evaluated.6 Also, patients who, in the opinion of the investigator, had prior ineffective treatment with sildenafil were excluded from the study and, hence, the results do not apply to them. Additionally, 6 patients with a history of ED who subsequently scored 26 to 30 (no ED) on the baseline IIEF EF domain were included in the study because ED is a selfreported condition. Because these patients represent a small percentage of the sample (table 1), they have little effect on the study results. CONCLUSIONS

Tadalafil (20 mg) significantly improved erectile function and increased the percentage of successful penetration and intercourse attempts compared with placebo. Furthermore, sexual intercourse attempts were not closely temporally linked with taking tadalafil. Tadalafil was also well tolerated in United States and Puerto Rican men with mild to severe ED.

TABLE 4. Successful intercourse attempts by interval after dosing Placebo Interval

ⱕ 15 Min or less 15–30 Mins 30 Mins–1 hr 1–4 Hrs 4–12 Hrs 12–24 Hrs 24–36 Hrs

20 Mg Tadalafil

No. Pts

No. Intercourse Attempts

No. Successful Intercourse Attempts (%)

1 20 32 37 33 25 9

2 92 191 370 165 176 9

0 (0) 9 (9.8) 43 (22.5) 120 (32.4) 39 (23.6) 21 (11.9) 3 (33.3)

No. Pts

No. Intercourse Attempts

No. Successful Intercourse Attempts (%)

14 58 91 141 134 105 61

24 209 447 1,307 1,471 840 135

16 (66.7) 153 (73.2) 285 (63.8) 806 (61.7) 1,008 (68.5) 622 (74.1) 98 (72.6)

p Value

— ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.017

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EFFICACY AND SAFETY OF TADALAFIL APPENDIX: DOSING INSTRUCTIONS

In clinical studies, IC351* was shown to be effective up to 36 hours after dosing and, in some patients, within 30 minutes after dosing. You may initiate sexual activity at varying time points after dosing in order to determine your own optimal window of responsiveness. The 36 hours of potential intimacy provides considerable flexibility in how you may choose to take your study drug and does not require that you closely link dosing to sexual activity. You may find your sex life to be more flexible and spontaneous by taking IC351 well in advance of anticipated sexual activity. The following are some possible ways you might choose to take study drug: ● Consider taking study drug in the morning if you feel the potential exists for sexual intimacy later in the day, in the evening, or even early the next day. ● Consider taking study drug the evening prior to sexual activity if you prefer to engage in sexual activity in the morning. ● While IC351 has been shown to be effective for 36 hours, the maximum dosing frequency is once per day. Hence, you may take a dose at the same time of day on several consecutive days if you so desire in order to be able to engage in sexual activity over that period whenever the mood strikes. ● Study drug can be taken with or without food. Hence, you may take a dose with any meal, if you choose. * IC351 refers to the study drug.

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1. Seftel, A. D.: Challenges in oral therapy for erectile dysfunction. J Androl, 23: 729, 2002 2. Atiemo, H. O., Szostak, M. J. and Sklar, G. N.: Salvage of sildenafil failures referred from primary care physicians. J Urol, 170: 2356, 2003 3. Sildenafil [Patient Product Information]: New York, New York: Pfizer, Inc. 2002. Available at: http://www.viagra.com/consumer/general/importantInfo.asp. Accessed February 12, 2004 4. Rajfer, J., Aronson, W. J., Bush, P. A., Dorey, F. J. and Ignarro, L. J.: Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med, 326: 90, 1992 5. Porst, H., Padma-Nathan, H., Giuliano, F., Anglin, G., Varanese, L. and Rosen, R.: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology, 62: 121, 2003 6. Brock, G. B., McMahon, C. G., Chen, K. K., Costigan, T., Shen, W., Watkins, V. et al: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol, 168: 1332, 2002 7. Rosen, R. C., Riley, A., Wagner, G., Osterloh, I. H., Kirkpatrick, J. and Mishra, A.: The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology, 49: 822, 1997 8. Cappelleri, J. C., Rosen, R. C., Smith, M. D., Mishra, A. and Osterloh, I. H.: Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology, 54: 346, 1999 9. Mulhall, J. P.: Deciphering erectile dysfunction drug trials. J Urol, 170: 353, 2003