The efficacy and safety of tadalafil: an update

Original Article C.C. CARSON et al. The efficacy and safety of tadalafil: an update C.C. CARSON, J. RAJFER, I. EARDLEY, S. CARRIER, J.S. DENNE, D.J. WALKER, W. SHEN and W.H. CORDELL Department of Surgery, Division of Urology, University of North Carolina, Chapel Hill, NC, Harbor-UCLA Medical Center, Division of Urology, Torrance, CA, St. James University Hospital, Leeds, UK, Department of Surgery, Division of Urology, McGill University, Montreal, PQ, Canada, and Eli Lilly and Company, Indianapolis, IN, USA Accepted for publication 25 February 24 OBJECTIVE To provide an update on the efficacy and safety of tadalafil, a phosphodiesterase-5 inhibitor, in the treatment of erectile dysfunction (ED). PATIENTS AND METHODS In all, 22 men (mean age 56 years) with mild-to-severe ED of various causes were randomized to placebo or tadalafil, taken as needed with no food restrictions, at fixed on-demand doses of or 2 mg in 11 randomized, double-blind, placebo-controlled trials lasting 12 weeks. The three co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function (IIEF) and the proportion of yes responses to questions 2 and 3 of the Sexual Encounter Profile (SEP). Additional efficacy instruments included a Global Assessment Question (GAQ). RESULTS Compared with placebo, tadalafil gave significantly better outcomes. Patients receiving either dose of tadalafil had a significant mean improvement of 6.5 and 8.6, respectively, in the IIEF erectile function domain score from baseline (P <.1 vs placebo). At both doses the mean success rate for intercourse attempts (SEP-Q3) was 58% and 68%, respectively, compared with 31% in the placebo group (P <.1), and 71% and 84% reported improved erections at the endpoint (GAQ), vs 33% on placebo (P <.1). Tadalafil was effective up to 36 h after dosing and was effective regardless of disease severity and causes, and in patients of all ages. The most frequent adverse events were headache, dyspepsia, back pain and myalgia. CONCLUSION Tadalafil was an effective and well-tolerated treatment for ED. KEYWORDS tadalafil, penile erection, impotence, efficacy, erectile dysfunction INTRODUCTION Erectile dysfunction (ED) occurs in ª15 million men worldwide [1] and in the USA may affect more than half of men aged 4 7 years [2]. An ageing population, together with an increased incidence of obesity and diabetes in the USA, Europe and other developed countries, and an increasing population in developing countries, will probably result in a dramatic increase in the number of men with ED in the future. Tadalafil, a potent phosphodiesterase type 5 (PDE-5) inhibitor, has an extended half-life of 17.5 h and is effective for 36 h after dosing [3]. Although sildenafil, the first PDE-5 inhibitor approved for ED, has a half-life of ª4 h, the two drugs nevertheless appear to have similar safety profiles, with most adverse events in clinical trials of both drugs being mild to moderate and transient. The safety and efficacy of tadalafil have previously been reported in an integrated analysis of five tadalafil studies that included 1112 men with ED [4]. In the present report this integrated analysis is updated to include an additional 1215 men with ED from six recently completed tadalafil studies. PATIENTS AND METHODS Eleven randomized, double-blind, placebocontrolled, parallel trials were conducted worldwide at 174 centres from April 1999 to February 23 (Table 1). Details of the general study design, efficacy and safety measures, and statistical analysis were published in a previous integrated analysis of five tadalafil trials [4]. To be included in these studies patients were required to make at least four attempts at sexual intercourse during a 4- week treatment-free run-in period. Patients were then randomly allocated to 12 weeks of treatment with placebo (638 men) or tadalafil at fixed doses of mg (321) or 2 mg (1143). An additional 225 patients were randomly assigned to 2.5 mg or 5 mg tadalafil in two of the earlier studies. These patients were previously reported [4] and are not included in the present analysis. Patients took the treatment as needed before sexual intercourse, with no restrictions on food intake or the timing of sexual activity. Patients visited at 4-week intervals until study completion or early discontinuation from the study. Men ( 18 years old) with a minimum 3- month history of mild to severe ED of organic, psychogenic or mixed causes, and having a steady female partner were eligible for participation in these studies. The exclusion criteria were similar to those listed in the 5- study analysis [4]. Most studies excluded nonresponders to previous sildenafil treatment. Tools used to evaluate the efficacy of tadalafil included the International Index of Erectile Function (IIEF) [5], the Sexual Encounter Profile (SEP) diary, and a Global Assessment Question (GAQ). The IIEF was administered at baseline and after treatment, with the mean change from baseline to endpoint on the erectile function (EF) domain being one of the co-primary outcome measures. Patients responded to the questions in the SEP diary after each sexual attempt throughout the study. The mean changes from baseline to endpoint in the 1276 24 BJU INTERNATIONAL 93, 1276 1281 doi:.1111/j.1464-4x.24.4819.x

TABLE 1 Summary of 11 tadalafil studies Study N Centres Placebo Tadalafil mg Tadalafil 2 mg Total 1 19 69 74 143 2 18 76 79 155 3 8 66 65 65 196 4 4 47 93 14 5 25 5 3 253 6 2 49 146 195 7 41 8 121 8 17 83 159 242 9 21 48 159 27 19 52 168 22 11 13 57 173 23 Total 174 638 321 1143 22 There were an additional 72 patients randomly assigned to 5 mg of tadalafil; There were an additional 74 patients and 79 patients randomly assigned to 2.5 mg and 5 mg of tadalafil, respectively. Number (%) of patients from participating countries: Argentina, 54 (3); Australia, 14 (7); Canada, 476 (23); Hong Kong, 38 (2); Indonesia, 21(1); Israel, 21 (1); Italy, 111 (5), Republic of Korea, 121 (6); Malaysia, 32 (2); Mexico, 21 (1); Philippines, 4 (2); Poland, 4 (5); Puerto Rico, 18 (1); Russia, 5 (5); Singapore, 3 (1); Taiwan, 277 (13); United Kingdom, 9 (5); United States, 384 (18). hypotheses were considered statistically significant if the two-sided P <.5. RESULTS Demographic and baseline characteristics were comparable in the three treatment groups (Table 2). The mean (range) age was 56 (22 88) years, with most patients (88%) having ED lasting at least 1 year. The number of patients was distributed similarly among the EF severity categories as measured by the IIEF EF domain score. Hypertension (29%), diabetes mellitus (2%), and hyperlipidaemia (16%) were the most common comorbidities. A slightly greater proportion (not significant) of tadalafil-treated patients ( mg, 88.5%; 2 mg, 89.7%) completed 12 weeks of treatment than placebo-treated patients (86.8%). There were no significant differences among the treatment groups for any of the reasons for discontinuing the study, apart from lack of efficacy (P <.1) and adverse events (P =.26; Table 2). proportion of yes responses to Question 2 (SEP-Q2): Were you able to insert your penis into your partner s vagina? and SEP-Q3: Did your erection last long enough for you to have successful intercourse? from the SEP diary were two additional co-primary outcome measures. The GAQ ( Has the treatment you have been taking over the past study interval improved your erection? ) was assessed at study completion or early termination. Additional efficacy measures included the mean change from baseline to endpoint in the IIEF intercourse satisfaction and overall satisfaction domains, the proportion of patients achieving a final IIEF EF domain score of at 26 (normal EF), and the completion rate of successful intercourse at distinct intervals after dosing (SEP-Q3). The mean change from baseline to endpoint in the proportion of yes responses to SEP-Q4: Were you satisfied with the hardness of your erection? was a secondary outcome measure. An additional measure of interest was the mean rate of successful intercourse (SEP-Q3) for those men on tadalafil 2 mg who responded Yes to the OAQ. Laboratory tests, medical history and a physical examination were performed during the screening visit before the run-in period. Clinical laboratory tests, including serum chemistry and haematology, were measured at each visit after baseline in six studies and at the endpoint in four. Urine was analysed at screening and the final visit in six studies, and an electrocardiogram was obtained at screening and at the final visit in five. Vital signs were assessed at each visit in all studies. All analyses were conducted on an intent-totreat basis. Efficacy analyses included all patients with a measurement at baseline and at least one afterward. The safety analyses included all randomized patients. The study design and patient population were consistent across all 11 studies, therefore efficacy and safety data could be pooled for these analyses. Analysis of covariance models were used to evaluate treatment differences for all continuous outcomes. Changes in proportions and scores were treated as continuous outcomes. Terms used in the models were baseline value, baseline by treatment group interaction, study, and treatment group. In any model, if the interaction was not significant (i.e. P.) then it was removed from the model, leaving the main-effects model. Pair-wise comparisons of tadalafil vs placebo were based on least-squares means adjusted by the method of Bonferroni. Categorical data were analysed using a logistic regression model. All tests of Tadalafil-treated patients in both the and 2 mg groups showed significantly greater improvement (P <.1) than placebo-treated patients on all three co-primary efficacy measures (Table 3). The mean IIEF EF domain score increased by 6.5 and 8.6 points for the and 2 mg tadalafil groups, respectively, compared to a <1 point change in the placebo group. The mean change in the intercourse satisfaction and overall satisfaction domains of the IIEF were also significantly better (P <.1) for both tadalafil doses than placebo (Table 3). The mean change in successful penetration (SEP-Q2) and intercourse completion (SEP-Q3) were significantly greater (P <.1) in the tadalafil (SEP-Q2, 24%; SEP-Q3, 34%) and 2 mg (SEP-Q2, 3%; SEP-Q3, 46%) groups than on placebo (SEP-Q2, 3%; SEP-Q3, 8%). Across all patients on tadalafil and 2 mg the total number of successful attempts (SEP-Q3), as a proportion of the total number of attempts made, was 61% and 72%, respectively, compared to 34% for placebo (P <.1). These proportions are slightly higher than the corresponding mean per-patient percentages presented in Table 3. A significantly greater percentage (P <.1) of patients in both the tadalafil groups (71% and 84%) reported improved erections (GAQ) at the endpoint vs the placebo group (33%). 24 BJU INTERNATIONAL 1277

C.C. CARSON ET AL. TABLE 2 Demographic and baseline characteristics of men with ED Variable Placebo Tadalafil mg Tadalafil 2 mg Total N 638 321 1143 22 Mean (range) or n (%) Age, years 57 (22 81) 58 (26 81) 56 (22 88) 56 (22 88) Age > 65 14 (22) 96 (3) 248 (22) 484 (23) Body mass index, kg/m 2 27.3 (18.1 53.7) 27.9 (18.2 46.) 27.3 (12.7 52.) 27.4 (12.7 53.7) Duration of ED 12 months 572 (9) 28 (87) 6 (88) 1858 (88) Cause of ED Organic 369 (58) 215 (67) 627 (55) 1211 (58) Psychogenic 82 (13) 2 (6) 147 (13) 249 (12) Mixed 187 (29) 86 (27) 369 (32) 642 (31) IIEF EF severity Normal (26 3) 33 (5) 16 (5) 39 (3) 88 (4) Mild (17 25) 212 (33) 113 (35) 425 (37) 75 (36) Moderate (11 16) 171 (27) 84 (26) 33 (27) 558 (27) Severe (1 ) 22 (34) 7 (33) 376 (33) 73 (33) Medical history, n (%) Coronary artery disease 33 (5) 17 (5) 62 (5) 112 (5) Depression 23 (4) 15 (5) 53 (5) 91 (4) Diabetes mellitus 13 (2) 68 (21) 223 (2) 421 (2) Hyperlipidaemia 1 (17) 51 (16) 166 (15) 327 (16) Hypertension 189 (3) 9 (28) 337 (29) 616 (29) Patient disposition; reason for discontinuation Completed 554 (86.8) 284 (88.5) 25 (89.7) Adverse event 8 (1.3) 5 (1.6) 36 (3.2) Lack of efficacy 32 (5.) 4 (1.3) 18 (1.6) Lost to follow-up 16 (2.5) 4 (1.3) 14 (1.2) Patient decision 16 (2.5) 12 (3.7) 26 (2.3) Protocol violation 9 (1.4) 4 (1.3) 14 (1.2) Others 3 (.5) 8 (2.8) (1.) Overall safety Subjects with 1 247 (39) 185 (58) 577 (51) treatment-emergent adverse event Discontinuation for adverse event 8 (1.3) 5 (1.6) 36 (3.2) Most common treatment-emergent adverse events Headache 3 (5) 38 (12) 173 (15) Dyspepsia 7 (1) 23 (7) 9 (8) Back pain 15 (2) 2 (6) 6 (5) Nasopharyngitis 24 (4) 26 (8) 23 (2) Myalgia 6 (1) 16 (5) 33 (3) Flushing 8 (1) (3) 39 (3) Nasal congestion 4 (1) 11 (3) 28 (2) Pain in limb 5 (1) (3) 31 (3) Patients were included based on a history of ED. Subsequent assessment of EF by the IIEF at baseline showed that a small proportion of men (4%) had an EF domain score of 26. The cause of ED was determined by the investigators based on the patient history, physical examination findings and any previous diagnostic testing. Adverse events were coded using the MedDRA dictionary (version 5.). Both tadalafil treatment groups had significantly greater mean improvements on the IIEF EF domain score (P <.1) in each category of baseline EF severity than in the placebo group (Fig. 1a). In addition, the 2 mg group had numerically greater mean changes across all severity groups than the mg group. There was a similar trend in the IIEF EF domain score improvements based on the cause of ED (Fig. 1b). The tadalafil treatments showed similar improvements in older and younger patients (Fig. 1c). During 12 weeks of treatment a total of 734 (5%) men on tadalafil ( or 2 mg) attempted intercourse at 12 24 h after dose on one or more occasions, and 479 (33%) at 24 36 h after dose (Fig. 2). The mean percentage of yes responses to 1278 24 BJU INTERNATIONAL

FIG. 1. Summary of IIEF EF domain mean score change (as classified in Table 2) at endpoint by subgroup. A, baseline severity; B, by cause of ED; C, by age (open, placebo; red, tadalafil mg; green, tadalafil 2 mg). P <.1 vs placebo. The numbers at the base of each bar show the number of men in each group. B A Mean change from baseline to endpoint 12 8 6 4 2 2 25 112 4 168 83 299 213 364 Mild Moderate Severe Mean change from baseline to endpoint 8 6 4 2 356 26 66 79 2 144 182 83 361 Organic Psychogenic Mixed C Mean change from baseline to endpoint 8 6 4 2 482 216 871 135 93 24 65 years >65 years TABLE 3 A summary of the major efficacy variables at the endpoint Placebo Tadalafil mg Tadalafil 2 mg Efficacy measure Endpoint Change Endpoint Change Endpoint Change Mean IIEF EF domain 15.3.9 21.1 6.5 23.2 8.6 Mean % success SEP SEP-Q2 5 3 73 24 8 3 SEP-Q3 31 8 58 34 68 46 % GAQ 33 71 84 Mean IIEF Intercourse satisfaction 7.6 1. 9.3 2.6.9 4.1 Overall satisfaction 5..5 6.7 1.8 7.4 2.8 Pairwise comparisons between placebo and each treatment were adjusted by the method of Bonferroni: P <.1. IIEF evaluable population: placebo, 616; mg, 39; 2 mg 1111; SEP evaluable population: placebo, 625; mg, 311; 2 mg 1119); GAQ results for the 12-week studies, placebo: 591; mg: 321; 2 mg: 5); evaluable population: placebo, 558; mg, 35; 2 mg 995. Both tadalafil doses were significantly better (P <.1) than placebo in improving patients EF into the normal range at endpoint (IIEF EF domain score 26) for all baseline severity levels (Fig. 3). As expected, the greatest percentage of tadalafil-treated patients having normal EF at endpoint were those with mild baseline ED, followed by patients with moderate and severe ED. Tadalafil significantly improved satisfaction with the hardness of erection, as measured by SEP-Q4 (mean change: placebo, 11%; tadalafil mg, 37%; tadalafil 2 mg, 5%; P <.1 vs placebo for both tadalafil doses). The mean rate of successful intercourse (SEP-Q3) for those patients on tadalafil 2 mg who responded Yes to the GAQ was 77%. SEP-Q3 for attempts made at both 12 24 h and 24 36 h after dosing was significantly greater (P <.1) for both tadalafil groups than in the placebo group (Fig. 2). Similarly, the mean percentage of yes responses to SEP-Q3 for attempts made in the other periods examined was also significantly greater. The most common adverse events were headache, dyspepsia and back pain (Table 2). Most adverse events were mild or moderate and generally decreased in frequency during 24 BJU INTERNATIONAL 1279

C.C. CARSON ET AL. continued treatment. Few patients discontinued from the study for adverse events in each of the treatment groups (placebo, 1.3%; tadalafil mg, 1.6%; 2 mg, 3.2%), although the difference was significant between tadalafil and placebo (P =.26). There were no clinically significant differences in the incidence of abnormal laboratory or electrocardiogram changes between patients treated with placebo or tadalafil. DISCUSSION Tadalafil at doses of and 2 mg resulted in robust improvements in EF in patients with varying causes and severity of ED. Both doses of tadalafil showed significantly greater improvement than placebo on the three coprimary and all secondary efficacy measures. Tadalafil was effective in treating ED of various causes (organic, psychogenic, or mixed). The improvement was similar across the three groups with 2 mg tadalafil, while the improvement with the mg dose appeared to vary among them, although there were relatively few patients with ED of psychogenic origin treated with mg. An 11- study integrated analysis of another PDE-5 inhibitor, sildenafil, showed similar improvement regardless of cause [6] but the measures were not analysed by sildenafil dose in that report. Tadalafil is also effective in treating men with ED and a variety of comorbid medical problems. A previous study showed significant improvements in patients with ED and diabetes mellitus taking either or 2 mg of tadalafil [7]. Men with ED, after undergoing bilateral nerve-sparing radical retropubic prostatectomy, had significant improvements (P <.1) on a variety of efficacy measures after 12 weeks of treatment with 2 mg tadalafil compared to those patients taking placebo [8]. The improvements in EF measures in that study were less in those taking 2 mg tadalafil than in the general population. The improvement in efficacy measures was also lower in a similar group of patients who had undergone prostatectomy and treated with sildenafil [6]. Analyses of the various subgroups within this integrated study will be presented in a future publication. In this integrated analysis the percentage of patients responding yes to SEP-Q3 was significantly higher than placebo in each FIG. 2. Mean per-patient successful intercourse (SEP-Q3). (open, placebo; red, tadalafil mg; green, tadalafil 2 mg). P <.1 vs placebo. The numbers at the base of each bar show the number of men in each group, and the dotted line is the baseline value. Mean per-patient success, % Percent normal at endpoint 8 6 4 2 7 6 5 4 3 2 436 193 761 542 282 21 43 237 887 251 154 58 152 84 395 >1/2 to 1 >1 to 4 >4 to 12 >12 to 24 >24 to 36 Time after doses, h Overall period to 36 h. This is consistent with the results of a study that was designed to study EF 24 and 36 h after dosing with 2 mg tadalafil [3]. In a separate study, the onset of action may begin as early as 16 min in some patients taking 2 mg of tadalafil [9]. Sildenafil [] and vardenafil [11] appear to offer a comparable onset of action. Tadalafil differs from the other approved PDE-5 inhibitors in that it offers a broader window of opportunity for sexual encounters, i.e. up to 36 h after dosing, based on its extended halflife of 17.5 h [3]. The absorption of tadalafil is not affected by food [12] whereas the absorption of sildenafil is, and which may delay or diminish the effectiveness of this drug [13,14]. The absorption of vardenafil may be delayed up to 1 h after consuming a high-fat meal [15]. The Mild Moderate Severe lack of food interaction with tadalafil might be an important factor for some men when considering treatment for ED. Tadalafil was well tolerated; treatmentemergent adverse events were primarily mild or moderate, with a generally decreasing frequency of adverse events over continued use. A 24-month extension trial of 1173 men with ED to assess the long-term safety and tolerability of tadalafil was recently completed [16]. Patients started on mg tadalafil and could increase to 2 mg or decrease to 5 mg. Most adverse events were considered mild or moderate, with the most common being headache, dyspepsia, nasopharyngitis and back pain. The discontinuation rate for adverse events was 5.4%, with discontinuations for a single adverse event being <1%. There was one FIG. 3. Percentage of patients normal at endpoint (EF domain score 26); overall, and by baseline severity. (open, placebo; red, tadalafil mg; green, tadalafil 2 mg). P <.1 vs placebo. Patients who were normal at baseline were excluded. 128 24 BJU INTERNATIONAL

episode of mild blue vision in a patient and no cases of priapism were reported. The findings from that study would suggest that tadalafil would be safe and well tolerated for treating ED. The cardiovascular effects of tadalafil in patients with ED appear to be minimal. An overview of the five phase 3 placebocontrolled studies that included an electrocardiogram at endpoint found no clinically important effects of tadalafil on the QT interval [17]. Furthermore, morbidity and mortality rates from serious cardiovascular adverse events were no greater in patients with ED taking tadalafil than in the general population of men with ED [18]. In the longterm safety study the incidence rate of myocardial infarction was no higher than expected for a similar matched population of men [16]. However, similar to sildenafil and vardenafil, tadalafil should not be used in combination with nitrates. In a separate safety analysis, treatment for 6 months with and 2 mg of tadalafil did not adversely affect spermatogenesis or reproductive hormone levels in men with no or mild ED who were aged 45 years [19]. The adverse events reported in that study were similar to those found in the present study, and in the long-term safety study [16]. In summary, in this integrated analysis of data from 22 patients enrolled in 11 placebocontrolled clinical trials, tadalafil was effective in improving EF in a wide range of patients with ED. More than two-thirds of intercourse attempts (SEP-Q3) were successful at 24 36 h after dosing. Tadalafil could be taken as needed with no restrictions on food intake, and was well tolerated in a wide spectrum of patients with ED. CONFLICT OF INTEREST C. Carson is a speaker and consultant for Lilly, Pfizer, Bayer and GSK; J. Rafjer is an investigator and consultant for Lilly, ICOS, Pfizer, Bayer and GSK; I. Eardley is a consultant, speaker and investigator for Lilly, ICOS, Bayer and Pfizer; S. Carrier is an investigator and consultant for Eli Lilly; J.S. Denne, D.J. Walker, W. Shen and W.H. Cordell are employees of Lilly. Source of funding: Lilly, ICOS LLC. REFERENCES 1 McKinlay JB. The worldwide prevalence and epidemiology of erectile dysfunction. IJIR 2; 12: S6 S11 2 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54 61 3 Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 23; 62: 121 6 4 Brock GB, McMahon CG, Chen KK et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. 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Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol 23; 43: 26 7 16 Montorsi F, Verheyden B, Meuleman E et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol 24; 45: 339 45 17 Emmick JT, Stuewe SR, Mitchell M. Overview of the cardiovascular effects of tadalafil. Eur Heart J 22; 4 (Suppl): H32 H47 18 Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol 23; 92: 37 46 19 Hellstrom WJG, Overstreet JW, Yu A et al. Tadalafil has no detrimental effect on human spermatogenesis or reproductive hormones. J Urol 23; 17: 887 1 Correspondence: C.C. Carson, Rhodes Distinguished Professor, Chief of Urology, 214 Bioinformatics Building, University of North Carolina, Chapel Hill, NC 27599 7235, USA. e-mail: culley_carson@med.unc.edu Abbreviations: ED, erectile dysfunction; PDE-5, phosphodiesterase type 5; IIEF, International Index of Erectile Function; SEP, Sexual Encounter Profile; GAQ, Global Assessment Question. 24 BJU INTERNATIONAL 1281