Michael G. Wyllie
Ian Eardley, UK
Jean Fourcroy, USA
Sidney Glina, Brazil
Julia Heiman, USA
Chris McMahon, Australia
Bob Millar, UK
Alvaro Morales, Canada
Michael Perelman, USA
Marcel Waldinger, Netherlands
Michael G. Wyllie
Ian Eardley, UK
Jean Fourcroy, USA
Sidney Glina, Brazil
Julia Heiman, USA
Chris McMahon, Australia
Bob Millar, UK
Alvaro Morales, Canada
Michael Perelman, USA
Marcel Waldinger, Netherlands
To determine whether patients with erectile dysfunction (ED) and treated with tadalafil use the 36-h duration of effect of the drug, and to discern if the timing of intercourse attempts is influenced by patient age, baseline severity of ED, or previous experience with sildenafil citrate.
In 11 multicentre, double-blind, placebo-controlled studies, 2102 patients with ED were randomized to a maximum of one dose per day of tadalafil 10 or 20 mg (1464 men), or placebo (638 men) with no time restrictions before attempting sexual activity after the dose. A post hoc analysis was used to determine the proportion of men with ED who attempted sexual intercourse during various intervals (>0 to ≤ 1, >1 to ≤ 4, and >4 to ≤ 36, including >12 to ≤ 36 h) after dosing with tadalafil or placebo over a 12-week period. Patients were stratified by age, baseline severity of ED, and previous history of sildenafil use.
Of patients in different age groups and various ED severity, ≥ 79% and ≥ 53% chose to attempt sexual intercourse at least once during the 12-week treatment period at 4–36 and 12–36 h, respectively, after taking tadalafil. Regardless of previous experience with sildenafil, about a third of patients using tadalafil attempted intercourse a mean of at least once per week at 4–36 h after the dose over 12 weeks. Furthermore, 58% of patients attempted intercourse at least once during two intervals (>1 to ≤ 4 h and >12 to ≤ 36 h) after separate doses of tadalafil.
Regardless of age, ED severity, or previous experience with sildenafil, most patients attempted sexual intercourse at least once at 12–36 h after one dose of tadalafil over a 12-week treatment period. Furthermore, by engaging in sexual intercourse at both earlier and later intervals after separate doses, most patients on treatment did not adhere to a fixed schedule of intimacy and thus took advantage of the 36-h duration.
phosphodiesterase type 5
International Index of Erectile Function
erectile function (domain)
Sexual Encounter Profile
Tadalafil (Cialis®, Lilly ICOS LLC) is a potent inhibitor of phosphodiesterase type 5 (PDE5) indicated for the treatment of erectile dysfunction (ED) . Previously approved PDE5 inhibitors, sildenafil citrate (Viagra®, Pfizer Inc.) and vardenafil (Levitra, Bayer Pharmaceuticals Corporation), have half-lives of ≈ 4 h [2,3]. This has a direct bearing on the duration of efficacy and patients are instructed to have sexual intercourse about an hour after taking the medication (sildenafil can be taken from 0.5–4 h before attempting sexual intercourse) . The mean terminal half-life of tadalafil is 17.5 h in healthy subjects  and its duration of efficacy has been shown to be up to 36 h after dosing [4,5]. Consequently, tadalafil may provide more flexibility in terms of timing of intercourse attempts relative to the time of dosing. However, unanswered questions include whether patients use this interval and whether the patient's age, ED severity, or previous use of oral therapies influence the timing of intercourse attempts selected by these patients over the 36-h period after taking tadalafil.
The aim of this retrospective analysis was to evaluate if patients with ED use the extended period of effectiveness provided by tadalafil; to determine if patients and their partners show flexibility in selecting the time to engage in sexual activity after dosing; and to discern if the pattern of sexual activity relative to timing after dosing was influenced by age, severity of ED, or previous history of sildenafil use.
Eleven randomized, double-blind, placebo-controlled, parallel-arm studies were conducted at 174 centres worldwide to evaluate the efficacy and safety of tadalafil at doses of 2.5–20 mg over a 12-week period (one of these studies had a 6-month duration, but for the purpose of this analysis only data from 12 weeks of treatment are included). Details of these studies were previously published in two integrated analyses of five and 11 efficacy and safety trials of tadalafil [6,7]. Briefly, patients enrolled in these studies were aged ≥ 18 years, reported having a history of ED of at least 3 months’ duration, and were to report on their sexual attempts with the same adult female partner. Nine of the 11 studies excluded patients who, in the opinion of the investigator, did not respond to sildenafil. The study design included a 4-week run-in period (no ED medication taken) to establish baseline data, and a 12-week treatment period with randomization to fixed doses of tadalafil 10 mg (321 men) or 20 mg (1143 men), or placebo (638 men). In these analyses, except for the efficacy analysis described below, patients on tadalafil 10 mg and 20 mg are considered as one group (1464 men). An additional 225 patients were randomized to tadalafil 2.5 mg or 5 mg; efficacy and safety results from these latter groups were reported previously .
Patients took the study medication as needed, up to once daily before expected sexual activity and with no restrictions on food intake. Patients were free to choose the time between taking the dose and the time of sexual intercourse attempts. Dosing instructions used in five of the 11 trials, included detailed information about the expected duration of efficacy of tadalafil up to 36 h after the dose. The remaining six trials used a simple dosing instruction without mentioning the 36-h duration of efficacy. Examples of dosing instructions are included in the Appendix.
Outcome measures of the efficacy of tadalafil included the International Index of Erectile Function (IIEF) questionnaire, the Sexual Encounter Profile (SEP) diary, and a Global Assessment Question. In this paper, the proportion of ‘yes’ responses to SEP question 3 (SEP3: ‘Did your erection last long enough for you to have successful intercourse’? [yes/no]) is presented as the efficacy variable. For the efficacy analysis patients on tadalafil 10 mg and 20 mg were considered separately.
Assessments of individual sexual attempts were obtained through the patient SEP diaries throughout the 12-week treatment period. Patients recorded the time of dosing and the time and outcome of each sexual attempt. Over this treatment period, we determined the proportion of patients having at least 1, 4, 8 or 12 attempts during the following intervals: >0 to ≤ 1 h, >1 to ≤ 4 h, and >4 to ≤ 36 h (including >12 to ≤ 36 h) after dosing. An individual patient could have attempted intercourse during one interval after one dose, and in a different interval after another dose. The number of attempts (≥1, ≥ 4, ≥ 8 or ≥ 12) represents a cumulative value over a 12-week treatment period. Flexibility relative to the time selected to engage in sexual activity after the dose was assessed by the percentage of patients who attempted intercourse during the >1 to ≤ 4-h interval after at least one dose and during the >4 to ≤ 36-h or >12 to ≤ 36-h intervals after another dose at least once during the 12 weeks of study. The percentage of patients who engaged in sexual activity at least once during three given intervals (>1 to ≤ 4 h, >4 to ≤ 12 h, and >12 to ≤ 36 h) after separate doses of tadalafil or placebo was also calculated.
Patients were stratified by age (≤44, >44–64 and >64 years), severity of ED as defined by the Erectile Function (EF) domain of the IIEF questionnaire (mild 22–25, mild to moderate 17–21, moderate 11–16, and severe 1–10) and previous history of sildenafil use (previous users or not). Analyses by age and severity only included data for at least one attempt at sexual intercourse within a given interval over the 12 weeks of treatment, while analyses based on previous history of sildenafil use included at least 1, 4, 8 or 12 attempts in the various intervals.
The statistical analyses presented, except for the efficacy during various intervals as measured by SEP3, reflect a descriptive behavioural observation. Stratification by number of attempts, age, baseline ED severity, or previous experience with sildenafil, each yields 16 possible comparisons to test. These multiple comparisons will inflate the type 1 error rate (probability of concluding that some differences are significant when in fact they are not). Thus, we made no attempt at establishing statistical comparisons between placebo- and tadalafil-treated patients based on the percentage of patients having sexual intercourse attempts in various intervals.
Analysis of covariance models were used to evaluate treatment differences in changes from baseline in the proportion of ‘yes’ responses to SEP3. The models included terms for baseline value, study, treatment group, and baseline by treatment group interaction (if P < 0.1). Pairwise comparisons of tadalafil vs placebo were based on least square means adjusted by the Dunnett method.
Demographic and baseline characteristics are shown in Table 1. In the nine trials (1804 men) that excluded patients who, in the opinion of the investigator, were not responders to previous sildenafil treatment, 739 (41%) were sildenafil-naïve and 1065 (59%) were previous users.
|Variable||Placebo||Tadalafil 10 mg||Tadalafil 20 mg||Total|
|Mean (range) age, years||57 (22–81)||58 (26–81)||56 (22–88)||56 (22–88)|
|Age > 65, n (%)||140 (22)||96 (30)||248 (22)||484 (23)|
|Duration of ED ≥ 12 months, n (%)||572 (90)||280 (87)||1006 (88)||1858 (88)|
|Cause of ED, n (%)|
|Organic||369 (58)||215 (67)||627 (55)||1211 (58)|
|Psychogenic||82 (13)||20 (6)||147 (13)||249 (12)|
|Mixed||187 (29)||86 (27)||369 (32)||642 (31)|
|IIEF EF severity, n (%)|
|Normal* (26–30)||33 (5)||16 (5)||39 (3)||88 (4)|
|Mild (22–25)||76 (12)||34 (11)||157 (14)||267 (13)|
|Mild to moderate (17–21)||136 (21)||79 (25)||268 (23)||483 (23)|
|Moderate (11–16)||171 (27)||84 (26)||303 (27)||558 (27)|
|Severe (1–10)||220 (34)||107 (33)||376 (33)||703 (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||130 (20)||68 (21)||223 (20)||421 (20)|
|Hyperlipidaemia||110 (17)||51 (16)||166 (15)||327 (16)|
|Hypertension||189 (30)||90 (28)||337 (29)||616 (29)|
Table 2 summarizes the percentage of patients who attempted intercourse at least 1, 4, 8 or 12 times during various intervals after dosing with tadalafil or placebo over the 12 weeks of treatment. After dosing with tadalafil, 82% of patients attempted intercourse during the 4–36-h interval at least once over 12 weeks. Importantly, 59% of patients on tadalafil attempted intercourse at least once during the 12–36-h interval after dosing. Also, over the duration of the study, 61%, 45% and 32% of patients on tadalafil engaged in sexual intercourse at least 4, 8 or 12 times, at 4–36 h after the dose; 28%, 14% and 8% did so at least 4, 8 or 12 times at 12–36 h after tadalafil during the treatment phase (Table 2). Overall, the percentage of patients who had at least one attempt within these intervals was numerically similar in the placebo group (Table 2).
|N attempts over 12 weeks|
|Time of intercourse after dose, h|
|Tadalafil 10 or 20 mg (1464), n (%)*|
|>0 to ≤1||1032 (71)||633 (43)||422 (29)||298 (20)|
|>1 to ≤4||1303 (89)||1048 (72)||759 (52)||544 (37)|
|>4 to ≤36||1201 (82)||897 (61)||658 (45)||475 (32)|
|>12 to ≤36||870 (59)||410 (28)||205 (14)||113 (8)|
|Placebo (638), n (%)*|
|>0 to ≤1||466 (73)||300 (47)||199 (31)||130 (20)|
|>1 to ≤4||542 (85)||417 (65)||281 (44)||162 (25)|
|>4 to ≤36||480 (75)||301 (47)||200 (31)||125 (20)|
|>12 to ≤36||318 (50)||114 (18)||49 (8)||20 (3)|
The percentage of patients on tadalafil who attempted sexual intercourse at least once during the 12 weeks of treatment within the interval >4–36 h (including >12–36 h) after dosing was similar in all age groups analysed (Fig. 1a); 79% and 57% of patients aged >64 years attempted intercourse during the >4–36 h and >12–36 h intervals, respectively, on at least one occasion after dosing with tadalafil (Fig. 1a). Overall, there was a similar pattern of timing of sexual activity, including attempts at intercourse at >4 h after dose, in the placebo group, regardless of age (Fig. 1b).
Regardless of ED severity, a similar proportion of patients attempted intercourse at least once within the interval 4–36 h (83%, 85%, 82% and 79% of those with mild, mild-to-moderate, moderate, and severe ED, respectively) after dosing with tadalafil (Fig. 2a). In addition, ≥53% of patients with any ED severity (64% mild, 63% mild to moderate, 60% moderate and 53% severe) chose to attempt sexual intercourse at least once during the 12–36-h interval. Figure 2b shows the percentage of men, stratified by baseline ED severity, who attempted intercourse during various intervals in the placebo group.
A similar percentage of patients in the sildenafil-naïve and sildenafil-experienced groups had ≥ 12 intercourse attempts (36% vs 31%) at 4–36 h after taking tadalafil, indicating that about a third of patients using tadalafil, irrespective of previous sildenafil use, had intercourse a mean of at least once a week during this interval (Table 3).
|N attempts at intercourse at interval (h) after dosing, % of men||No previous use of sildenafil*||Previous use of sildenafil*|
|>4 to ≤36|
|>12 to ≤36|
The results shown in Table 4 summarize the proportion of patients who had intercourse during two or three given intervals after separate doses of tadalafil or placebo over the 12 weeks of treatment. When assessing the time selected to engage in sexual activity by the same individual, 81% engaged in sexual activity at least once during both the >1 to ≤ 4-h and >4 to ≤ 36-h intervals, and 58% during both the >1 to ≤ 4-h and >12 to ≤ 36-h intervals, after separate doses of tadalafil; 54% of patients attempted intercourse at least once during each of the following intervals: >1 to ≤ 4, >4 to ≤ 12 and >12 to ≤ 36 h, after separate doses of tadalafil.
|Interval, h||Tadalafil 10, 20 mg, n (%)||Placebo, n (%)|
|>1 to ≤4 and >4 to ≤36||1130 (80.5)||440 (72.0)|
|>1 to ≤4 and >12 to ≤36||814 (57.8)||288 (47.0)|
|>1 to ≤4 and >4 to ≤12 and 12 to ≤36||749 (53.7)||245 (40.4)|
Tadalafil was statistically superior to placebo in the percentage of successful intercourse attempts at all intervals after dosing, as measured by SEP3 (P < 0.001 vs placebo; Fig. 3). The mean per-patient percentages of sexual intercourse attempts that were successful on tadalafil 10 mg during the >0 to ≤ 1, >1 to ≤ 4, >4 to ≤ 36, and >12 to ≤ 36 h intervals were 57%, 59%, 60% and 66%, respectively, and on tadalafil 20 mg 65%, 69%, 70% and 71%, vs 31%, 32%, 36% and 39% for placebo-treated patients (Fig. 3).
Consistent with a mean terminal half-life of 17.5 h, tadalafil is effective for treating ED up to 36 h after dosing [1,4,5], but few reports address the question of whether patients with ED use this period to engage in sexual activity. This retrospective analysis shows that a high proportion of patients treated with tadalafil 10 or 20 mg engaged in sexual intercourse during the 4–36-h (including 12–36 h) interval after dose, at least once over 12 weeks of treatment (Table 2). The mean (range) per-patient success rate for intercourse attempts completed during the 4–36 and 12–36 h intervals after the tadalafil dose was ≥ 60 (60–71)% (Fig. 3). Importantly, to the best of our knowledge, this is the first detailed report to show this pattern of timing of sexual activity at >4 h after the tadalafil dose in a high percentage of patients, regardless of their age, severity of ED, or previous history of sildenafil use. The results presented in Table 4 also support the novel hypothesis that patients with ED use the flexibility provided by tadalafil in the timing of intercourse relative to time of dosing, as indicated by the high proportion who engaged in sexual activity during the earlier (1–4 h) and later (4–36 and 12–36 h) intervals after separate doses of tadalafil.
A recently published retrospective analysis of 11 integrated phase 3 clinical trials of tadalafil  showed that during 12 weeks of treatment a large percentage of patients on tadalafil attempted intercourse at least once at 4–36 h after dosing, with 50% and 33% of patients engaging in sexual intercourse during 12–24 and 24–36 h after the dose, respectively . These data seem to indicate that, when given the opportunity, patients with ED tend to use the extended period of efficacy provided by a longer-acting PDE5 inhibitor. The present data show that across the 12-week treatment period, 82% and 59% of patients had at least one sexual intercourse attempt during the 4–36 and 12–36-h intervals, respectively, after a single dose of tadalafil (Table 2). Furthermore, the percentage of patients on tadalafil who attempted intercourse at least once over the treatment period at >4 h after dosing (4–36 h, including 12–36 h) was generally similar irrespective of patient age (Fig. 1), baseline ED severity (Fig. 2), or previous history of sildenafil use (Table 3).
Although there is a higher prevalence of ED in ageing men [8,9], it is known that those aged ≥ 60 years remain sexually active . The present analysis of the timing of sexual intercourse by men of various ages (Fig. 1) shows that a large percentage of patients in all age groups analysed, including those aged >64 years, engaged in sexual activity at >4 h after the tadalafil dose (4–36 h, including 12–36 h). These results might indicate that regardless of age the patients’ timing of sexual activity extends to >4 h after the tadalafil dose. This might appear to contradict results from previous research , which suggested in a cohort of British men aged >40 years that the average time from first thinking of intercourse to beginning intercourse was <1 h. However, we think that these two studies are not necessarily incompatible. The present data suggest that for many men there is a considerable delay between taking the medication and having intercourse, while the period alluded to in the previous research  was from thinking about intercourse to having intercourse. It seems reasonable to suggest that the prolonged duration of action of tadalafil allows a man to use the medication with no concerns about time limitations, while allowing him to have spontaneous intercourse within the context of the timings reported by the previous research. For patients and their partners, this flexibility may translate into a dissociation between taking the medication and timing intercourse at a fixed time after dosing.
A large percentage of patients in the present analysis chose to have intercourse at 4–36 h (including 12–36 h) after dosing, regardless of ED severity (Fig. 2). Patients on tadalafil had a higher success rate for intercourse attempts made at all intervals evaluated up to 36 h after dose than those on placebo (P < 0.001; Fig. 3). Importantly, the high proportion of patients who had intercourse during both the earlier (1–4 h) and later (4–36, 12–36 h) intervals after dosing (Table 4), highlights the flexibility that patients had to choose the time to engage in sexual activity according to their individual needs and circumstances.
The present analyses of sildenafil-naive vs sildenafil-experienced patients showed that a high proportion engaged in intercourse at least once over 12 weeks at 4–36 h (84% and 81%, respectively) and 12–36 h (63% and 58%, respectively). In addition, about a third of patients attempted intercourse a mean of at least once a week (≥12 attempts over 12 weeks) during the 4–36-h interval, regardless of their previous history of sildenafil use. These findings suggest that regardless of previous experience with sildenafil, patients understood the tadalafil dosing instructions and used the time available to them to engage in sexual activity (Table 3).
Some limitations of the present analyses include: (i) the integration of 11 clinical studies with two distinctive dosing instructions (see Appendix) limits the direct correlation of patients’ behavioural pattern of timing of sexual intercourse relative to time of dosing, with their clear understanding of tadalafil's duration of effectiveness; (ii) the nature of the analyses does not allow for a statistical comparison between tadalafil- and placebo-treated patients, restricting the results to a descriptive behavioural observation of the timing of sexual activity after dosing.
In summary, the overall results suggest that patients with ED used the 36-h period of effectiveness of tadalafil regardless of their age, baseline ED severity or previous experience with sildenafil. Importantly, the behavioural observations reported here clearly indicate that patients not only used the extended time available to them, but also had the flexibility to engage in sexual activity after the tadalafil dose at the most convenient time to them.
Funding for this study was provided by Lilly ICOS LLC (Bothell, Washington, and Indianapolis, Indiana).
R. Shabsigh is a paid consultant and speaker for Bayer Pharmaceuticals, Lilly ICOS LLC, and Pfizer Inc., and a study investigator for Bayer and Pfizer. I. Sharlip is a paid consultant, study investigator, and speaker for Bayer, Lilly ICOS, and Pfizer. C. Garcia, F. Natanegara and S. Ahuja are employees and stockholders for Eli Lilly and Company. I. Eardley is a paid consultant, study investigator and speaker for Lilly ICOS, Pfizer, Bayer, GSK and J&J. P. Ellsworth is a study investigator and speaker for Eli Lilly, paid consultant for Pfizer, and speaker for Bayer. Source of funding: Lilly ICOS LLC.
Simple dosing instructions listed in the study protocol for LVBN, LVCE, LVCO, LVCQ, LVCR, and LVDJ Clinical Studies.
Patients will be instructed to take one dose of medication with water prior to expected sexual activity. The patients will also be instructed to take no more than one (1) dose daily.
Detailed dosing instructions listed in the study protocol for LVEF, LVEG, LVDZ, LVEL, and LVDW clinical studies.
Patients will be instructed to take one dose of study drug with water prior to the potential for sexual activity. In clinical studies, IC351 (tadalafil) has shown to be effective up to 36 h after dosing and, in some patients, as early as 16 min after dosing. Patients may initiate sexual activity at various times after dosing in order to determine their own optimal window of responsiveness. They will be instructed to take no more than one dose per day.
Patient dosing instruction sheet given to patients participating in LVEF, LVEG, LVDZ, LVEL, and LVDW clinical studies.
In clinical studies, IC351 (tadalafil) has shown to be effective up to 36 h after dosing and, in some patients, within 30 min 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 h 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 (tadalafil) well in advance of anticipated sexual activity.
The following are some possible ways you might choose to take study drug: