A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy

Selective phosphodiesterase type 5 inhibitors (PDE5Is) have revolutionized the treatment of erectile dysfunction (ED) in men. As an on-demand treatment, PDE5Is have excellent efficacy and safety in the treatment of ED due to a broad spectrum of etiologies. Nevertheless, these drugs do have side-effect profiles that are troublesome to some patients, eg, headache, dyspepsia, myalgia, etc. Furthermore, many patients and their partners dislike the necessity of on-demand treatment for ED, citing a desire for greater spontaneity with sexual interactions. In 2008, approximately 10 years after the release of the first commercially available PDE5I, a paradigm shift in the management of ED occurred with the approval of once-daily dose of tadalafil by the US Food and Drug Administration for the management of ED. The prolonged half-life of tadalafil lends itself well to this dosing regimen and conveys the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. In this study, we review the current state of the art with respect to this new management strategy for ED, highlighting published reports of the efficacy and tolerability of the daily dose tadalafil regimen.

Introduction

Erectile dysfunction (ED) is defined as the persistent and/or recurrent inability to attain and/or maintain a penile erection sufficient for satisfactory sexual intercourse.1 This problem is prevalent throughout the world and is strongly associated with age-related comorbidities; hence, the incidence of ED will likely increase dramatically as the world’s population ages.2 ED is associated with substantial psychological distress for both men and their partners and has been clearly linked to cardiovascular health problems both as a comorbid condition and as a sentinel event for serious vascular diseases in the future.2–5

In this modern era, selective phosphodiesterase type 5 inhibitors (PDE5Is) are the mainstay of treatment for ED.6 These medications are highly efficacious, are well tolerated, and have very favorable safety profiles. In the United States, 3 PDE5Is are currently available; sildenafil (Viagra ® , Pfizer), vardenafil (Levitra ® , Bayer), and tadalafil (Cialis ® , Lilly-ICOS).7 Each of these drugs is highly efficacious in the management of ED although pharmacokinetic and side-effect profiles differ and results for each drug may vary for individual men.7,8 Another PDE5I, udenafil, has been approved for use in South Korea, and a number of novel PDE5Is are currently in various stages of development.9,10

Tadalafil was approved for use in the United States in November 2003, after both sildenafil and vardenafil were approved.11 Tadalafil differs from the other 2 PDE5Is in that the absorption does not appear to be influenced by the intake of fatty meals or alcohol.11 Peak serum concentration is attained about 2 hours postdose rather than 1 hour as occurs with the other 2 PDE5Is.12 Tadalafil is also unique in that it has a long elimination half-life of approximately 18 hours.13 The potential advantage of this prolonged duration of action is that the other medications can be separated temporally from sexual activity.14 The theoretical impact of this pharmacokinetic property is that sexual spontaneity may be more easily restored using this medication.15 However, the prolonged half-life of tadalafil also makes it more prone to long-lasting adverse effects (such as headache) relative to the other PDE5Is, with up to 30% of men on tadalafil treatment reporting side effects lasting greater than 12 hours.16 Importantly, chronic dosing of tadalafil has not been shown to lead to upregulation of PDE5 in human penile tissue,17 an effect that has been observed in rat penile tissue exposed continuously to high doses of sildenafil.18 This difference may theoretically make tadalafil less likely than sildenafil to lose its efficacy over time due to tachyphylaxis.

There has long been a substantial interest in routine dosing of PDE5Is as a new and novel approach to the management of ED. The advantage of daily dosing for management of ED is the complete separation of medication use from sexual activity.14,19 Furthermore, routine low-dose exposure may diminish overall drug exposure in men who engage in sexual intercourse more than twice weekly and may minimize side effects in men who have trouble tolerating higher doses of the PDE5I.19,20

The prolonged half-life of tadalafil makes it ideally suited for daily dosing and attainment of steady-state serum levels.21,22 In the multicenter, randomized, Scheduled Use versus on-demand Regimen Evaluation (SURE) study, 4,262 men with ED were treated with 20 mg of tadalafil 3 times weekly or 20 mg on-demand in a 12-week cross-over design. At follow-up, more than 60% of men in both arms reported normalization of erectile function. More than 70% of men in both groups reported ability to successfully penetrate and complete sexual intercourse relative to 21% at baseline. There were no differences in success rate between routine and on-demand dosing for any efficacy parameter.23 There was a substantial difference in the timing of intercourse between the treatment arms, with 53% of attempts in the on-demand arm and 29% of attempts in the routine dose arm occurring within 4 hours of dosing.24 This suggests that greater flexibility with respect to timing was possible in the routine dose group. Although efficacy data did not demonstrate a difference, the 3 times a week dosing regimen for tadalafil was preferred only by 43% of enrolled patients.25 Although on-demand therapy was preferred by a majority of men, it was apparent that routine dosing was also a good option for a substantial minority of subjects.

The SURE study was 1 of the first of many studies investigating the utility of chronic dosing for tadalafil. These efforts culminated, in 2008, in US Food and Drug Administration’s approval of tadalafil at a 2.5-mg or 5-mg daily dose for the management of ED.11,19 This paradigm shift in the management of ED represented not only a new way to treat the condition but also a change in our conception of the disorder; ED is no longer strictly a situational problem in need of on-demand treatment but rather is a chronic condition that can be managed with routine-dose pharmacotherapy.

In this study, we will discuss the current state of the art for daily dose of tadalafil in the management of ED from the studies published before April 2010. The particular areas of investigation will include safety, efficacy, and compliance. Routine-dose tadalafil is also under investigation for a number of non-ED conditions;26–28 however, in the interest of conciseness, we will focus our attention on indications related to erectile function.

A literature review was conducted to obtain all publications pertaining to routine-dose tadalafil. The search terms used on PubMed included tadalafil, ED, daily dosing, routine dosing, and Cialis. Manuscripts were identified and selected based on their relevance to the subject matter of daily dose tadalafil for ED. Selected manuscripts were read and critically reviewed. Particular attention was directed to manuscripts based on randomized, double-blind, placebo-controlled studies (RDBPCSs).

Assessing efficacy of ED treatments

When interpreting data on efficacy in the ED literature, it is essential to be familiar with the existing validated instruments for assessment of treatment response. The International Index of Erectile Function (IIEF) is the most widely used quantitative validated scale for studies of ED treatments. Consisting of 15 items covering 5 domains of male sexual function, it is most commonly utilized to assess the change in erectile function after treatment.33 Six items of the IIEF pertain directly to erectile function and comprise the IIEF erectile function domain (IIEF-EF or IIEF-6; score range 5–30).33 A score of 26–30 points on the IIEF-EF is generally consistent with normal erectile function, with progressively lower scores indicative of ED of worsening severity (22–25 = mild ED, 17–21 = mild to moderate ED, 11–16 = moderate ED, and ≤10 = severe ED).34 Additional domains of sexual function assessed by the IIEF include sexual desire, intercourse satisfaction, orgasmic function, and overall satisfaction.33 Although similar but distinct instruments for the assessment of ED (such as the IIEF-5 or Sexual Health Inventory for Men) are also used in both clinical and research contexts, most studies of daily dose tadalafil to date are relied mostly on IIEF-EF domain scores.

The sexual encounter profile (SEP) questions are also common end points for studies of ED treatments.35 Designed as diary entries to be made after each attempt at sexual inter-course, the SEP profile consists of 5 questions, each of which is primarily dependent on an affirmative response to the prior question. The SEP questions are in the following order – SEP1: “During sexual activity, did your penis become erect?” SEP2: “Whether you were able to insert your penis into your partner’s vagina?” SEP3: “Did your erection last long enough for you to have a successful intercourse?” SEP4: “Are you satisfied with the hardness of your erection?” SEP5: “Are you overall satisfied with this sexual experience?”35 Although the instruments are subjective in nature, they do encompass the efficacy of any given drug treatment in a simple “yes” and “no” fashion.

Efficacy of daily dose tadalafil

There have been numerous trials of tadalafil as a routine dose therapy. Many of the published reports have included analyses of existing older data sets with new statistical methods or primary outcome measures. A summary of all publications derived from RDBPCSs is presented in Table 1 . Statistical significance is set at P ≤ 0.05 for all of the studies detailed below unless otherwise noted.

Partner preference studies

The impact of tadalafil daily dosing on female partners’ satisfaction with sexual activity has also been a topic of recent interest and research. A partner preference study of on-demand sildenafil vs tadalafil indicated that 79% of female partners preferred tadalafil, citing a more relaxed approach to sexual intimacy and greater flexibility with respect to timing of intercourse.51 Based on this, it may be inferred that the flexibility of completely separating medication from sexual activity (as is the case for daily dose therapy) would be appealing to many female partners of men with ED.

Summary statement of efficacy

It is clear from numerous high-quality studies that tadalafil as a daily dose is highly efficacious in the management of ED from a variety of causes. It is also clear that daily dose of tadalafil will have a beneficial effect on the sexual relationship between partners.

Side-effect profile of daily dose tadalafil

Side effects from daily dose tadalafil in clinical trials have generally been mild, with 54%–80% of reported events mild in nature and with no more than a third of events moderate in severity.21,42 Serious side effects have not been reported in some studies; in studies where serious events occurred, the effect was considered not to be related to the study drug itself.42,52 Although the effects may be mild, it should be noted that the prolonged half-life of tadalafil may tend to produce side effects of longer duration compared with PDE5I with shorter half-lives.16 Steady-state kinetics have been observed in daily dose tadalafil, with the steady-state levels being roughly 1.6 times greater than those of a single dose. Although this might lead to a greater incidence of side effects, this dosing regimen may permit lower dosing overall.19,20 A summary of reported incidence of the most commonly reported side effects in RDBPCSs is presented in Table 2 .

In a report on open-label extension of tadalafil, 53% of subjects reported at least 1 adverse event in 1 year and 73% within 2 years of therapy.48 Generally, the incidence of these side effects declines over time on chronic therapy.48 The rate of consistent bothersome side effects (headache, back pain, dyspepsia, etc) of on-demand therapy with tadalafil has not been measured to be greater than 10%.43 Discontinuation rates due to the side effects of medication are reportedly between 1% and 6%21,42,46–48,52 although higher rates of discontinuation (

10%) have been reported in studies in which men received 20 mg of tadalafil daily for months on end.55

The most common side effects of daily dose tadalafil include headache (1%–14%), dyspepsia (1%–11%), facial flushing (7%–8%), nasal congestion (6%–7%), back pain (2%–11%), myalgias (1%–5%), abdominal pain (3%–9%), and dizziness (1%–4%).21,42,46,47,52 In some studies, side effects were more common at higher dosages of tadalafil,42,49,55 but this dose–response relationship was not confirmed in every study.21,50 In at least 1 study, there was no significant difference in the rate of side effects between the treatment and the placebo arms,52 but other studies suggested that flushing, dyspepsia, back pain, abdominal pain, and myalgia were more frequent with tadalafil than placebo.42,49,50

Tadalafil and hemodynamics

In 2 small randomized controlled trials of short (<1 month) duration, the influence of daily dose of 5 mg tadalafil on hemodynamic parameters in healthy men given α blockers (doxazosin or tamsulosin; n = 45 and 39, respectively) was assessed. There was essentially no change in the mean standing systolic blood pressure or the heart rate between placebo- and tadalafil-treated men on either α blocker. One man, in both the tamsulosin and the doxazosin 4-mg arms experienced a standing systolic blood pressure of <85 mm Hg while taking tadalafil; this rate did not differ significantly from what was observed in placebo-treated men.57 Generally, studies have been congruous with this one, suggesting a very low rate of clinically significant hypotension with tadalafil with or without α blockers; this effect held true regardless of the dosing regimen (on-demand, daily, etc).58

Ophthalmology effects of daily dose tadalafil

A study of ophthalmological effects of daily placebo vs daily dose tadalafil (5 mg) or sildenafil (50 mg) in 244 subjects (194 of whom completed the 6-month protocol) detected a significantly higher increase in β-wave amplitude during electroretinographic response to flash in light-adapted eyes for tadalafil relative to placebo. There were no other significant differences in the rate of ophthalmological abnormality or in the morbidity from drug treatment at study conclusion and 4–6 weeks after cessation of treatment. Additional parameters assessed included the combined electroretinographic response to flash after darkness adaptation, visual acuity, color discrimination, visual-field testing, and intraocular pressure. The only ophthalmological adverse event was a retinal artery occlusion in 1 patient in the placebo arm.38 Based on the relatively similar results, the authors concluded that there is no evidence to suggests clinically relevant side effects from this daily dose regimen.

Daily tadalafil and semen parameters

In the largest and longest duration study of tadalafil and its affect on male reproduction, Hellstrom et al55 investigated the influence of high-dose (20 mg) daily tadalafil for 9 months, with a 6-month follow-up in men older than 45 years of age. All men enrolled had normal values for testosterone, gonadotropins, and semen parameters that were within the World Health Organization reference ranges. This double-blind, placebo-controlled, randomized, noninferiority trial enrolled 253 men, 191 (75%) of whom completed the 9-month protocol and 179 (70%) of whom completed the 6-month follow-up. The geometric mean sperm concentration was significantly lower in tadalafil-treated men at 9-month follow-up, 54.3 M/mL vs 63.4 M/mL in placebo, although after adjustment for multiple comparisons, the difference was no longer strictly significant (P = 0.06) and was not apparent after 6-month wash-out. A 50% decline in sperm concentration was reported in 2 (2%) of placebo-treated men compared with 12 (13%) of tadalafil-treated men at 9-month follow-up. Although the difference was substantial, it did not meet the criteria for inferiority given the upper 95% confidence interval for proportion of subjects with a greater than 50% decline on concentration was 17.5%, less than the 20% prescribed for inferiority. Interestingly, the mean ejaculatory frequency was significantly higher in men who experienced a greater than 50% drop in sperm concentration compared with those who did not (5.4 times per week vs 2.9 times per week, respectively). After 6 months of drug wash-out, sperm concentrations returned to baseline in 8 of 12 men treated with tadalafil and 1 of 2 treated with placebo.55 Fertility may not be a concern for many men taking tadalafil, and the study by Hellstrom et al55 did not conclusively demonstrate a negative influence on sperm parameters; indeed, it is possible that the much higher ejaculatory frequency in men who experienced a greater than 50% decline in sperm concentration was responsible for the results observed. Furthermore, the doses used in this study were much higher than those recommended for daily dose therapy. Be that as it may, the trend toward a decline in sperm concentration in some men is of note and should be kept in mind by men taking tadalafil who are concerned about conceiving children.

Daily tadalafil and serum androgen levels

In the study of semen parameters by Hellstrom et al,55 it was determined that the mean change in serum testosterone after 9 months of daily dose tadalafil (20 mg) was significantly higher in the treatment group relative to the placebo group (P = 0.01 before adjustment and P = 0.03 after adjustment for multiple comparisons). Mean serum of luteinizing hormone (LH) was also significantly higher (P = 0.05) in the treatment group at the 9-month time point; this relationship was not significant after the adjustment for multiple comparisons (P = 0.21). Free testosterone level was not found to be affected by the treatment.55 Although strict clinical and statistical significance for difference in serum testosterone was not met, it is somewhat intriguing to speculate that tadalafil might have some sort of impact (either direct or indirect) on testosterone levels by a centrally mediated mechanism involving LH secretion because of the absence of a local effect on the testes themselves as noted by the authors.55 Although this explanation is strictly hypothetical, enhancement of erectile and sexual functions may have led to secondary changes in neurochemical modulation of testosterone secretion by psychogenic mechanisms. To our knowledge, this effect has not been confirmed and this finding may be worthy of further investigation and verification.

Miscellaneous and potential side effects of tadalafil

Although the clinical relevance is not entirely clear, a single 20-mg dose has been shown to produce detectable electroencephalographic changes in up to 34% of healthy men.59 Animal studies have demonstrated a blunting of the cerebral vasoconstrictive response to hyperbaric oxygen therapy and subsequent lowering of seizure threshold in tadalafil-treated rats.60 The clinical relevance of these findings is unclear, but these may be important topics for future research. PDE5Is have also been associated with sudden sensorineural hearing loss,61 and studies of audiometric properties in men and experimental animals using sildenafil or vardenafil have suggested changes in hearing.62,63 Although we are not aware of any published studies directly linking tadalafil to hearing changes, the possibility of a PDE5I class effect on hearing must be considered and taken seriously by patients and providers.

Future directions for daily dose tadalafil therapy

Although the evidence at this time is scanty, it is tantalizing to speculate that daily therapy with a PDE5I such as tadalafil may produce beneficial humoral and tissue effects, which tend to be erection protective. More research is required to determine what role these drugs may play in maintenance of sexual health rather than simple treatment of sexual problems.

Tadalafil is the first ED treatment approved for daily dosing. This represents an important change in our conception of ED as a disorder and has the potential to dramatically alter the way we approach this prevalent and vexing concern. Although not necessarily the optimal management schema for every man with ED, this exciting dosing option has the potential to expand our capacity to care for men with ED in a novel and unprecedented direction.