Tadalafil is used orally as vasoactive therapy to facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence). Tadalafil may be used as needed (on demand) or on a daily basis (without regard to timing of sexual activity).
Assessment of the clinical need for ED therapy, including the use of tadalafil, should take into account the psychologic effect on the man and his partner. With the availability of orally active and convenient vasoactive (erectogenic) therapies (e.g., selective phosphodiesterase [PDE] type 5 inhibitors such as sildenafil, tadalafil, and vardenafil), most experts (e.g., the American Urological Association [AUA]) now consider these drugs to be first-line therapies for a broad range of patients with ED unless contraindicated. Although differences in the pharmacokinetics and certain adverse effects (e.g., potential visual effects, back pain, QT prolongation) exist, data currently are insufficient to support the superiority of one selective PDE type 5 inhibitor over another. However, tadalafil generally has a slower onset but substantially longer duration compared with sildenafil or vardenafil.
The safety and efficacy of as-needed therapy with tadalafil in men with ED of various etiologies are based principally on the results of 7 randomized, double-blind, placebo-controlled trials of 12 weeks' duration. In these and other trials of up to 24 weeks' duration in patients with ED, including trials in individuals with diabetes mellitus or those who had undergone bilateral nerve-sparing radical prostatectomy, tadalafil (2.5-20 mg, generally 5, 10, or 20 mg) produced clinically important improvement in erectile function that did not diminish over time. In these clinical trials, patients generally were allowed to choose the interval between drug administration and sexual activity. In 2 clinical trials specifically evaluating efficacy of tadalafil 20 mg at 24 hours (range: 22-26 hours) and 36 hours (range: 33-39 hours) after administration, the proportion of patients reporting at least 1 successful intercourse at each of these time points was higher with tadalafil (61 or 64% at 24 or 36 hours, respectively) than with placebo (37% of patients at each time point).
The safety and efficacy of once-daily therapy with tadalafil are based principally on the results of 3 multicenter, double-blind, placebo-controlled trials of 12- or 24-weeks' duration in men with ED of various etiologies. In 2 of these trials in patients with ED, including in those with complications from diabetes mellitus, hypertension, hyperlipidemia, or prostatic disease, tadalafil (2.5, 5, or 10 mg once daily) produced clinically important improvements in erectile function. The mean per-patient rate of maintenance of erection to successful completion of intercourse was 50 or 57% with 2.5 or 5 mg of tadalafil, respectively, in the 24-week trial compared with 31% with placebo; the per-patient rate for this efficacy measure in the 12-week trial was 67 or 37% for tadalafil 5 mg or placebo, respectively. In the 24-week clinical trial, these effects did not diminish over time. In another randomized, double-blind, placebo-controlled trial in patients with ED and diabetes mellitus, the mean per-patient rates of maintenance of erection to successful completion of intercourse were 46 or 41% with 2.5 or 5 mg of tadalafil, respectively, compared with 28% with placebo.
Like sildenafil and vardenafil, tadalafil is effective only in the presence of adequate sexual stimulation.
Benign Prostatic Hyperplasia
Tadalafil is used for the symptomatic management of patients with benign prostatic hyperplasia (BPH, benign prostatic hypertrophy). In clinical studies, tadalafil improved lower urinary tract symptoms associated with BPH (e.g., urinary frequency, urgency, nocturia, straining, incomplete emptying, weak urinary stream) but generally did not affect peak urinary flow rate or postvoid residual volume.
Efficacy and safety of once-daily tadalafil therapy for the symptomatic management of BPH are based principally on the results of 3 multinational, double-blind, placebo-controlled studies of 12 weeks' duration. Two of these studies included men with BPH alone; the third study included men with both BPH and ED. In the 2 studies evaluating the effects of tadalafil in men with BPH alone (i.e., without ED), treatment with tadalafil 5 mg once daily substantially improved the scores for severity of irritative (e.g., frequency, urgency, nocturia) and obstructive (e.g., incomplete bladder emptying, stopping and starting urination, weak stream, pushing or straining on urination) symptoms of BPH as measured by a 4-week recall questionnaire (International Prostate Symptom Score [IPSS]). A reduction in symptoms was observed at 4 weeks and continued throughout the remainder of the study periods. Tadalafil therapy also was associated with an improvement in quality of life (e.g., as measured by the Benign Prostatic Hyperplasia Impact Index [BII]); however, changes in peak urinary flow rate and postvoid residual volume with tadalafil were not substantially different from those with placebo. Results of an open-label extension study in patients with symptomatic BPH indicate that improvements in lower urinary tract symptoms are maintained during long-term (e.g., 1 year) tadalafil therapy.
The combination of tadalafil and an α-adrenergic blocking agent (e.g., doxazosin, terazosin) currently is not recommended for the treatment of BPH because of inadequate data and the potential for additive vasodilatory and hypotensive effects.
(See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions: Warnings/Precautions.)
Concomitant Erectile Dysfunction and Benign Prostatic Hyperplasia
Tadalafil also is used in the management of coexisting ED and symptomatic BPH. In a randomized, placebo-controlled study, tadalafil 5 mg once daily improved ED (as measured principally by the International Index of Erectile Function-Erectile Function [IIEF-EF] domain score) and symptoms of BPH (as measured principally by the total IPSS score) in men with both conditions; a dosage of 2.5 mg once daily improved IIEF-EF but not IPSS. Tadalafil 5 mg once daily resulted in substantial improvement in maintenance of erection to successful intercourse. In addition, a reduction in the IPSS score was observed at 2 weeks and remained decreased throughout the remainder of the 12-week study. Although peak urinary flow rates were increased from baseline with tadalafil in this study, these changes were not substantially different from those with placebo.
Pulmonary Arterial Hypertension
Tadalafil is used for the management of pulmonary arterial hypertension (PAH; World Health Organization [WHO] group 1 pulmonary hypertension) to improve exercise capacity. Clinical studies establishing efficacy of tadalafil for the treatment of PAH were conducted principally in patients with New York Heart Association (NYHA)/WHO functional class II-III symptoms and a diagnosis of idiopathic or heritable PAH or PAH associated with connective tissue diseases.
In addition to general treatment measures and supportive therapy (e.g., warfarin anticoagulation, diuretics, supplemental oxygen, digoxin), experts recommend PDE type 5 inhibitors (e.g., sildenafil, tadalafil) as one of several treatment options for the initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed; alternative therapies include endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan), soluble guanylate cyclase stimulators (e.g., riociguat), or prostanoids (e.g., IV epoprostenol; inhaled iloprost; inhaled, IV, or subcutaneous treprostinil. Current guidelines for the management of PAH state that an oral agent such as a PDE type 5 inhibitor generally is preferred for initial therapy in patients with NYHA/WHO functional class II symptoms, while those with more advanced NYHA/WHO functional class III disease may be treated with any currently approved PAH therapy; IV epoprostenol generally is recommended as the treatment of choice for patients with NYHA/WHO class IV PAH because of its demonstrated survival benefit. In general, choice of PAH therapy should be individualized, taking into account factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.
Efficacy of tadalafil for the treatment of PAH has been established in a 16-week randomized, double-blind, placebo-controlled study in patients 12 years of age or older with PAH (i.e., resting mean pulmonary artery pressure of 25 mm Hg or more with a pulmonary capillary wedge pressure of 15 mm Hg or less and pulmonary vascular resistance of 3 Wood units or more). The study population consisted principally of patients with idiopathic or familial pulmonary hypertension or PAH associated with connective tissue disease, with the majority having NYHA functional class II or III symptoms at baseline. Patients who were receiving stable dosages of bosentan prior to study entry (approximately 53%) were allowed to continue such therapy; however, other PAH-specific therapies such as prostacyclin or prostacyclin analogs were not permitted. Tadalafil was administered at a dosage of 2.5, 10, 20, or 40 mg once daily in this study. Treatment with tadalafil 40 mg once daily resulted in substantial improvements in exercise capacity, as measured by the change from baseline to 16 weeks in 6-minute walking distance (placebo-corrected mean increase of 33 m at 16 weeks); the improvement was apparent after 8 weeks of therapy and maintained throughout the duration of the study. Patients who were receiving tadalafil without concomitant bosentan therapy had greater improvements in walking distance than those receiving both drugs (44 versus 23 m, respectively). Although dose-related increases in walking distance were observed with other tadalafil dosages evaluated in this study, the improvements were not statistically significant. Time to clinical worsening (defined as death, lung or heart-lung transplantation, atrial septostomy, hospitalization for worsening PAH, initiation of new PAH therapy, or worsening functional WHO class) was substantially improved in patients receiving tadalafil 40 mg once daily; however, tadalafil did not affect WHO functional class.
Preliminary results of a long-term, uncontrolled extension of the placebo-controlled study suggest that improvements in exercise capacity are maintained with tadalafil for at least 10 months; a survival rate of 96.5 per 100 patient-years was reported in this extension study.
Current expert consensus guidelines recommend combination therapy in patients who have an inadequate response to initial monotherapy with a PAH-specific agent. Combination therapy with drugs that target the different pathophysiologic pathways in PAH may provide additive and/or synergistic benefits. These experts state that combined use of a PDE type 5 inhibitor with a prostanoid or an endothelin-receptor antagonist (added sequentially) may be considered; however, concomitant use of PDE type 5 inhibitors and riociguat is contraindicated because of the risk of hypotension.
(See Drug Interactions: Riociguat.)