BERKELEY, CA (UroToday.com) - The primary treatments for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) are alpha-1 adrenergic receptor antagonists (ARA) and 5-alpha reductase inhibitors (5-ARI). Tadalafil, along with other phosphodiesterase (PDE)-5 inhibitors, have been shown to improve LUTS in patients with BPH. The initial positive findings were first seen in secondary analyses in patients treated for erectile dysfunction (ED). There is a high prevalence of ED with co-morbid BPH-related LUTS ranging from 43 – 84%. Positive results from pivotal trials led to the expanded indication of tadalafil to “the signs and symptoms of BPH and ED and the signs and symptoms of BPH” by the FDA in October 2011. Our review assessed the use of PDE-5 inhibitor monotherapy from 5 randomized, double-blind, placebo-controlled trials published prior to January 2012.[5, 6, 7, 8, 9] These trials showed improvements in the International Prostate Symptom Score (IPSS) by 1.9 to 4.9 points when compared to placebo. A follow up PubMed search, revealed no new trials assessing the use of tadalafil monotherapy in men with BPH related LUTS. No update has been made in the American Urological Association (AUA) Guidelines since tadalafil received an indication for BPH. Currently, there is no clear guidance on how to best incorporate this agent with a novel mechanism of action.
There are several considerations that may limit widespread use of PDE-5 for treatment. First, there is a well-established drug-interaction with ARA. Co-administration of PDE-5 inhibitors and ARA can result in an additive blood pressure lowering effect. A randomized, double-blind, placebo-controlled trial of healthy patients compared tadalafil plus the non-selective ARA, doxazosin, to tadalafil plus tamsulosin which is selective for the alpha-1a receptor. There was a greater than 20 mm Hg decrease in systolic blood pressure in 28% of patients in the doxazosin plus tadalafil group with no clinically significant changes in blood pressure in patients receiving tadalafil plus tamsulosin. Moreover, in a cross-over analysis comparing doxazosin plus tadalafil and tamsulosin plus tadalafil, there was a higher incidence of clinically important hypotension in those receiving doxazosin plus tadalafil. Based on these studies, non-selective ARAs like doxazosin may be poorly tolerated when used in conjunction with PDE5; whereas, the newer alpha-1a receptor antagonists, like tamsulosin, appear to have less risk.
Second, tadalafil and other PDE-5 inhibitors were studied primarily as monotherapy. There are limitations to the studies examining the role of combination therapy with ARAs. A cross-over study of 30 patients assessed tamsulosin plus placebo and tamsulosin plus tadalafil. There was a significant reduction in IPSS in tamsulosin plus tadalafil compared to tamsulosin alone (-2.5; p<0.05) with two patients experiencing hypotension. Third, there is limited information on the impact of PDE-5 inhibitors on long-term complications of BPH such as acute urinary retention and avoidance of prostate surgery as is available with ARA and 5ARI.
Based on the available data, future AUA guidelines in BPH may recommend tadalafil monotherapy for men with concomitant BPH-related LUTS, with or without ED. Specifically, it may be useful as monotherapy in patients without an enlarged prostate and considered to be poor candidates for ARA, due to orthostasis, low baseline blood pressure, or sexual side effects. Moreover, smaller studies do show minimal adverse drug events and statistically significant, but not necessarily clinically significant, improvements in IPSS in combination tadalafil with an alpha-1a receptor antagonist compared to PDE-5 inhibitor monotherapy. Currently, with the dearth of studies examining combination PDE-5 inhibitor and ARAs, it is an unknown as to how combination therapy will be incorporated into practice.
- American Urological Association Guideline: Management of benign prostatic hyperplasia (BPH), revised 2010. Accessed at: www.auanet.org/common/pdf/education/clinical-guidance/Benign-Prostatic-Hyperplasia.pdf. Accessed on October 8, 2013.
- Cialis (tadalafil). Prescribing information. Eli Lilly and Company: Indianapolis, IN: October 2011.
- Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
- Cantrell MA, Baye Jordan, Vouri SM. Tadalafil: a phosphodiesterase-5 inhibitor for benign prostatic hyperplasia. Pharmacotherapy.2013;33(6):639-649.
- McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407.
- Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234.
- Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E . A Randomised, Placebo-Controlled Study to Assess the Efficacy of Twice-Daily Vardenafil in the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Eur Urol. 2008;53(6):1236-1244.
- Porst H, Kim ED, Casabe AR, et al. Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International Randomized, Double-Blind, Placebo-Controlled Trial. Eur Urol. 2011;60(6):1105-1113.
- Egerdie RB, Auerbach S, Roehrborn CG, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med. 2012;9(1):271-281.
- Kloner RA, Jackson G, Emmick JT, et al. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol. 2004;172(5):1935-1940.
- Guillaume M, Lonsdale F, Darstein C, Jimenez MC, Mitchell MI. Hemodynamic interaction between a daily dosed phosphodiesterase 5 inhibitor, tadalafil, and the alpha-adrenergic blockers, doxazosin and tamsulosin, in middle-aged healthy male subjects. J Clin Pharmacol. 2007;47(10):1303-1310.
- Bechara A, Romano S, Casabe A, Haime S, et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot Study. J Sex Med. 2008;5:2170-2178.
Scott Martin Vouri, PharmD, BCPS, CGPa and Matthew A. Cantrell, PharmD, BCPSb, c as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aDivision of Pharmacy Practice, St. Louis College of Pharmacy, St. Louis, Missouri
bDepartment of Pharmacy Practice and Science, University of Iowa College of Pharmacy, Iowa City, Iowa
cIowa City VA Health Care System, Iowa City, Iowa