What evidence is there for use of doses over 5 mg of tadalafil for treatment of BPH?

Comment by InpharmD Researcher

The available evidence does not strongly support the use of tadalafil doses >5 mg for treating BPH, due to the lack of data directly comparing between doses. While one urodynamic study suggested higher doses (e.g., 20 mg) were not associated with adverse effects, most meta-analyses found significant benefits only with the 5 mg dose, particularly for Qmax. Primarily literature observed a trend towards greater effects with higher doses, but robust efficacy and safety comparisons to confirm a benefit is lacking.

Background

A 2015 systematic review and meta-analysis evaluated the clinical efficacy of phosphodiesterase type 5 inhibitors (PDE5-Is), including tadalafil, in the management of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), both with and without concurrent erectile dysfunction (ED). The analysis incorporated data from 16 randomized, double-blind, placebo-controlled trials to assess the various primary outcomes. Tadalafil 2.5 mg, 5 mg, 10 mg, and 20 mg were only assessed together for the outcome of maximum urinary flow rate (Qmax) in LUTS/BPH, which was found to not be statistically significant (effect estimate 0.22; mean difference -0.04 to 0.49; p= 0.10). There did not appear to be any further assessments for tadalafil doses > 5 mg. In contrast, the 5 mg dose of tadalafil alone significantly improved the Qmax (mean difference 0.33; p= 0.03). [1]

Additionally, a 2013 meta-analysis synthesized data from eight randomized, double-blind, placebo-controlled trials involving 2,913 male participants to evaluate the efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). The trials included patients aged ≥45 years with moderate to severe LUTS (International Prostate Symptom Score [IPSS] ≥13) and peak urinary flow rate (Qmax) ranging between 4–15 mL/s. Tadalafil was administered in once-daily doses of 2.5, 5, 10, or 20 mg across intervention arms with durations up to 12 weeks. Primary endpoints included changes from baseline in IPSS, International Index of Erectile Function (IIEF), and Qmax, while secondary outcomes were stratified into IPSS subdomains (irritative and obstructive), IPSS-related quality-of-life (QoL) index, and the BPH Impact Index (BII). Notably, while tadalafil at all doses did not result in statistically significant improvements in Qmax (mean difference +0.26 mL/s; p = 0.14), a focused analysis of the 5 mg dose revealed a modest but significant increase in Qmax (+0.63 mL/s; p= 0.04). In terms of safety, adverse events were overall more frequent in the tadalafil group (12.6% vs 4.8% with placebo). One urodynamic study suggests that tadalafil at higher doses (20 mg once daily) was not associated with adverse effects. Overall,these findings support tadalafil 5 mg once daily as a well-tolerated and effective option for men with LUTS/BPH, particularly those with coexisting erectile dysfunction, but evidence for doses higher than 5 mg remains conflicting. [2]

References:

[1] Zhang LT, Park JK. Are phosphodiesterase type 5 inhibitors effective for the management of lower urinary symptoms suggestive of benign prostatic hyperplasia?. World J Nephrol. 2015;4(1):138-147. doi:10.5527/wjn.v4.i1.138
[2] Dong Y, Hao L, Shi Z, Wang G, Zhang Z, Han C. Efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a meta-analysis. Urol Int. 2013;91(1):10-18. doi:10.1159/000351405
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What evidence is there for use of doses over 5 mg of tadalafil for treatment of BPH?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

Tadalafil Administered Once Daily for Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Dose Finding Study
Design

Randomized, double-blind, placebo-controlled, parallel design, dose finding study

N= 1,058
Objective

To examine the efficacy, dose response, and safety of tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia
Study Groups

Placebo (n= 211)

Tadalafil 2.5 mg (n= 208)

Tadalafil 5 mg (n= 212)

Tadalafil 10 mg (n= 216)

Tadalafil 20 mg (n= 209)
Inclusion Criteria

Men at least 45 years old with a history of LUTS secondary to BPH of 6 months or longer, total I-PSS of 13 or greater, Qmax of 4 to 15 ml per second, voided volume of 125 ml or greater
Exclusion Criteria

prostate specific antigen (PSA) >10 ng/ml, PVR volume ≥300 ml, recent finasteride or dutasteride treatment, penile or pelvic surgery, urinary retention, bladder stones, neurological conditions affecting bladder function, significant renal or hepatic insufficiency, cardiovascular conditions, recent stroke or spinal cord injury, current treatment with nitrates, cancer chemotherapy, antiandrogens, or potent cytochrome P450 3A4 inhibitor, uncontrolled diabetes
Methods

After a 4-week placebo run-in period, participants were randomly allocated to receive 12-week, once daily treatment with placebo or tadalafil (2.5, 5, 10, or 20 mg). 
Duration 12 weeks
Outcome Measures

Primary: I-PSS change from baseline

Secondary: I-PSS irritative and obstructive subscores, I-PSS QOL index, BPH-II, GAQ, IIEF-EF, Qmax
Baseline Characteristics Characteristic Placebo (n= 211) Tadalafil 2.5 mg (n= 208) Tadalafil 5 mg (n= 212) Tadalafil 10 mg (n= 216) Tadalafil 20 mg (n= 209)
Mean age (range) 61.75 (45.59–80.62) 62.03 (44.99–92.64) 61.95 (46.10–85.60) 62.22 (45.53–80.04) 62.55 (45.81–79.47)
% Younger than 65 64.93 61.06 64.62 63.89 58.85

% Race or ethnic group

White

Hispanic

Black

Other

 

84.83

13.74

1.42

0

 

88.46

9.62

1.44

0.48

 

84.43

11.79

3.30

0.47

 

86.11

11.11

2.31

0.46

 

84.21

11.96

2.39

1.44
% Previous α-blocker use 29.86 29.33 27.83 26.85 30.14
Mean PSA (range) 1.65 (0.03–9.21) 1.71 (0.19–8.78) 1.79 (0.11–6.69) 1.82 (0.21–6.83) 1.73 (0.18–5.92)
Results Endpoint Placebo Tadalafil 2.5 mg Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg p-value vs placebo

I-PSS change from baseline

Irritative subscore

Obstructive subscore

QOL subscore

 

-2.27

-0.99

-1.26

-0.49

 

-3.88

-1.58

-2.23

-0.74

 

-4.87

-1.89

-2.94

-0.86

 

-5.17

-1.96

-3.13

-0.92

 

-5.21

-2.07

-3.12

-0.88

 

<0.001

<0.01

<0.001

<0.01
BPH-II change from baseline -0.83 -0.96 -1.40 -1.38 -1.45 <0.05
Qmax change from baseline, cm/sec 1.24 1.41 1.64 1.58 1.96 Not significant
Yes Lower urinary tract symptoms GAQ endpoint 54.8% 61.9% 69.2% 73.0% 74.2% <0.05
Sexually active erectile dysfunction IIEF-EF change from baseline 2.20 5.59 6.97 7.98 8.34 <0.001

BPH-II: BPH Impact Index; GAQ: Global Assessment Question; IIEF: International Index of Erectile Function; IIEF-EF: IIEF Erectile Function domain; I-PSS: International Prostate Symptom Score; Qmax: peak urinary flow rate; QOL: quality of life
Adverse Events

Treatment emergent adverse events were infrequent in all tadalafil groups. Back pain, myalgia, and headache were more frequent at higher tadalafil doses but no clear dose relationship was evident.
Study Author Conclusions

Once daily tadalafil demonstrated clinically meaningful and statistically significant efficacy and it was well tolerated in men with benign prostatic hyperplasia lower urinary tract symptoms. Of the doses studied, 5 mg tadalafil appeared to provide a positive risk-benefit profile.
Critique

The exclusion of patients with certain comorbidities and the use of a placebo run-in period may limit the generalizability of the results to the broader population of men with BPH. Additionally, the study did not explore the long-term effects of tadalafil treatment beyond 12 weeks.

 

References:

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. doi:10.1016/j.juro.2008.06.079

Effects of Once-Daily Tadalafil on Erectile Function in Men with Erectile Dysfunction and Signs and Symptoms of Benign Prostatic Hyperplasia
Design

Post hoc analysis of a phase 2–3, multinational, randomized, double-blind, placebo-controlled, parallel-group study

N= 581
Objective To evaluate the effects of once-daily tadalafil on erectile function in men with erectile dysfunction (ED) and lower urinary tract syndrome secondary to benign prostate hyperplasia (BPH-LUTS)
Study Groups

Placebo (n= 115)

Tadalafil 2.5 mg (n= 113)

Tadalafil 5 mg (n= 117)

Tadalafil 10 mg (n= 120)

Tadalafil 20 mg (n= 116)
Inclusion Criteria

Men ≥45 years old with a history of BPH-LUTS >6 months, IPSS ≥13, and Qmax 4–15 ml/s; sexually active with a female partner
Exclusion Criteria

Not specified in the provided text
Methods

Screening and 4-week washout period for BPH/ED treatments; 4-week placebo run-in; 12-week treatment with once-daily placebo or tadalafil (2.5, 5, 10, or 20 mg).
Duration 12 weeks
Outcome Measures

Primary: IIEF-EF domain score improvements

Secondary: IPSS improvements, Qmax, and PVR changes
Baseline Characteristics Characteristic Placebo (n= 115)

Tadalafil 2.5 mg (n= 113)

 Tadalafil 5 mg (n= 117) Tadalafil 10 mg (n= 120) Tadalafil 20 mg (n= 116)

Erective dysfunction

Normal or mild (IIEF-EF 17–30)

Moderate (IIEF-EF 11–16)

Severe (IIEF-EF 1–10)

 

33 (28.7%)

69 (60.0%)

13 (11.3%)

 

38 (33.6%)

65 (57.5%)

10 (8.9%)

 

37 (31.6%)

67 (57.3%)

13 (11.1%)

 

45 (37.5%)

58 (48.3%)

17 (14.2%)

 

38 (32.8%)

67 (57.8%)

11 (9.5%)

ED duration

< 3 months

3- <6 months

6 months to < 1 year

1 year or more

 

1 (0.9%)

3 (2.6%)

15 (13.0%)

96 (83.5%)

 

5 (4.4%)

2 (1.8%)

14 (12.4%)

92 (81.4%)

 

0

2 (1.7%)

17 (14.5%)

98 (83.8%)

 

2 (1.7%)

1 (0.8%)

10 (8.3%)

107 (89.2%)

 

0

5 (4.3%)

17 (14.7%)

94 (81.0%)

IIEF-EF domain score, visit 2

IIEF-EF domain score, visit 3

16.1

17.3

17.1

17.4

15.6

15.3

15.8

17.2

16.0

16.3
Results Endpoint Placebo (n= 114)

Tadalafil 2.5 mg (n= 113)

 Tadalafil 5 mg (n= 117) Tadalafil 10 mg (n= 120) Tadalafil 20 mg (n= 115) p-value
IIEF-EF domain score change 2.0 ± 1.0 5.4 ± 1.0 6.8 ± 1.0 7.9 ± 1.0 8.2 ± 1.0 <0.001
IPSS change -2.1 ± 0.8 -3.6 ± 0.8 -4.2 ± 0.8 -4.7 ± 0.8 -4.7 ± 0.8 <0.05
Qmax change 1.9 ± 0.7 1.4 ± 0.7 1.7 ± 0.7 1.3 ± 0.7 2.0 ± 0.7 NS
PVR change -6.8 ± 8.4 8.6 ± 8.2 -1.8 ± 8.3 3.8 ± 8.0 -14.2 ± 8.3 NS

IIEF-EF: International Index of Erectile Function–Erectile Function; IPSS: International Prostate Symptom Score; Qmax; peak urinary flow rate; PVR: postvoid residual volume
Adverse Events

Common adverse events: headache, back pain, dyspepsia, and myalgia reported in ≥2% of tadalafil-treated patients. No deaths occurred. PVR change from baseline was significantly different with tadalafil 2.5 mg versus placebo, but not clinically relevant.
Study Author Conclusions

Once-daily tadalafil improved erectile function in sexually active men with ED and BPH-LUTS, supporting its use in this population. Tadalafil may improve EF in a broad group of men with ED and BPH-LUTS, independent of baseline characteristics.
Critique

The lack of a minimum number of sexual intercourse attempts required may have limited the ability to measure the full benefit of tadalafil. The absence of a control group without BPH-LUTS and the potential for type 1 error in subgroup analyses are limitations.
References:

Porst H, McVary KT, Montorsi F, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia [published correction appears in Eur Urol. 2011 Jun;59(6):1082]. Eur Urol. 2009;56(4):727-735. doi:10.1016/j.eururo.2009.04.033

Effects of Tadalafil on Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia in Men With or Without Erectile Dysfunction
Design

Randomized, placebo-controlled, double-blind, dose-ranging clinical trial

N= 1058
Objective To compare the safety and efficacy of the daily erectogenic therapy, tadalafil, on lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS) in men with or without comorbid erectile dysfunction (ED)
Study Groups

With ED (n= 716)

Without ED (n= 340)
Inclusion Criteria Men aged ≥45 years with a history of LUTS secondary to BPH for ≥6 months, an International Prostate Symptom Score (IPSS) ≥13, peak urinary flow rate (Qmax) 4-15 mL/s, and postvoid residual volume ≤300 mL at screening
Exclusion Criteria Men with no sexual intercourse attempts during the placebo run-in period or the subsequent months were not excluded
Methods

Following a 4-week placebo run-in period, men were randomized to placebo or tadalafil 2.5, 5, 10, or 20 mg once daily for 12 weeks. IPSS, IPSS quality of life, and BPH Impact Index were measured every 4 weeks. Safety was assessed via spontaneous reports of adverse events.
Duration August 2006 to October 2007
Outcome Measures

Primary: Change in IPSS from baseline to endpoint

Secondary: IPSS quality of life, BPH Impact Index
Baseline Characteristics Characteristic

With ED (n= 716)

Without ED (n= 340)
Age, y (mean ± SD) 62.6 ± 7.9 60.9 ± 7.7
Age ≥ 65 y 40.5% 30.7%
BMI, kg/m2 (mean ± SD) 28.6 ± 4.3 28.0 ± 4.1
Previous α-blocker use  29.8% 26.8%
Previous 5-ARI use 1.5% 1.4%
Sexually active 82.1% 77.3%
Hypertension 39.3% 28.8%
Hyperlipidemia 27.1% 19.4%
Coronary artery disease 13.8% 9.7%
Diabetes 12.4% 4.7%
IPSS (mean ± SD) 17.5 ± 5.8 17.1 ± 6.4
IPSS QoL (mean ± SD) 3.6 ± 1.2 3.6 ± 1.3
BII (mean ± SD) 4.9 ± 3.0 4.7 ± 2.8
Results Endpoint With ED Without ED Subgroup P/Interaction P

IPSS (LS mean ± SE)

2.5 mg

5 mg

10 mg

20 mg

 

-4.3

-4.8

-5.3

-5.6

 

-2.4

-3.2

-5.3

-5.1

 0.352/0.644
IPSS QoL (LS mean ± SE) -0.6 to -1.1 -0.6 to -0.9 .090/.773
BII (LS mean ± SE) -0.7 to -1.4 -0.7 to -1.3 .753/.852
Adverse Events Tadalafil was generally well tolerated. The incidence of treatment-emergent adverse events (TEAE) was similar in men with or without ED. Dyspepsia was more frequent in men without ED. No notable differences in ECG readings or serious adverse events between subgroups.
Study Author Conclusions Changes in BPH-LUTS after 12 weeks of treatment with placebo or various doses of once daily tadalafil were similar in men with or without comorbid ED.
Critique

The posthoc nature of some analyses may increase the risk of false-positive findings. The study was not designed to conclusively determine differences in cardiovascular-related adverse events, and the mechanisms by which tadalafil might relieve LUTS remain incompletely defined.

 

References:

Broderick GA, Brock GB, Roehrborn CG, Watts SD, Elion-Mboussa A, Viktrup L. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-1458. doi:10.1016/j.urology.2009.09.093