Sexual Medicine

Efficacy and safety of tadalafil 5 mg once daily in

the treatment of lower urinary tract symptoms
associated with benign prostatic hyperplasia in
men aged ≥75 years: integrated analyses of
pooled data from multinational, randomized,
placebo-controlled clinical studies
Matthias Oelke*, Adrian Wagg†, Yasushi Takita‡, Hartwig Bu
€ ttner§ and Lars Viktrup¶
*Department of Urology, Hannover Medical School, Hannover, Germany, †Geriatric Medicine, University of Alberta,
Edmonton, AB, Canada, ‡Medicines Development Unit Japan, Eli Lilly Japan, Kobe, Hyogo, Japan, §Eli Lilly
Biomedicines BU – Men’s Health Therapeutic Area Europe, c/o Lilly Deutschland, GmbH, Bad Homburg, Germany, and
¶
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
M.O., A.W., H.B. and L.V. contributed equally to the work.

Objective Tadalafil was not statistically significantly better than placebo

To assess efficacy and safety of tadalafil in men aged
≥75 years with lower urinary tract symptoms associated with
benign prostatic hyperplasia (LUTS/BPH) and additional
safety in men aged ≥75 years with erectile dysfunction (ED).
Patients and Methods
We conducted an integrated analysis of 12 phase II–III
randomized, double-blind and/or open-label extension
studies to evaluate short-term (12–26 weeks) efficacy and
short- and longer-term (42–52 weeks) safety in men aged
<75 years vs men aged ≥75 years. All men received once-
daily tadalafil 5 mg or placebo. The efficacy outcome was
International Prostate Symptom Score (IPSS). Safety
measurements included treatment-emergent adverse events
(TEAEs), adverse events (AEs) leading to discontinuation,
serious AEs (SAEs), and cardiovascular AEs. All analyses
were intention-to-treat. Changes from baseline to efficacy
endpoint and differences in changes between treatment
groups were estimated as least-squares means using analysis
of covariance models.
Results
Change in the mean IPSS was significantly different in men
aged <75 years vs those aged ≥75 years across tadalafil and
placebo groups (treatment-by-age interaction P = 0.034).
in men aged ≥75 years, but effect size varied between studies.
Maintenance of efficacy with tadalafil was observed across age
groups. Short-term tadalafil safety findings for men aged <75
vs ≥75 years included: TEAEs (52 [33.8%] vs 503 [30.1%]),
AEs leading to discontinuation (3 [1.9%] vs 50 [3.0%]), SAEs
(4 [2.6%] vs 15 [0.9%]) and cardiovascular AEs (4 [2.6%] vs
30 [1.8%]). Long-term tadalafil safety data did not reveal
clinically relevant differences between age groups. Limitations
include exclusion of men with serious co-existing conditions
and limited sample sizes of men aged ≥75 years.
Conclusions
Efficacy with once-daily tadalafil 5 mg in the treatment of
LUTS/BPH differed between men aged <75 vs ≥75 years, with
significant efficacy in the <75-year age group. The older age
group had more concomitant diseases and used more drugs,
which may have reduced efficacy. The small sample size
precluded uni-/multivariate analyses to assess plausible
interference from confounding factors. Tadalafil had a
reassuring safety profile and no evidence of increased
cardiovascular AEs in aging men.
Keywords
tadalafil, elderly, lower urinary tract symptoms, benign
prostatic hyperplasia, #erectiledysfunction, #UroBPH

© 2016 The Authors

BJU International © 2016 BJU International | doi:10.1111/bju.13744 BJU Int 2017; 119: 793–803
Published by John Wiley & Sons Ltd. www.bjui.org wileyonlinelibrary.com
Oelke et al.
Introduction
In aging men, LUTS associated with BPH (LUTS/BPH) are
common [1]. Erectile dysfunction (ED) often coexists with
LUTS/BPH and increases with LUTS severity [2]. Most men
seeking treatment for either LUTS/BPH or ED have both
conditions [3].
Seven LUTS/BPH studies:
LVHG (North America/Europe; NCT00384930*)
LVHJ (North America/Europe; NCT00827242)
LVHR (North America/Europe; NCT00855582)
LVID (North America/Europe; NCT00970632)
LVIA (Asia; NCT00783094)
LVHB (Asia; NCT00861757)
LVHT (Asia; NCT00540124)
Five ED studies:
LVCV (South America, Europe; conducted before clinical trials.gov requirement)
LVFP (United States; NCT00381732)
LVFZ (North America, Europe, Australia; NCT00547183)
LVGH (Multinational; NCT00422734)
LVHX (Europe; NCT00836693)
*Clinicaltrials.gov registration number
LUTS/BPH + ED Demographic
LUTS/BPH Demographic Population (12 studies)
Population (7 Studies)
N=2198
<75 years
n=1935 (88%)
≥75 years
n=263 (12%)
34 subjects in <75 year
cohort excluded from
efficacy analysis due to
lack of post-baseline data
Evaluable for 12-week
efficacy (7 studies)
N=2164
<75 years
n=1926 (88%)
≥75 years
n=263 (12%)
Evaluable for 42-52 week
efficacy (2 open-label
extension studies)
N=810
<75 years
n=711( 88%)
≥75 years
n=99 (12%)
© 2016 The Authors
794 BJU International © 2016 BJU International
A recent comprehensive literature search on the efficacy and
safety of drugs commonly used to treat LUTS revealed a
paucity of data in men aged ≥65 years for a-blockers,
antimuscarinics, 5a-reductase inhibitors, phosphodiesterase
type 5 (PDE5) inhibitors and b3-agonists. Data in men aged
≥75 years could not be identified for any of the drug classes [4].
Fig. 1 Study analysis flow chart. Short-term
(12-week) efficacy of tadalafil included seven
lower urinary tract symptoms associated with
benign prostatic hyperplasia (LUTS/BPH)
clinical studies [7,13–18]. Maintenance of
efficacy from end of 12-week double-blind
period to end of open-label extension period
(42- to 52-week) included two LUTS/BPH clinical
studies [17,19]. Twelve-week safety of once-
daily tadalafil 5 mg vs placebo was based on
12 pooled studies, including the seven
aforementioned LUTS/BPH studies [7,13–18]
and five erectile dysfunction (ED) studies
[20–24]. Long-term safety included two
uncontrolled open-label LUTS/BPH extension
studies [17,19] and two uncontrolled open-
label ED extension studies [25]. Long-term
safety was defined as events occurring after
the end of the double-blind period to the end
of the open-label extension period. ED studies
in this integrated safety analysis did not
include studies conducted in Japan and South
Korea, as only as-required (p.r.n.) dosing was
N=3309 investigated for this condition in Asian men.
<75 years
n=3012 (91%)
≥75 years
n=297 (9%)
Evaluable for 12-week
safety (12 studies)
N=3309
<75 years
n=3012 (91%)
≥75 years
n=297 (9%)
Evalulable for 42-52 week
safety (4 open-label extension
studies)
N=1294
<75 years
n=1167 (90%)
≥75 years
n=127 (10%)
 Tadalafil in elderly with LUTS/BPH

Tadalafil, a long-lasting PDE5 inhibitor with an elimination
half-life of 17.5 h, has been approved worldwide for on-
demand or once-daily use in men with ED and for
continuous use in men with signs or symptoms of BPH
(LUTS/BPH) [5–9]. The efficacy and safety of tadalafil 5 mg,
the licensed dose for LUTS/BPH, has been established in
studies in predominantly middle-aged and older men [8]. Its
effect in men aged ≥65 years has also been assessed [5,10,11];
however, there is no information on tadalafil use in men aged
≥75 years, where comorbidity and concomitant medication
are more common.
Because aging is often associated with altered
pharmacokinetic/pharmacodynamic drug profiles secondary
to changes in organ blood flow, metabolizing capacity and
elimination patterns, reduced physiological reserve of organ
function and drug–drug interactions, there may be an
increased prevalence of adverse events (AEs) or a unique AE
profile [12]. The aim of the present analysis was to assess the
efficacy and safety of once-daily tadalafil (5 mg) in men aged
≥75 years with LUTS/BPH (some of whom had ED) and
safety in men aged ≥75 years with ED based on data from
phase II/III studies worldwide.
Patients and Methods
Study Design
Data were pooled from multicentre, randomized, double-
blind, placebo-controlled clinical studies and/or open-label
extension studies to evaluate the short-term efficacy and
maintenance of effect for LUTS/BPH and short- and long-
term safety (LUTS/BPH and/or ED) of once-daily tadalafil
5 mg in men aged ≥75 years (Fig. 1) [7,13–25]. Data from
men aged <75 years were used as a comparator. Studies of
tadalafil for ED were included in the safety analysis to
increase the sample size. Only placebo-controlled, suitably
powered studies from the sponsor (Eli Lilly and Company,
Indianapolis, IN, USA) were included to secure a more
homogeneous population for this pooled analysis.
No ethical committee approval was required for this
integrated analysis. Each underlying study was performed in
accordance with all applicable laws and regulations.
Institutional review boards for each site approved each study
and all men provided written informed consent before
initiating any trial.
Study Population
The inclusion and exclusion criteria, which varied slightly
across LUTS/BPH studies, have been previously described
[7,13–19]. Briefly, LUTS/BPH study eligibility included men
aged ≥45 years with LUTS/BPH for >6 months, moderate-
to-severe symptoms based on an IPSS ≥13, and a maximum
urinary flow rate ≥4 and ≤15 mL/s before the placebo lead-
in period. In one study, men also had to have ED and be
sexually active with a female partner [15]. In Asian studies,
a prostate volume ≥20 mL according to ultrasonography was
required, but prostate size was not assessed in the non-
Asian studies. For all studies, men were excluded if their
PSA level was >10 ng/mL (in men with a PSA of 4–10 ng/
mL, negative prostate biopsies for malignancy within
12 months were required), post-void residual urine volume
was ≥300 mL at screening visit, or finasteride or dutasteride
was taken within 3–12 months [13]. Finasteride, dutasteride
or a-adrenergic receptors antagonists were not allowed after
enrolment.

Table 1 Baseline demographic and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) characteristics in 3 309 men
from 12 placebo-controlled studies enrolling men with LUTS associated with BPH and/or erectile dysfunction (all randomized men).

Study drug Age group

<75 years ≥75 years

Tadalafil 5 mg once daily Placebo Tadalafil 5 mg once daily Placebo

Number of patients, n 1 662 1 350 154 143

Demographics
Mean  SD age, years 58.6  9.1 60.0  8.4 77.2  2.6 77.6  3.0
Race, n (%)
White 1 149 (69.1) 897 (66.4) 98 (63.6) 91 (63.6)
Asian 315 (19.0) 315 (23.3) 47 (30.5) 40 (28.0)
Other* 198 (11.9) 138 (10.2) 9 (5.8) 12 (8.4)
Mean  SD body mass index, kg/m2 27.4  4.3 27.5  4.6 26.1  4.2 26.5  4.1
LUTS/BPH characteristics†
LUTS severity, n (%)
Mild-to-moderate (IPSS <20) 636 (65.5) 640 (66.4) 92 (70.8) 88 (66.2)
Severe (IPSS 20–35) 335 (34.5) 324 (33.6) 38 (29.2) 45 (33.8)
Mean  SD total IPSS 17.4  5.9 17.2  5.9 17.1  5.1 17.0  5.8

BMI, body mass index; IPSS, International Prostate Symptom score. *Includes Black, American Indian or Alaskan Native, multiple races, Hispanic or Latino, and undefined.
†
Includes men enrolled in the 7 LUTS/BPH clinical studies only [7,13–18].

© 2016 The Authors

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Oelke et al.

For previously described ED studies [20–24], inclusion with subsequent ED, clinically significant hepatobiliary or
criteria were, among others: age ≥18 years; an ED history renal disease and uncontrolled diabetes mellitus.
≥3 months; and being in a heterosexual relationship. Men
Men with unstable cardiovascular disease: myocardial
were excluded if their ED was caused by other sexual or
infarction within last 90 days; unstable angina or angina
endocrine disorders, such as premature ejaculation or
occurring during sexual intercourse; New York Heart
hypogonadism, a history of radical prostatectomy (except
Association Class ≥2–3 heart failure in previous 6 months;
bilateral nerve-sparing prostatectomy) or other pelvic surgery
Table 2 Baseline comorbidities and concomitant medications in 3 309 men from 12 placebo-controlled studies enrolling men with LUTS associated with
BPH and/or erectile dysfunction (all randomized men).

Study drug Age group

<75 years ≥75 years

Tadalafil 5 mg once daily Placebo Tadalafil 5 mg once daily Placebo

Number of patients, n 1 662 1 350 154 143

Comorbidities*, n (%)
Cardiovascular disorders 690 (41.5) 581 (43.0) 95 (61.7) 94 (65.7)
Cardiac disorders 168 (10.1) 147 (10.9) 37 (24.0) 29 (20.3)
Ischaemic heart disease 74 (4.5) 76 (5.6) 17 (11.0) 10 (7.0)
Cardiac arrhythmias 62 (3.7) 53 (3.9) 20 (13.0) 11 (7.7)
Cardiac failure 9 (0.5) 13 (1.0) 2 (1.3) 1 (0.7)
Cardiomyopathy 1 (0.1) 1 (0.1) 1 (0.6) 0 (0.0)
†
Other cardiac disorders 42 (2.5) 29 (2.1) 5 (3.2) 8 (5.6)
Cerebrovascular disorders 19 (1.1) 18 (1.3) 8 (5.2) 4 (2.8)
Haemorrhagic cerebrovascular disorders 11 (0.7) 9 (0.7) 3 (1.9) 1 (0.7)
Ischaemic cerebrovascular disorders 16 (1.0) 16 (1.2) 8 (5.2) 4 (2.8)
Other cerebrovascular disorders 0 (0) 3 (0.2) 0 (0) 0 (0)
Other vascular disorders 617 (37.1) 527 (39.0) 87 (56.5) 85 (59.4)
Hypertension 592 (35.6) 500 (37.0) 80 (51.9) 82 (57.3)
Renovascular disorders 1 (0.1) 0 (0) 0 (0) 0 (0)
Embolic and thrombotic events 27 (1.6) 31 (2.3) 5 (3.2) 3 (2.1)
Vasculitis 5 (0.3) 0 (0) 1 (0.6) 0 (0)
Other‡ 29 (1.7) 34 (2.5) 10 (6.5) 6 (4.2)
Hyperlipidaemia 333 (20.0) 271 (20.1) 42 (27.3) 44 (30.8)
Diabetes mellitus 313 (18.8) 256 (19.0) 24 (15.6) 29 (20.3)
Concurrent medications*, n (%)
Antihypertensive medications used, n (%)
None 806 (48.5) 642 (47.6) 39 (25.3) 39 (27.3)
1 489 (29.4) 394 (29.2) 51 (33.1) 49 (34.3)
>1 367 (22.1) 314 (23.3) 64 (41.6) 55 (38.5)
Type of antihypertensive medication use among men using antihypertensive medications, n (%)
Angiotensin-converting enzyme inhibitor 268 (16.1) 195 (14.4) 28 (18.2) 35 (24.5)
Angiotensin receptor blocker 177 (10.6) 175 (13.0) 24 (15.6) 24 (16.8)
Diuretic 152 (9.1) 126 (9.3) 25 (16.2) 17 (11.9)
Centrally-acting sympathomimetics 11 (0.7) 7 (0.5) 2 (1.3) 0 (0)
b-blockers 188 (11.3) 132 (9.8) 35 (22.7) 21 (14.7)
Calcium channel blockers 185 (11.1) 149 (11.0) 28 (18.2) 30 (21.0)
Diabetic therapy use, n (%)
No therapy 1 381 (83.1) 1 135 (84.1) 134 (87.0) 121 (84.6)
Oral agent 232 (14.0) 186 (13.8) 18 (11.7) 20 (14.0)
Insulin 82 (4.9) 53 (3.9) 5 (3.2) 4 (2.8)
Hyperlipidaemia therapy use, n (%)
No lipid-lowering agent therapy 1 354 (81.5) 1 107 (82.0) 108 (70.1) 103 (72.0)
Statin medication 275 (16.5) 222 (16.4) 41 (26.6) 37 (25.9)
Other lipid-lowering medication 56 (3.4) 48 (3.6) 6 (3.9) 8 (5.6)
Statin and/or other lipid-lowering agent therapy 308 (18.5) 243 (18.0) 46 (29.9) 40 (28.0)
Antidepressant use, n (%) 46 (2.8) 45 (3.3) 4 (2.6) 2 (1.4)
Cytochrome P450 3A4 inhibitor use, n (%)§ 232 (14.0) 159 (11.8) 38 (24.7) 30 (21.0)
Prior phosphodiesterase type 5 inhibitor use, n (%) 157 (16.2) 147 (15.2) 16 (12.3) 20 (15.0)
Prior a-blocker use, n (%)¶ 422 (25.4) 393 (29.1) 71 (46.1) 61 (42.7)

*Men may be counted in more than one category. Primary exclusionary medical conditions included clinically significant renal (creatinine clearance <30 mL/min) or severe hepatic
insufficiency, cardiovascular conditions such as clinically significant angina, recent myocardial infarction or poorly controlled blood pressure, and a recent history of stroke or spinal
cord injury. †Includes terms related to pulmonary hypertension, cardiac valve disease, cardiac murmur, septal defects and pacemaker-related procedures. ‡Includes terms related to
peripheral aneurysms or dissections; peripheral atherosclerosis; and other miscellaneous vascular disorders. §Per LUTS/BPH study exclusion criteria, current systemic treatment with
a potent cytochrome P450 3A4 (CYP3A4) inhibitor was prohibited. Data presented here do not include potent CYP3A4i use. ¶For the LUTS/BPH studies, men were not allowed to
continue on a-blockers. Accordingly, these drugs were discontinued on enrolment, followed by a washout period, before initiating study treatment.

© 2016 The Authors

796 BJU International © 2016 BJU International
 Tadalafil in elderly with LUTS/BPH

uncontrolled arrhythmias, hypotension (<90/50 mmHg), or

Treatment-by-age

LS, least squares; N, number of men in the analysis population; n, number of men in each age subgroup with non-missing baseline and at least one post-baseline visit data; QoL, quality of life. *Number of men who received
uncontrolled hypertension (e.g. systolic blood pressure >160–

at least one dose of study treatment. †Number of men who received at least one dose of study treatment and had both baseline and post-baseline IPSS. ‡Interaction tests for differences in symptoms for men aged ≥75 years
interaction
170 mmHg or diastolic blood pressure >100 mmHg); stroke

P value‡

0.034

0.045

0.068

0.018
within previous 6 months; and current treatment with
nitrates were excluded. All of these exclusions contribute to

Table 3 Summary and analysis of mean changes from baseline in International Prostate Symptom Score (IPSS) (last observation carried forward at week 12) by age groups.
the current label of conditions where tadalafil is not
recommended [8].

2.7, 1.7

1.0, 0.6

1.8, 1.1

0.5, 0.3
95% CI

2.0, 0.7

0.7, 0.5

1.4, 0.4

0.3, 0.3
Efficacy and Safety Outcome Measures
Short- (12–26 weeks) and longer-term efficacy (42–52 weeks)
of tadalafil for LUTS/BPH, stratified by age (≥75 years vs

Placebo-adjusted
<75 years), was based on the following outcome measures:

change (SE)

0.02 (0.15)
LS mean

2.2 (0.3)
0.7 (0.7)

0.8 (0.1)
0.1 (0.3)

1.4 (0.2)
0.5 (0.5)

0.4 (0.1)
total IPSS; IPSS storage and voiding subscores; and
IPSS-quality of life (QoL).
Short- and long-term safety outcome measures included:
treatment-emergent AEs (TEAEs); AEs that led to
discontinuation; serious AEs (SAEs); vital signs analyses; and

change (SE)
LS mean

6.4 (0.3)
5.3 (0.6)

2.5 (0.1)
1.9 (0.2)

3.9 (0.2)
3.4 (0.4)

1.3 (0.1)
0.9 (0.1)
orthostatic blood pressure assessment.

treated with tadalafil or placebo vs men aged <75 years treated with tadalafil or placebo were performed at two-sided 0.10 significance level.
Statistical Analysis
Analyses were performed on an intention-to-treat basis for Tadalafil 5 mg (N = 1 098)*
all randomized men who started double-blind study Endpoint (SD)

11.7 (6.7)
12.7 (6.7)

5.0 (3.0)
5.9 (3.1)

6.7 (4.5)
6.8 (4.5)

2.7 (1.5)
3.1 (1.6)
medication. Demographic and baseline clinical characteristics
of the men, comorbidities, concurrent medications and
safety data were summarized by treatment group and within
each age group (≥75 years vs <75 years) using descriptive
Baseline (SD)

statistics.
17.4 (5.9)
17.1 (5.1)

7.1 (2.9)
7.6 (2.9)

10.3 (4.1)
9.6 (3.8)

3.8 (1.3)
3.7 (1.3)
Short-term efficacy analyses assessed changes from baseline
(defined as randomization visit [end of placebo lead-in
period or start of double-blind treatment period]) to
endpoint (defined as data collected at week 12 of double-
956
130

956
130

956
130

954
130
†
n

blind period, or last non-missing, post-baseline data).

Changes from baseline to endpoint and differences in these
change (SE)
LS mean

4.1 (0.3)
4.6 (0.5)

1.7 (0.1)
1.7 (0.2)

2.4 (0.2)
2.9 (0.4)

0.9 (0.1)
0.9 (0.1)

changes between placebo and tadalafil 5 mg treatment

groups were estimated as least-squares means using analysis
of covariance models. The model included terms for
protocol, centred-baseline value, treatment group, geographic
Placebo (N = 1 091)*

region, age category, treatment-by-age category interaction,

Endpoint

13.8 (7.1)
13.2 (6.7)

5.8 (3.2)
6.0 (2.9)

8.0 (4.7)
7.2 (4.5)

3.1 (1.5)
3.0 (1.4)
(SD)

centred-baseline-by-treatment interaction, and treatment-by-

geographic region interaction. Between-group comparisons
(tadalafil vs placebo) within each age category were
performed at the two-sided 0.05 significance level.
Baseline (SD)

17.2 (5.9)
17.0 (5.8)

7.1 (2.9)
7.5 (2.8)

10.1 (4.1)
9.6 (4.3)

3.8 (1.3)
3.7 (1.2)

Interaction tests for differences in symptoms for men aged

≥75 years treated with tadalafil or placebo vs men aged
<75 years treated with tadalafil or placebo were performed
at a two-sided 0.10 significance level.
IPSS voiding subscore
IPSS storage subscore
945
133

945
133

945
133

943
133
†
n

IPSS-QoL index

Results
Total IPSS
<75 years

<75 years

<75 years

<75 years
≥75 years

≥75 years

≥75 years

≥75 years

Twelve studies including 3 309 men formed the sample for

this pooled analysis. Baseline demographics and
characteristics for all randomized men (3 012 men [91%]

© 2016 The Authors

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Oelke et al.

Table 4 Summary and analysis of mean changes from baseline in total IPSS (last observation carried forward at week 12) by age: individual study
findings.*

Study Placebo Tadalafil 5 mg

n Baseline (SD) Endpoint (SD) Mean change (SD) n Baseline (SD) Endpoint (SD) Mean change (SD)

LVHG
Age <75 years 193 17.0 (6.4) 14.8 (7.8) 2.2 (6.3) 185 17.1 (5.9) 12.0 (7.0) 5.1 (5.5)
Age ≥75 years 12 17.8 (5.2) 14.9 (6.4) 2.8 (3.9) 20 19.4 (6.2) 16.3 (8.4) 3.1 (6.8)
LVHJ
Age <75 years 129 16.3 (5.9) 12.7 (7.1) 3.6 (5.8) 130 17.1 (6.3) 11.3 (6.9) 5.8 (7.2)
Age ≥75 years 35 17.7 (6.3) 14.2 (7.5) 3.5 (5.7) 30 17.0 (4.7) 11.5 (6.0) 5.5 (7.4)
LVHR
Age <75 years 171 18.3 (5.5) 14.5 (6.5) 3.8 (5.7) 185 18.7 (5.8) 12.4 (6.7) 6.3 (6.6)
Age ≥75 years 23 17.7 (3.9) 13.0 (5.4) 4.6 (5.5) 21 15.9 (4.6) 9.6 (5.5) 6.3 (6.3)
LVID
Age <75 years 149 17.4 (5.9) 13.4 (7.8) 4.0 (6.4) 158 17.3 (4.9) 10.9 (6.7) 6.4 (5.9)
Age ≥75 years 23 17.0 (6.6) 12.0 (5.5) 5.0 (5.5) 13 15.9 (5.2) 12.4 (7.1) 3.5 (6.6)
LVIA†
Age <75 years 121 16.4 (5.5) 12.9 (6.7) 3.5 (4.5) 123 16.3 (6.0) 11.8 (6.1) 4.4 (5.3)
Age ≥75 years 18 17.3 (5.1) 12.6 (7.0) 4.7 (6.7) 17 17.8 (4.8) 10.9 (5.4) 6.9 (4.3)
LVHB
Age <75 years 139 17.0 (6.0) 13.7 (6.8) 3.2 (5.5) 142 17.2 (6.2) 11.7 (7.1) 5.4 (5.8)
Age ≥75 years 15 14.7 (6.7) 12.6 (8.4) 2.1 (6.0) 12 18.0 (3.9) 17.7 (4.7) 0.3 (5.4)

LS, least squares; n, number of men in each age subgroup with non-missing baseline and at least one post-baseline visit data. *Four studies were conducted in North America or
European Union (LVHG, LVHJ, LVHR, LVID). †Two studies were conducted in Japan (LVIA, LVHB); Study LVHT did not enrol men aged ≥75 years.

aged <75 years vs 297 men [9%] aged ≥75 years) were
generally well balanced between treatments (Table 1);
however, men aged ≥75 years had more comorbidities and
received more concomitant medications (Table 2).
Efficacy with Regard to LUTS/BPH
for men on tadalafil (0.1 vs 1.2, respectively), suggesting
maintenance of efficacy in both age groups. Figure 2 shows the
mean change in total IPSS over time during the open-label
extension phase for the subset of men aged ≥75 years who
received tadalafil in the double-blind phase.

Efficacy at Weeks 12–26 Fig. 2 Long-term efficacy (end of double-blind treatment at week 12 to

Based on the integrated analyses from seven 12-week studies, end of open-label extension period) based on total International Prostate
Symptom Score (IPSS) after treatment with once-daily tadalafil 5 mg in
the changes in mean IPSS, IPSS storage subscore, IPSS
men aged ≥75 years in two clinical studies: 24 men of predominant white
voiding subscore and IPSS-QoL index were statistically
origin entering the open-label extension period [13] and 26 men of
significantly different in men aged ≥75 years vs men aged predominantly Japanese origin entering the open-label extension period
<75 years across tadalafil and placebo treatment groups [17]. Weeks 0–12 represent the double-blind treatment period of tadalafil
(treatment-by-age interaction term P = 0.034, P = 0.045, P = vs placebo. All men received tadalafil during the double-blind treatment
0.068 and P = 0.018). The magnitude of improvement in phase before enrolment in the open-label extension.
LUTS/BPH, as assessed by placebo-adjusted mean total IPSS,
Placebo Double-Blind Open-Label
IPSS storage subscore, IPSS voiding subscore and IPSS-QoL Run-In Period Period
25 Period
index differences after treatment with tadalafil were
statistically significantly smaller in men aged ≥75 years vs
men aged <75 years (Table 3); however, in some individual 20
12-week studies, tadalafil-treated men aged ≥75 years had a
Mean Total IPSS

similar improvement in total IPSS compared with tadalafil- 15

treated men aged <75 years (Table 4).
10

Maintenance of Efficacy n= 24
5
n= 26
Regardless of assigned treatment group in the double-blind phase,
mean change in total IPSS score for 99 men aged ≥75 years vs 711 0
men aged <75 years was small from the end of the 12-week -4 0 12 54 64
double-blind period to the end of the open-label extension period Week of Therapy

© 2016 The Authors

798 BJU International © 2016 BJU International

Safety
Safety at Weeks 0–12
A higher proportion of men aged ≥75 years (tadalafil 33.8%,
placebo 26.6%) experienced TEAEs than men aged <75 years
(tadalafil 30.3%, placebo 23.3%; Table 5). For men aged
≥75 years, diarrhoea (4.5% vs 2.8%) and dizziness (3.2% vs
0.7%) rates were numerically slightly higher, but not
statistically different between tadalafil vs placebo groups.
Among men aged ≥75 years, one (0.7%) in the placebo group
and five (3.2%) in the tadalafil group reported dizziness as a
TEAE. All events were mild in severity, none led to early
study discontinuation or were associated with clinical
sequelae, and all but one event resolved during treatment
with tadalafil. One tadalafil-treated man had treatment-
emergent orthostasis (10 mmHg reduction in diastolic blood
pressure upon standing, temporally unrelated to the reporting
of dizziness), and another experienced dizziness during
orthostatic vital sign assessment, although no criteria for
orthostatic hypotension were met. All five tadalafil-treated
men had multiple concurrent illnesses.
At least one cardiovascular TEAE in tadalafil-treated men was
reported for four men (2.6%) aged ≥75 years and 30 men
(1.8%) aged <75 years. The corresponding rates in placebo
recipients were five (3.5%) and 19 (1.4%), respectively. Five
cardiovascular events were reported in four tadalafil-treated
men aged ≥75 years, including one acute myocardial
infarction (SAE and premature discontinuation), angina
pectoris, coronary artery disease (SAE), peripheral oedema,
and abnormal myocardial perfusion scan. Only the acute
myocardial infarction was considered by the investigator to be
possibly related to treatment with tadalafil.
The percentage of men discontinuing the study drug because
of an AE was similar for the ≥75-year (6/297, 2.0%) and the
<75-year age groups (72/3 012, 2.4%; Table 5).
Discontinuations because of AEs for both groups occurred at
similar rates when stratified by treatment group: for men
aged ≥75 years (placebo 3 [2.1%]; tadalafil 3 [1.9%]) vs
<75 years (placebo 22 [1.6%]; tadalafil 50 [3.0%]). For
tadalafil-treated men aged ≥75 years, each individual
discontinuation was for a unique event: acute myocardial
infarction (n = 1), internal fixation of fracture (n = 1) and
myalgia (n = 1).
For men aged ≥75 years, four (2.6%) SAEs occurred in
tadalafil-treated men and no events were reported for placebo
recipients. For men aged <75 years, a similar proportion of
SAEs was reported for the placebo and tadalafil treatment
groups (14 [1.0%] vs 15 [0.9%], respectively [Table 5]).
The four SAEs in tadalafil-treated men aged ≥75 years
included: myocardial infarction 2.5 months post-
Tadalafil in elderly with LUTS/BPH
randomization, coronary artery disease 8 weeks post-
randomization, renal cancer 6 months post-randomization,
and femur fracture secondary to accident 26 days post-
randomization.
Small mean decreases in diastolic and systolic blood pressure
were observed for tadalafil-treated men in both age groups.
None of the changes were significantly different from placebo.
There was no evidence for a statistically significant treatment-
by-age interaction for change in blood pressure (P value for
interaction 0.486 and 0.633 for diastolic and systolic blood
pressure, respectively). No treatment group difference was
found in the percentage of men with clinically significant low
systolic (<90 mmHg) or diastolic (<60 mmHg) blood
pressure in either age group, and no statistical evidence for
an age-by-treatment interaction was found. Based on available
data from two LUTS/BPH studies (n = 369 tadalafil, n = 364
placebo) [14,15], the percentages of men meeting at least one
criterion for treatment-emergent orthostatic hypotension were
similar in the two age groups, regardless of treatment (Fig. 3).
Fig. 3 Percentage of men meeting at least one criterion for treatment-
emergent orthostatic hypotension in two phase III double-blind placebo-
controlled once-daily tadalafil 5 mg clinical studies in men with lower
urinary tract symptoms associated with benign prostatic hyperplasia
(LUTS/BPH) [14,15]. Treatment-emergent orthostatic hypotension was
based on first occurrence of one or more of the following criteria at any
time after baseline: systolic blood pressure decrease ≥20 mmHg; diastolic
blood pressure decrease ≥10 mmHg; heart rate increase ≥20 bpm; and
unable to remain standing. Numbers above bar represent number of
men with treatment-emergent orthostatic hypotension over total number
of men in age cohort.
Placebo Tadalafil 5 mg
25 P=0.693 P=0.701 P=0.450 P=0.100
30/129 8/35
5/23
37/177
Percentage of Subjects with ≥1 Orthostatic Test
20 25/131
35/187
6/30
15 3/21
10
5
0
<75 years ≥75 years <75 years ≥75 years
Study 1 Study 2
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BJU International © 2016 BJU International 799
Oelke et al.

Table 5 Short-term integrated safety in 3 309 men from 12 placebo-controlled studies enrolling men with LUTS associated with BPH and/or erectile
dysfunction (aged ≥75 years vs <75 years) by decreasing frequency in men aged ≥75 years for tadalafil.

Study drug Age group

<75 years ≥75 years

Tadalafil 5 mg once Placebo (N = 1 350) Tadalafil 5 mg once Placebo (N = 143)

daily (N = 1 662) daily (N = 154)

TEAEs, n (%)
Overall 503 (30.3) 315 (23.3) 52 (33.8) 38 (26.6)
Diarrhoea 17 (1.0) 11 (0.8) 7 (4.5) 4 (2.8)
Nasopharyngitis 43 (2.6) 40 (3.0) 7 (4.5) 8 (5.6)
Dizziness 11 (0.7) 10 (0.7) 5 (3.2) 1 (0.7)
Cough 9 (0.5) 6 (0.4%) 3 (1.9) 0 (0)
Headache 75 (4.5) 35 (2.6) 3 (1.9) 1 (0.7)
Back pain 40 (2.4) 15 (1.1) 2 (1.3) 2 (1.4)
Dyspepsia 52 (3.1) 5 (0.4) 2 (1.3) 0 (0)
Dyspnoea 3 (0.2) 0 (0) 2 (1.3) 0 (0)
Fall 2 (0.1) 2 (0.1) 2 (1.3) 0 (0)
Micturition urgency 1 (0.1) 0 (0) 2 (1.3) 0 (0)
Nocturia 1 (0.1) 1 (0.1) 2 (1.3) 0 (0)
Pain extremity 21 (1.3) 0 (0) 2 (1.3) 0 (0)
PSA increased 1 (0.1) 2 (0.1) 2 (1.3) 0 (0)
Vomiting 5 (0.3) 5 (0.4) 2 (1.3) 1 (0.7)
Abdominal pain 3 (0.2) 0 (0) 1 (0.6) 0 (0)
Abdominal pain upper 11 (0.7) 4 (0.3) 1 (0.6) 1 (0.7)
Acute myocardial infarction 0 (0) 0 (0) 1 (0.6) 0 (0)
Angina pectoris 0 (0) 0 (0) 1 (0.6) 0 (0)
Discontinuation secondary to AE, n (%)
Overall 50 (3.0) 22 (1.6) 3 (1.9) 3 (2.1)
SAE, n (%)
Overall 15 (0.9) 14 (1.0) 4 (2.6) 0 (0)

AE, adverse event; TEAE, treatment-emergent adverse event; SAE, serious adverse event.

osteoarthritis (n = 2) and one each of atrial fibrillation,

Safety at Weeks 12–42 (12–52)
The frequency of TEAEs was generally higher in the open-
label studies and in both age groups compared with the
double-blind studies. The overall frequency of TEAEs was
similar in both age groups of men who received tadalafil for
at least 6 months: 63 (49.6%) men aged ≥75 years reported at
least one TEAE vs 611 (52.4%) men aged <75 years
(Table 6). Types of TEAE in both age groups were generally
similar. The most common TEAEs (≥3%) in men aged
≥75 years were insomnia, diarrhoea, nasopharyngitis and
osteoarthritis.
A higher percentage of discontinuations because of AEs
was reported for men aged ≥75 years (12 [9.4%]) vs
men aged <75 years (70 [6.0%]) after long-term exposure
to tadalafil (Table 6). Individual events in men aged
≥75 years considered unrelated to tadalafil or study
procedures contributed to the higher percentage of
discontinuations (e.g. lung neoplasm, pancreatic carcinoma
and prostatitis).
A higher percentage of SAEs was reported for men aged
≥75 years (12 [9.4%]) vs men aged <75 years (53 [4.5%])
after long-term exposure to tadalafil (Table 6). For
the ≥75-year age group, 15 SAEs were reported, including
back pain, benign lung neoplasm, congestive heart
failure, acute cholecystitis, colonic polyps, fibula fracture,
hip arthroplasty, cholestatic jaundice, myocardial
infarction, pancreatic carcinoma, renal cancer and urinary
retention.
Discussion
In the present integrated analysis the improvements in LUTS/
BPH were statistically significantly different in men aged
≥75 years vs men aged ≤75 years across tadalafil and placebo
treatment groups. Tadalafil was well tolerated regardless of
age in men with LUTS/BPH and/or ED. Most TEAEs were
reported at similar rates in the two age groups.
Discontinuation did not seem to increase with age and there
were only few SAEs in men aged ≥75 years, which were all
unrelated to tadalafil therapy. No new cardiovascular safety
concerns were identified in tadalafil-treated men aged
≥75 years.
Based on analyses of total IPSS, IPSS storage and IPSS
voiding subscores and IPSS-QoL index from baseline to end
of 12-week treatment, efficacy in men aged ≥75 years was
statistically significantly lower than that observed in men aged
<75 years; however, there was considerable variability across

© 2016 The Authors

800 BJU International © 2016 BJU International
 Tadalafil in elderly with LUTS/BPH

Table 6 Long-term integrated safety following once-daily tadalafil dosing predominantly white study population [5] and in a
from 4 open-label extension clinical studies in men with lower urinary tract
symptoms associated with benign prostatic hyperplasia and/or erectile predominantly Japanese study population [11]. While all age
dysfunction that occurred in greater than one subject (≥75 years vs. cohorts experienced an improvement with tadalafil, the
<75 years) by decreasing frequency in age ≥75.*
predominantly Japanese men aged >65 years reported
Age group <75 years ≥75 years statistically significantly lower improvement. Regardless, in a
N = 1 167 N = 127 similar fashion to younger men, men aged >65 years
TEAEs, overall n (%) 611 (52.4) 63 (49.6)
receiving tadalafil for up to 52 weeks during open-label
Insomnia 15 (1.3) 6 (4.7) extension studies maintained their reduction in symptoms
Diarrhoea 25 (2.1) 4 (3.1) long-term (per total IPSS) [17,19].
Nasopharyngitis 55 (4.7) 4 (3.1)
Osteoarthritis 8 (0.7) 4 (3.1) The short- and long-term safety profiles of tadalafil in men
Dyspepsia 29 (2.5) 3 (2.4)
Headache 36 (3.1) 3 (2.4)
aged ≥75 years with LUTS/BPH (many of whom also have
Abdominal distension 2 (0.2) 2 (1.6) ED) and men aged ≥75 years with ED (many of whom also
Back pain 41 (3.5) 2 (1.6) have LUTS/BPH) were generally similar to men aged
Biliary drainage – 2 (1.6)
Chest pain 7 (0.6) 2 (1.6)
<75 years with these conditions, despite a higher use of
Conjunctival haemorrhage 1 (0.1) 2 (1.6) concomitant medications. Possible exceptions included
Constipation 5 (0.4) 2 (1.6) numerically higher rates of diarrhoea and dizziness rates in
Eczema 7 (0.6) 2 (1.6)
Haematuria 10 (0.9) 2 (1.6)
men aged ≥75 years. The small numerically higher incidence
Hot flush 2 (0.2) 2 (1.6) of diarrhoea observed in tadalafil-treated men aged
Hypertension 27 (2.3) 2 (1.6) ≥75 years (4.5%) vs men aged <75 years (1.0%) is a
Influenza 20 (1.7) 2 (1.6)
Memory impairment – 2 (1.6)
recognized AE in older men treated with tadalafil as-
Neck pain 4 (0.3) 2 (1.6) required (p.r.n.) for ED (data on file, Eli Lilly and
Neoplasm prostate 2 (0.2) 2 (1.6) Company). Dizziness was also more commonly reported by
Onychomycosis 3 (0.3) 2 (1.6)
Pain in extremity 5 (0.4) 2 (1.6)
tadalafil-treated men aged ≥75 years (3.2%) vs men aged
Periodontitis – 2 (1.6) <75 years (0.7%). Reported dizziness did not correspond to
Tooth infection 7 (0.6) 2 (1.6) hypotensive events. Nonetheless, the mild systemic
Upper respiratory tract infection 17 (1.5) 2 (1.6)
Discontinuation secondary to adverse 70 (6.0) 12 (9.4)
vasodilatory properties of tadalafil may result in unwanted
event, overall n (%) decreases in blood pressure and dizziness, especially in men
Serious adverse events, overall n (%) 53 (4.5) 12 (9.4) with left ventricular outflow obstruction or in men using
n = number; TEAE = treatment-emergent adverse event. For the 1 294 men who
* nitrates or non-selective a1-adrenoceptor antagonists and
received tadalafil during the open-extension period, after excluding missing data in 51 should not be used together [8]. Overall tolerability, as
men, 313 received tadalafil 2.5, 363 received tadalafil 5 mg, 156 received tadalafil
10 mg, 71 received tadalafil 20 mg and 340 received placebo during the double-blind
assessed by discontinuations because of AEs, was similar in
treatment studies. both age groups.
Other pooled analyses in men of all ages [5,26], together with
the different studies (Table 4), suggesting that some men
two reports comparing men aged >65 vs <65 years [5] or
aged ≥75 years may still experience a clinically significant
aged ≥65 vs ≤65 years [11] corroborate these safety findings.
improvement with tadalafil. Additionally, the overall sample
Data from an integrated analysis of ~1 500 US and European
size was small and may not reflect the total experience of
men with LUTS/BPH treated with once-daily tadalafil 5 mg
older men. Yet, most tadalafil studies in men with LUTS/BPH
did not identify any statistically significant difference in
had adequately powered sample size per treatment arm (>150
TEAEs between men with or without cardiovascular disease
patients) [7,13–16]. The small sample size of men aged
when stratified by age (≥65 years vs <65 years) [5]; however,
≥75 years also precluded any meaningful uni- and
most cardiovascular events occurred in men with reported
multivariate analyses. Given tadalafil’s mechanism of action,
pre-existing cardiovascular risk factors. Likewise, in 12 500
the loss of smooth and striated muscle tissue in aging
men with ED, of whom 5 939 tadalafil-treated men (48%)
superimposed upon smooth muscle loss from cardiovascular
had diabetes mellitus, hyperlipidaemia, hypertension and/or
disease, together with generally less CNS descending urinary
coronary artery disease, tadalafil (2–50 mg as needed, three
inhibition and increased incidence of cerebrovascular
times/week, or once/day dosing) was not associated with an
disorders (Table 2), may explain the observed reduced effect
increased risk of serious cardiovascular AEs [27]. In an
in older men. Higher use of concurrent medication and
observational cohort study of 6 229 tadalafil-treated men
greater prevalence of comorbidity in these men may also be a
(median age 61 years), cardiovascular events included chest
contributing factor in the observed reduced efficacy, similar
pain in 20, angina in 18, myocardial infarction in 15
to that previously reported [26].
(including six fatal) and ischaemic heart disease (IHD) in 11
Changes in IPSS in men aged >65 years treated with once- men (including five fatal events) [28]. Myocardial infarction
daily tadalafil 5 mg for 12 weeks were recently assessed in a rates were not higher after treatment with tadalafil 5 mg, and

© 2016 The Authors

BJU International © 2016 BJU International 801
Oelke et al.
few overall cardiovascular TEAEs were considered related to
treatment.
The treatment of older men with LUTS/BPH may be
particularly challenging because of the presence of clinically
significant comorbidity and related polypharmacy; selected
treatments should, if possible, have proven efficacy and safety
in older populations. Until recently, data that specifically
addressed the needs of older patients were lacking, requiring
treating physicians to extrapolate findings from studies in a
largely middle-aged, healthier population. Avoidance of drug–
drug interactions is important, as is limiting the burden of
adding more medications than absolutely necessary. Tadalafil
has advantages for the treatment of men with LUTS/BPH and
ED in offering a single medication for treatment of closely
allied conditions. Likewise, tadalafil could potentially address
storage symptoms without the adverse tolerability profile or
potential for impaired cognition associated with antimuscarinic
agents [29] or the problem of ejaculatory dysfunction
associated with a-blockers [30]; however, the present pooled
analyses suggest little overall benefit in LUTS/BPH, albeit with
considerable variability. By comparison, antimuscarinic agents
are also known to be less efficacious in the elderly [31].
The findings of the present integrated analysis have several
limitations. Because of the controlled settings of clinical
studies, certain serious co-existing conditions were excluded
(e.g. unstable cardiovascular disease, uncontrolled diabetes
mellitus, clinically significant hepatobiliary or renal disease),
thus the analysed patient population does not necessarily
represent everyone with LUTS/BPH and/or ED. Such
patients, however, should not use PDE5 inhibitors [8]. In
addition, these results were derived from a post hoc analysis
with a relatively small number of men aged ≥75 years, which
limits the ability to generalize the results to patients in
clinical practice. Furthermore, plausible interference of age-
related confounding factors on the efficacy cannot be
excluded in the absence of uni-/multivariate analyses. A
prospective suitably powered study in men aged ≥75 years
would provide more conclusive results. Preparatory
quantitative and qualitative work to establish what constitutes
a clinically meaningful improvement in men aged ≥75 years
compared with younger men would also be informative.
In conclusion, the change in LUTS/BPH (total IPSS, storage
IPSS, voiding IPSS and IPSS-QoL) was statistically
significantly different in men aged ≥75 years vs men aged
<75 years across tadalafil and placebo treatment groups.
Once-daily tadalafil 5 mg was statistically significantly less
efficacious in the treatment of LUTS/BPH in men aged
≥75 years than in younger men (<75 years), albeit with
considerable variability between studies. Aside from events
commonly associated with tadalafil treatment, the types of
TEAE reported in men aged ≥75 years were generally not
unexpected in a population with multiple comorbidities and
© 2016 The Authors
802 BJU International © 2016 BJU International
concomitant medications. No new safety signals for
cardiovascular disease were observed in men aged ≥75 years
after treatment with tadalafil. While clinicians may continue
to prescribe tadalafil in men aged ≥75 years, efficacy and
safety in this population should be closely monitored.
Acknowledgements
The authors would like to acknowledge Teresa Tartaglione,
PharmD (Synchrogenix, A Certara Company, Wilmington,
Delaware) for medical writing assistance during the
preparation of this article. This study was supported by Eli
Lilly and Company, who played a role in the design and
conduct of the study, collection of the data, management of
the data, analysis and interpretation of the data, and
preparation, review, and approval of the manuscript. Eli Lilly
and Company is the manufacturer of Tadalafil.
Conflict of Interest
Matthias Oelke is a consultant and/or speaker for Apogepha,
Astellas, Bayer, Duchesnay, Eli Lilly and Company,
GlaxoSmithKline, and Pfizer, and participated in studies for
Apogepha, Astellas, Eli Lilly and Company, GlaxoSmithKline,
and Pfizer. Adrian Wagg is a consultant and/or speaker for
Astellas Pharma, Pfizer Corporation, Duchesnay (Canada),
and Svenska Cellulosa Aktiebolaget AB (SCA). He has also
participated in clinical trials for Astellas Pharma and Pfizer
Corp. Lars Viktrup, Hartwig B€ uttner and Yasushi Takita are
full-time employees and minor stockholders of Eli Lilly and
Company.
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Correspondence: Matthias Oelke, Department of Urology, OE
6240, Hannover Medical School, Carl-Neuberg-Str. 1, 30625
Hannover, Germany.
e-mail: oelke.matthias@mh-hannover.de
Abbreviations: AE, adverse event; ED, erectile dysfunction;
PDE5, phosphodiesterase type 5; QoL, quality of life; SAE,
serious adverse event; TEAE, treatment-emergent adverse
event.
© 2016 The Authors
BJU International © 2016 BJU International 803