European European Urology 45 (2004) 339–345

Urology

Long-Term Safety and Tolerability of Tadalafil in the

Treatment of Erectile Dysfunction
F. Montorsia,*, B. Verheydenb, E. Meulemanc, K.-P. Jünemannd, I. Moncadae,
L. Valiquettef, A. Casabég, C. Pachecoh, J. Dennei, J. Knighti, S. Segalj, V.S. Watkinsi
a
Department of Urology, Università Vita e Salute San Raffaele, Via Olgettina 60, 20312 Milan, Italy
b
Department of Urology, University Hospital of Antwerp, University of Antwerp, Edegem, Belgium
c
Department of Urology, University Hospital Nijmegen, Nijmegen, The Netherlands
d
Department of Urology, Christian-Albrechts University, Kiel, Germany
e
Urology Department, Hospital General Universitario Gregorio Maranon, Madrid, Spain
f
Department of Urology, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
g
Instituto Médico Especializado, Buenos Aires, Argentina
h
Clinica Londres, Mexico City, Mexico
i
Eli Lilly and Company, Indianapolis, IN, USA
j
Lilly ICOS LLC, Bothell, WA, and Indianapolis, IN, USA
Accepted 12 November 2003
Published online 2 December 2003

Abstract
Objective: To assess the long-term safety and tolerability of tadalafil for patients with erectile dysfunction (ED).
Patients and Methods: This was a multicentre, open-label, 24-month extension trial involving 1173 men with ED.
The mean age was 57 (range 23–83) years and 74.8% of patients were taking concomitant medications for comorbid
conditions, including diabetes mellitus in 30.5% of men and hypertension in 29.5%. These patients had participated
in 1 of 5 previous 8-week or 12-week randomised, double-blind, placebo-controlled tadalafil studies. In the present
trial, the starting 10 mg dose of tadalafil could be increased to 20 mg if the patient could not achieve satisfactory
intercourse or reduced to 5 mg for an adverse event that was persistent, intolerable and judged by the investigator to
be related to tadalafil.
Results: Four hundred ninety-three (42.0%) men completed 24 months of treatment. In addition, a further 234
(19.9%) completed 18 months of treatment due to a sponsor decision to reduce the study duration. The total tadalafil
exposure was 1676.0 patient-years. Tadalafil was safe and well tolerated. Headache (15.8%), dyspepsia (11.8%),
nasopharyngitis (11.4%), and back pain (8.2%) were the most common treatment-emergent adverse events. The rate
of discontinuations due to adverse events for this 18–24-month study was 6.3% and the rate for any individual event
was <1%. Serious adverse events occurred in 8.6% of patients. No consistent pattern of serious adverse events
assessed as causally associated with tadalafil administration was observed. None of the four deaths that occurred
during the study was assessed as tadalafil related. There were no clinically significant laboratory or electrocardio-
graphic findings or changes in vital signs in mean baseline-to-endpoint analysis attributable to tadalafil. Tadalafil
administration was not causally associated with drug-induced hepatotoxicity, neutropenia, thrombocytopenia, or
renal dysfunction.
Conclusion: Tadalafil at doses of 5, 10, or 20 mg taken as needed up to once daily for 18 to 24 months was safe and
well tolerated. These findings support the long-term use of tadalafil in the clinical management of erectile
dysfunction.
# 2003 Elsevier B.V. All rights reserved.

Keywords: Drug therapy; Impotence; Phosphodiesterase inhibitors; Safety; Tolerability

*
Corresponding author. Tel. þ1-39-02-26437286; Fax: þ1-39-02-26437298.
E-mail address: montorsi.francesco@hsr.it (F. Montorsi).

0302-2838/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2003.11.010
340 F. Montorsi et al. / European Urology 45 (2004) 339–345
1. Introduction
Erectile dysfunction (ED) affects approximately 150
million men worldwide and the prevalence is projected
to more than double by the year 2025 [1,2]. The
anticipated increase in the population of patients seek-
ing treatment for ED and the consequent requirement
for safe and effective therapy have prompted develop-
ment of novel therapies for ED, with oral dosing being
the preferred route [3–5].
Tadalafil is a selective, reversible phosphodiesterase
type 5 (PDE5) inhibitor with demonstrated efficacy as
an oral ED treatment [6]. PDE5 inhibitors potentiate the
male erectile response to sexual arousal by amplifying
the nitric oxide–cyclic guanosine monophosphate sig-
nalling pathway, with consequent penile vasodilation
resulting in engorgement of the corpus cavernosum.
Tadalafil possesses a favourable pharmacokinetic
profile, with a rapid onset and prolonged duration of
proerectile effects [7]. In integrated analyses of 12-
week randomised, double-blind, placebo-controlled
trials, more than 70% of sexual-intercourse attempts
were successfully completed from >30 minutes to 36
hours after tadalafil dosing [6]. The pharmacokinetics
of tadalafil are not affected by food intake [8].
Because most patients with ED require treatment on
a chronic basis, therapeutic agents for ED treatment
must have satisfactory long-term safety profiles. To
assess the long-term safety and tolerability of tadalafil,
we conducted a multicentre, long-term, open-label
extension study in men with ED who had participated
in prior tadalafil placebo-controlled clinical trials.
2. Methods
2.1. Patients
Men who had participated in prior placebo-controlled tadalafil
studies, did not discontinue prematurely, and wished to continue
ED treatment were eligible. The starting dose of tadalafil was
10 mg taken as needed before sexual intercourse at a maximum
frequency of once daily. No other ED therapies were permitted for
7 days before the initial study dose and for 96 hours after the final
visit.
The 5 parent studies contributing patients into this open-label
study enrolled men aged 18 years who experienced a 3-month
history of ED of various severities (i.e. mild, moderate, severe) and
aetiologies (i.e. organic, psychogenic, mixed), and who were in a
stable heterosexual relationship. Erectile dysfunction was defined
as a consistent alteration in the quality of erections that adversely
affected the patient’s satisfaction with sexual intercourse. None of
the 5 parent studies excluded patients who had used sildenafil prior
to entry, although 2 of the 5 did exclude patients with prior
unsuccessful sildenafil treatment.
Exclusion criteria included any of the following 6 months before
screening: myocardial infarction, cardiac intervention (e.g. coronary
artery bypass surgery, percutaneous coronary intervention), unstable
angina pectoris, angina pectoris during intercourse, or congestive
heart failure. Also excluded were patients with (1) any supraven-
tricular arrhythmia with an uncontrolled ventricular response
(mean heart rate >100 beats per minute) at rest despite medical or
device therapy, (2) any history of spontaneous or induced sustained
ventricular tachycardia (heart rate >100 beats per minute for 30
seconds) despite medical or device therapy, or (3) an automatic
internal cardioverter-defibrillator. Patients with poorly controlled
blood pressure (systolic >170 or <90 mmHg; diastolic >100 or
<50 mmHg) or malignant hypertension at screening were also
excluded. These cardiovascular exclusions are consistent with con-
sensus guidelines for risk-stratifying patients with sexual dysfunction
and cardiovascular disease [9].
Other exclusion criteria were clinically significant hepatobiliary
disease (e.g. alanine aminotransferase [ALT] or aspartate amino-
transferase [AST] elevations >3 times the upper limit of normal at
screening); a recent (6-month) history of clinically significant
renal insufficiency; stroke or other significant central nervous
system injury; or drug, alcohol, or substance abuse. Treatment
with nitrates, cancer chemotherapy, or antiandrogens during the
study period was prohibited.
2.2. Study design
This was a multicentre, open-label, 24-month extension trial for
ED patients who had participated in any 1 of 5 prior 8-week or
12-week randomised, double-blind, placebo-controlled tadalafil
studies. In the 5 parent studies, patients received tadalafil, sildenafil,
or placebo. In this open-label trial, 1173 patents were enrolled at 69
centres in Canada (n ¼ 563), Europe (Belgium, Germany, Italy,
Spain, The Netherlands) (n ¼ 520), Argentina (n ¼ 68), and Mexico
(n ¼ 22). An additional 5 patients (2 in Canada and 3 in Italy) were
entered (consented) but discontinued before taking any study drug.
The study was conducted in accordance with the Declaration of
Helsinki and Good Clinical Practice guidelines. Local ethical
review boards approved the protocol and informed consent docu-
ment before study onset. Patients and their sexual partners provided
written informed consent.
Patients who met eligibility criteria and signed informed con-
sents were seen at months 1, 3, 6, 9, 12, 15, 18, 21, and 24.
Individuals who had completed a placebo-controlled active-com-
parator trial underwent a 7-day washout period prior to screening
laboratory tests. For patients completing a tadalafil study 28 days
before entry into this extension study, the physical examination and
electrocardiograms (ECGs) of the prior study’s termination visit
were allowed to serve as baseline. Haematology, chemistry, and
urinalysis data from the prior trial’s termination visit could serve as
baseline if obtained 14 days of entry into the extension.
The initial tadalafil dose was 10 mg taken as needed before
intercourse at a maximum frequency of once daily. Increases or
decreases in doses according to prespecified rules were allowed at
subsequent visits. At subsequent visits, of which some could be
unscheduled visits, doses could be increased by 1 dose level
(e.g. from 10 to 20 mg or 5 to 10 mg) or decreased by 1 dose
level (e.g. from 10 to 5 mg or 20 to 10 mg). A decrease in dose of 1
level was permitted if the patient experienced an adverse event that
was persistent or disrupted daily activities and was deemed by the
investigator to be related to treatment. A dose increase of 1 level
was allowed if the patient could not attain sufficient hardness or
successfully complete intercourse after an adequate number of
sexual attempts. At each of these visits, blood pressure and pulse,
adverse events, concomitant medications and the reason for dose
modification were recorded.
 F. Montorsi et al. / European Urology 45 (2004) 339–345 341

2.3. Safety analysis months, 72% of patients received 20 mg. The mean
The primary objective of this trial was to evaluate the safety and duration of treatment with tadalafil was 523.3 days
tolerability of tadalafil (5–20 mg) taken as needed prior to inter-
course at a maximum frequency of once daily for up to 24 months.
(range: 2.0–815.0), during which patients received a
Patients were seen 1 month after study entry and at 3-month mean of 149.3 total doses of tadalafil (1.9 doses/week).
intervals beginning with month 3. Total exposure to tadalafil was 1676.0 patient-years,
Safety analyses included the evaluation of adverse events, vital including 1192.3 patient-years with tadalafil 20 mg and
signs, serum chemistry, haematology, ECGs, and urinalysis. Treat- 472.7 patient-years with tadalafil 10 mg.
ment-emergent adverse events were defined as any untoward
medical occurrences that either first appeared or worsened in a
Nine hundred ninety-one (84.5%) men received treat-
patient receiving tadalafil. Serious adverse events were defined ment with tadalafil at an as-needed dose of 10 mg for
according to regulatory requirements as adverse events that resulted a continuous interval of 6 months, including 870
in 1 of the following outcomes (or was significant for any other (74.2% of all enrolled patients) for 12 months and
reason): death; initial or prolonged inpatient hospitalisation; a life- 670 (57.1%) for 18 months. An as-needed tadalafil
threatening experience (i.e. immediate risk of dying); severe or
dose of 20 mg was taken continuously for 6 months
permanent disability; cancer; or congenital anomaly.
by 746 patients (63.6% of all enrolled patients), includ-
2.4. Statistical analysis ing 624 (53.2%) for 12 months and 374 (31.9%) for
Safety and tolerability were evaluated for all patients enrolled in 18 months.
the open-label extension study (n ¼ 1173). Data were summarised Baseline characteristics are presented in Table 1. The
according to treatment received in the previous study. Continuous mean patient age was 57 years; 94.6% of patients were
variables were summarised by mean, standard deviation, median
and minimum/maximum values, and categorical variables by
Caucasian; 25.5% of patients reported smoking; and
numbers and frequencies. 74.8% of patients were taking medications for con-
Treatment-emergent adverse events were coded using the Med- comitant conditions, including hypertension, diabetes
ical Dictionary for Regulatory Activities (MedDRA) version 5.0. mellitus, and hypercholesterolaemia. The mean body
Proportions of patients experiencing an adverse event were calcu- mass index was 28.0 kg/m2. A total of 438 (37.3%)
lated and summarised by MedDRA body system and preferred term
and by severity. If a patient reported an event more than once, the
patients were taking concomitant antihypertensive
most closely related event and the most severe event were included. medication; 75 (6.4%) were on alpha-blockers.
Reasons for premature study discontinuation, including adverse
events, were also recorded and summarised by numbers and 3.2. Safety and tolerability
frequencies. Tadalafil was safe and well tolerated during long-term
Analyses of the proportions of patients with treatment-emergent
treatment. The most frequently reported treatment-
adverse events, abnormal ECGs, or laboratory analytes outside
reference ranges at the final visit (or at the maximum or minimum emergent adverse events included headache (15.8%),
value) were based on pooled data from all sites. dyspepsia (11.8%), nasopharyngitis (11.4%), and back
Table 1
Baseline characteristics
3. Results
Tadalafil (n ¼ 1173)
3.1. Patient characteristics Age, yrs (mean, range) 57.0 (23.4–82.8)
Of 1173 patients enrolled, most had been treated in Body mass indexa, kg/m2 (mean  S:D:) 28.0  4.2
the prior parent double-blind trials with tadalafil (n ¼ Systolic/diastolic blood pressureb, 132.4/80.3  14.8/8.4
mmHg (mean  S:D:)
727, 62.0%). Others had received either placebo (n ¼ Smokers (n (%)) 299 (25.5)
335, 28.6%) or sildenafil (n ¼ 111, 9.5%). A total of
Race/ethnicity (n (%))
493 (42.0%) patients completed 24 months of open- Caucasian 1110 (94.6)
label treatment. An additional 234 (19.9%) patients African 20 (1.7)
discontinued after 18 months of treatment due to a Hispanic 24 (2.0)
Asian 16 (1.4)
sponsor decision to reduce the duration of the study to
Other 3 (0.3)
18 months. Of the remaining 446 patients, there were 4
Comorbidity (n (%))
deaths, 40 lost to follow-up, and 402 study disconti-
Hypertension 346 (29.5)
nuations. For the 402 discontinuations, 173 were due to Diabetes mellitus 358 (30.5)
patient-perceived lack of efficacy, 94 personal conflict Hypercholesterolaemia 143 (12.2)
or other patient decision, 74 adverse events, 42 proto- Hyperlipidaemia 45 (3.8)
Depression 44 (3.8)
col and entry criteria violations, and 19 investigator or >1 concomitant medication 877 (74.8)
sponsor decisions.
a
Most patients increased the starting dose of tadalafil No baseline weight available for 6 patients.
b
No baseline blood pressure available for 5 patients.
to a dose of 20 mg within the first 3 months. At 3
342 F. Montorsi et al. / European Urology 45 (2004) 339–345

Table 2 7 (0.6%), myocardial infarction in 7 (0.6%), back pain

Treatment-emergent adverse events reported by 2% of patientsa
in 5 (0.4%), cerebrovascular accident in 5 (0.4%), and
Tadalafil (n ¼ 1173) angina pectoris in 4 (0.3%).
Patients with 1 adverse event 840 (71.6) Ocular events that may have been related to PDE
Headache 185 (15.8) inhibition—including eyelid oedema, conjunctival
Dyspepsia 139 (11.8) hyperaemia, and sensations described as pressure—
Nasopharyngitis 134 (11.4)
Back pain 96 (8.2)
were uncommon and generally mild or moderate. One
Influenza 52 (4.4) patient discontinued due to eyelid oedema. With regard
Hypertension 48 (4.1) to visual symptoms known to be associated with PDE6
Flushing 42 (3.6) inhibition, 1 patient complained of a single episode of
Nasal congestion 42 (3.6)
Arthralgia 41 (3.5)
mild blue vision, but the patient did not report this
Cough 38 (3.2) event after subsequent doses. No cases of priapism
Influenza-like illness 37 (3.2) were reported.
Myalgia 34 (2.9)
Bronchitis 32 (2.7)
Diarrhoea 30 (2.6)
Dizziness 28 (2.4) 4. Discussion
Upper-abdominal pain 27 (2.3)
Nausea 25 (2.1) In this open-label, long-term extension study, tada-
Limb pain 23 (2.0)
lafil was safe and well tolerated. Most patients received
a
Values are numbers (%). a tadalafil dose of 20 mg, and most of the remainder
received a dose of 10 mg. Tadalafil treatment was not
associated with any major safety concerns.
pain (8.2%) (Table 2). Most adverse events were mild or Demographics of this study reflected those of the
moderate. The percentage of events reported as mild or parent studies and ED populations in general [6,10],
moderate was 88% and the percentage of events reported including various degrees of ED severities and aetiol-
as severe was 12%. ogies. Compared with the Massachusetts Male Aging
Four deaths (3 cardiac deaths and 1 suicide) occurred Study (MMAS) [10], the present study population had
during the 24-month open-label study, none of which similar proportions of patients with vascular diseases
was assessed as related to study drug. Two additional or other factors that increase the risk of developing ED
deaths were reported after the patients had discontin- [11–13], including hypertension in 29.5% of patients,
ued from the study: 1 patient with bile-duct cancer and diabetes mellitus in 30.5% (vs. 6.8% in MMAS [10])
1 patient with metastatic prostate cancer (both assessed and smoking in 25.5% (vs. 22%). The incidence of
as unrelated to study drug). There were no clinically diabetes mellitus was increased because patients who
significant laboratory or ECG findings or changes in enrolled in this study also included patients from 1
vital signs in mean baseline-to-endpoint analysis attri- randomised clinical trial that investigated the effects of
butable to tadalafil. Tadalafil administration was not tadalafil in patients with diabetes mellitus who had ED.
causally associated with drug-induced hepatotoxicity, Treatment-emergent adverse events, including head-
neutropenia, thrombocytopenia, or renal dysfunction. ache, dyspepsia, flushing, back pain, myalgia, and nasal
Serious adverse events were experienced by 101 congestion, that occurred in this study are consistent
(8.6%) patients. Of these, 35 withdrew from treatment with the pharmacodynamic effects of PDE5 inhibition.
(3.0% of total enrolled). Serious adverse events All these adverse events have been reported previously
included myocardial infarction in 9 (0.8%) patients in association with this and the other PDE5 inhibitors,
and cerebrovascular accident in 5 (0.4%) patients. No sildenafil and vardenafil [14,15]. There is no obvious
consistent pattern of serious adverse events causally pharmacological explanation for myalgias associated
related to tadalafil emerged from this long-term study. with PDE5 inhibitor therapy [16]. Of the 1173 men in
Seventy-four (6.3%) patients discontinued the trial this long-term safety study, 34 (2.9%) reported myalgia
prior to completion of the 18–24 months of therapy and 96 (8.2%) back pain. However, of the 74 patients in
because of adverse events. Thirty-six (3.1%) patients this study who discontinued prior to completion of 18–
discontinued due to adverse events that were assessed 24 months of therapy because of adverse events, only 5
by the investigator as possibly related to tadalafil. For (0.4%) discontinued due to back pain.
any single adverse event, the discontinuation rate was In all, treatment-emergent adverse events prompted
less than 1%. Adverse events leading to discontinua- discontinuation in 6.3% of patients prior to completion
tion in 0.3% were headache in 9 (0.8%), dyspepsia in of the long-term (18–24 months) open-label therapy. A
 F. Montorsi et al. / European Urology 45 (2004) 339–345
total of 173 (14.7%) men discontinued because of
patient-perceived lack of efficacy over 18–24 months
of treatment. Most discontinuations occurred within
the first 6 months of this extension study. Sixty-eight
percent of patients who discontinued due to perceived
lack of efficacy did so within the first 6 months, and
90% did so within the first 12 months.
Cardiovascular events occurred at low rates in the
present patient population, given the presence at base-
line of vascular disease or risk factors (e.g. hyperten-
sion, diabetes, hypercholesterolaemia). Nine patients
experienced myocardial infarction. There were 3
deaths attributable to cardiac causes. In an analysis
of prior studies in which 4399 patients were treated
with tadalafil, the incidence rate of myocardial infarc-
tion was 0.43 per 100 patient-years [17]. The incidence
rate for placebo controls in tadalafil and sildenafil
studies was 0.60–1.17 [17,18] per 100 patient-years.
In the present long-term study, for 1676.0 patient-years
of exposure to open-label tadalafil, the incidence rate of
myocardial infarction was 0.54 per 100 patient-years.
This rate is no higher than that expected for a similarly
age-matched population [19]. The incidence rate of
cardiac death in this long-term study was 0.18 per 100
patient-years. This rate was no higher than that
observed in the general male population under 75 years
of age in the United Kingdom (an incidence rate of 0.26
per 100 patient-years) [19].
Cyanopsia (usually described as blue vision), other
colour-visual abnormalities, increased brightness/sen-
sitivity to light, haziness, and other generally mild and
transient visual effects have been reported with the
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Editorial Comment
Jeremy P.W. Heaton, Kingston, Ontario, Canada
In the world of erectile dysfunction (ED) long-term
safety and tolerability studies are the less glamorous
relatives of the beautiful acute efficacy studies. In
practice they probably reveal more about the future as
long as the efficacy side of the equation is solid. This is
because studies like ‘‘Long-term safety and tolerability
of tadalafil in the treatment of erectile dysfunction’’
document the modern benign reality of living with ED
and ED therapy. Furthermore long-term safety issues are
possibly the most likely to express the divergence in
molecular design that places tadalafil as the least ‘typi-
cal’ of the current generation of the class of selective,
reversible phosphodiesterase type 5 (PDE5) inhibitors.
This is not a comparative study but certainly there
are particular issues that will interest clinicians that
have been highlighted by personal experience, prior
literature and rumour or urban legend. In fact compar-
isons should not be constructed from these data
because of the individual nature of study design,
patient inclusion and exclusion criteria and eventual
patient demographics including severity.
Staying in a long-term study is burdensome for the
patient even if the drug is free—more than 60%
remained in evaluation until the end of their study
period. Why the patients left the study is of some interest
but whatever the data say these patients are still impo-
tent—needing drug to function sexually—they have the
same partner, the same image in the mirror and the same
[22] Hellstrom WJG, Gittelman M, Karlin G, Segerson T, Thibonnier M,
Taylor T, the Vardenafil Study Group. Vardenafil for treatment of
men with erectile dysfunction: efficacy and safety in a randomized,
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financial and domestic situations. In a few patients the
effects of the drug itself will cause the patients to
discontinue prematurely—here only 3.1% of patients.
Most patients will choose to migrate to the highest
dose (72% at 3 months had chosen 20 mg tadalafil)
following the well established trend of men wanting to
be as good as they imagined themselves to be.
With a different selectivity profile from other pub-
lished PDE5 inhibitors visual disturbances were here
limited to just 1 patient who complained of a single
episode that did not recur.
The patient population looked very like those
reported in the Massachusetts Male Aging Study
(MMAS) and other ED clinical trials. The present
study population had similar proportions of patients
with cardiovascular diseases and in the 1676 patient
years represented here there were no deaths attributable
to drug. There were just 9 myocardial infarctions (0.8%
of patients) giving a rate that is similar to that reported
in similar studies—with an average rate of 1.9 tablets a
week and a long half-life it would be difficult to make a
case for complete absence of drug during all these
events but neither did it alter the profile. There were 75
patients (6.4%) who were on alpha blockers and there
is no specific mention of safety signals from them.
Back pain (8.2%) joins the more familiar headache
(15.8%), dyspepsia (11.8%) and nasopharyngitis
(11.4%) that should be mentioned to patients as minor
issues that may affect a proportion of them at one time
or another. We are no further ahead from this paper in
 F. Montorsi et al. / European Urology 45 (2004) 339–345 345

understanding the various myalgias associated with
PDE5 inhibitor therapy but neither was that an intent
for the study.
In summary therefore, the growing diversity in oral
therapies for ED appears to be entirely in the patient’s
favour. The new clinical properties for tadalafil we
have seen documented elsewhere are complemented by
a solid long-term safety profile. Patients will tell their
physicians how they want their PDE5 inhibitor served
up.