Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00019
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: January 2004
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Bibliographic ID: UF00087345
Volume ID: VID00019
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Michael Comber, Pharm.D. Candidate

The National Institute of Health (NIH) has
defined erectile dysfunction (ED) as the inability to
achieve or maintain an erection sufficiently rigid
for satisfying sexual intercourse.1 Under this defini-
tion, it is estimated that greater than 150 million
men worldwide suffer from this condition.2'3 How-
ever, some experts question this definition as it may
be too broad to truly evaluate the population af-
fected. The definition encapsulates those unable to
attain an erection, those unable to maintain an erec-
tion, and the subjective judgment of 'satisfactory'
intercourse. It is important to keep this in mind as
we evaluate the available studies pertaining to ED,
in order to appropriately identify the populations
being treated which may impact our ability to ex-
trapolate data to our clinical practices.
Tadalafil (Cialis) is the third phosphodi-
esterase 5 (PDE5) inhibitor approved by the FDA
for the treatment of ED. It is being marketed by
Lilly and received approval in December 2003.
Unfortunately, there is a lack of head-to-head com-
parisons between taladafil and the other available
PDE5 inhibitors. Therefore, in order to chose the
best option for a particular patient, it is important to
understand the potential risks and benefits attrib-
uted to each medication. In this article we will dis-
cuss the safety, efficacy and tolerability of tadalafil.

At the same time, we will explore the pharmacoki-
netic and pharmacodynamic differences that distin-
guish tadalafil from the other PDE5 inhibitors.

Mechanism of Action and Pharmacokinetics
In the presence of sexual stimulation, nitric
oxide (NO) is responsible for initiating a cascade of
events that ultimately leads to an erection. Nitric
oxide activates guanylyl cyclase, which converts
guanosine triphosphate (GTP) into cyclic guanosine
monophosphate (cGMP). cGMP is responsible for
relaxation of smooth muscle in the corpus caverno-
sum of the penis allowing the inflow of blood re-
sponsible for the erection. Tadalafil selectively in-
hibits PDE5, which is the enzyme responsible for
the catabolism of cGMP, leading to increased con-
centrations of cGMP in the corpus cavernosum.
Since tadalafil has no direct relaxant effect on
smooth muscle, it cannot cause an erection in the
absence of sexual stimulation-mediated release of
Tadalafil reaches its maximum plasma con-
centration (Cmax) approximately 2 hours after a sin-
gle oral dose.5 Its absorption is not affected by food
intake, age, diabetes or mild to moderate hepatic
insufficiency.6 Comparatively, vardenafil and silde-
nafil achieve lower Cmax's when administered with a
high fat meal, and should be initiated at lower
doses in the elderly.7 This allows for a more con-
venient administration regimen with tadalafil when
compared to other PDE5 inhibitors. Tadalafil's on-
set of action is between 16 and 45 minutes. Once
absorbed, it is widely distributed to the tissues
(Vd=62.6L) and protein binding is 94% at thera-
peutic concentrations. It has a half-life of 17.5
hours, with an effective duration of action of ap-
proximately 36 hours,5 allowing for a for a longer
dosing interval than current PDE5 inhibitors. Me-

Pha rma Note Volume 19, Issue 4 January 2004




Volume 19, Issue 4 January 2004

Table 1. Comparison of PDE5 inhibitors in regards to selected parameters

Parameter Tadalafil Sildenafil Vardenafil

High fat meals none Cm, ? 29% Cm, ? 18% to 50%
Half-life (hours) 17.5 4 4 5
Metabolism CYP 3A4 CYP 3A4 CYP 3A4
Active Metabolites No Yes* Yest
Available doses 5 mg, 10 mg, 20 mg 25 mg, 50 mg, 100 mg 2.5 mg, 5 mg, 10 mg, 20 mg
PDE5 phosphodiesterase 5, Cmaxpeak plasma concentration. *accounts for 20% of activity accounts for 7% of activity

tabolism is via the CYP3A4 isoenzyme to an inac-
tive metabolite.8 It is recommended that those tak-
ing potent CYP3A4 inhibitors should not exceed a
maximum daily dose of 10 mg every 72 hours. Ta-
dalafil is excreted predominantly as inactive me-
tabolites in the feces (approx. 61%) and to a lesser
extent in the urine (approx. 36%).8 A brief profile
of the three PDE5 inhibitors is listed in Table 1.

Clinical Trials
Relatively few clinical trials have been
completed with tadalafil to date. Some prominent
trials include: a general safety and efficacy study of
tadalafil versus placebo,9 a similar study that in-
cluded only men with diabetes,10 and a third that
evaluated its efficacy at 24 and 36 hours after dos-
ing versus placebo.7

Tadalafil versus placebo
Padma-Nathan and colleagues9 randomized
179 men (mean age 56y) to placebo or tadalafil 2
mg, 5 mg, 10 mg and 25 mg respectively. The In-
ternational Index of Erectile Function (IIEF) and
Sexual Encounter Profile (SEP) were used to meas-
ure primary outcomes versus baseline. Both ques-
tionnaires were completed after each sexual en-
counter. All four of the tadalafil groups had signifi-
cantly greater SEP scores in regards to whether or
not they, 'were able to insert their penis into their
partner's vagina,' while only the 5, 10 and 25 mg
groups reported significantly greater scores in,
'completing intercourse with ejacula-
tion,' (p=0.0005).
As for the IIEF outcomes, all four treatment
groups had significant increases in erectile func-
tion, orgasmic function, sexual desire and overall
satisfaction (p=0.05). Moreover, only the 5, 10 and

25 mg groups had significant increases in overall
intercourse satisfaction (p=0.05). Results from this
trial are summarized in Table 2. Reported adverse
events in this trial were minimal, with only head-
ache, dyspepsia and back pain being reported in >
3% of the men. Only seven subjects withdrew from
the study, two of those were related to adverse
events. The authors concluded that tadalafil is a
safe and effective treatment for ED in doses up to
25 mg.
Porst and colleagues7 evaluated the safety
and efficacy of 24- or 36-hour post dose intervals
of tadalafil 20 mg or placebo. This multicenter, ran-
domized, double-blind, placebo-controlled, paral-
lel-group study of 348 men (mean age 57y) used a
SEP to record subject's attempts at intercourse and
results from intercourse attempts. The authors con-
cluded that both the 24-hour and 36-hour post dose
tadalafil groups had more successful attempts at in-
tercourse than placebo (52.9% and 59.2%, respec-
tively). On the other hand, only 29.1% and 28.3%
of men were successful in the placebo groups. Ad-
verse events in this trial were similar to others that
involved PDE5 inhibitors, with headache (8%),
flushing (5.7%), dyspepsia (5.1%) and myalgia
(3.4%) occurring more often in the treatment group.

Tadalafil versus Sildenafil
Govier and colleagues" conducted a ran-
domized, double-blind, crossover trial of tadalafil
versus sildenafil. Two hundred and fifteen men
(mean age 49.8y) were randomized to receive either
tadalafil 20 mg or sildenafil 50 mg in a four-week
interval, before switching to the alternative treat-
ment. This study found that tadalafil was the pre-
ferred treatment group in 66.3% of men, while
33.7% of men preferred sildenafil. Patient's prefer-

Pha rma Note Volume 19, Issue 4 January 2004


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Table 2. Efficacy outcomes for tadalafil versus placebo
Placebo 2 mg 5 mg 10 mg 5 mg
(n=35) (n=35) (n=37) (n=36) (n=36)
Ability to insert (-0.3) 0.6 1.2 1.0 1.3
Ability to complete 0.2 0.8 1.4 1.7 1.7
Erectile Function 1.0 4.11 7.3T 7.8 9.4
Orgasmic Function 0.2 1.71 2.0 1.31 2.1
Sexual Desire (-0.2) 0.6 0.9s 0.9 1.0
Intercourse Satisfaction 1.3 2.5 3.4t 3.2T 4.2
Overall Satisfaction 0.3 1.8s 2.5T 2.5 3.7
Figures shown represent mean changes from baseline in SEP and IIEF scores.
p = 0.005 vs placebo. I p = 0.0005 vs placebo. p = 0.05 vs placebo.

ence did not differ between age, duration of treat-
ment, treatment sequence, or previous exposure to
sildenafil. It was presumed by the author's that pa-
tient preference was probably based on the longer
effective window for tadalafil that allowed a more
'natural' sexual encounter, as opposed to a planned
encounter, and the fact that taking it without regard
of food consumption allows for a simpler admini-
stration schedule. This study also showed similar
adverse events including headache, dyspepsia, na-
sopharyngitis and flushing occurring in > 3% of
subjects, with no significant differences between
the two treatment groups.

Adverse Events
The most frequently reported adverse ef-
fects (=2% reported) associated with tadalafil are
listed in Table 3. The majority of the events were
classified as either mild or moderate in severity.
With regards to the myalgias and pain, no underly-
ing cause was elucidated, <5% of all reports were
classified as severe, and they were all treated suc-
cessfully with NSAIDs.
Rare cases of prolonged erection (>4 hours)
or priapism (painful erection lasting >6 hours) have
occurred in patients taking PDE5 inhibitors. It is
important to note that an erection lasting >4 hours
can cause irreversible erectile tissue damage, and
people with this condition should seek medial at-

Tadalafil is contraindicated in those patients
who are concomitantly receiving nitrates or alpha-

blockers (excluding tamsulosin 0.4 mg once daily )
because it has the potential to greatly increase the
hypotensive effects of these agents. It is also con-
traindicated in anyone with a known hypersensitiv-
ity to tadalafil or any of its components. In clinical
trials, tadalafil has been co-administered with other
classes of antihypertensive agents, with none result-
ing in a greater than 8/4 mm reduction in blood
pressure. None of the changes in these studies
were concluded to be of clinical significance.
Patients on potent inhibitors of the CYP
3A4 isoenzyme should limit their tadalafil dose to
10 mg every 72 hours. In clinical trials, the area
under the curve (AUC) increased 312% and 124%,
with ketoconazole and ritonavir, respectively.

The recommended starting dose of tadalafil
is 10 mg taken one-half to four hours prior to an-
ticipated sexual activity. The dose may be titrated
to 20 mg, or decreased to 5 mg on an individual ba-
sis, and may be dosed everyday in most popula-
tions. Tadalafil may be given without regards to
meals, and is not affected by co-administration of
antacids or H2-antagonists.8
Patients who have mild to moderate hepatic
impairment should be limited to an oral dose of 10
mg daily. For those with severe disease, tadalafil is
not recommended. For renal insufficiency, it is rec-
ommended that those with a creatinine clearance
(CrC1) of less than 30 ml/min should be limited to 5
mg daily. For those with a CrCl between 31 and 50
ml/min, it is recommended to start at 5 mg, with a
maximum dose of 10 mg every 48 hours.

Pha rma Note Volume 19, Issue 4 January 2004


Volume 19, Issue 4 January 2004

Table 3. Number of adverse events with tadalafil versus placebo8
Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg
Adverse Event (N=476) (N=151) (N=394) (N=635)

Headache 5% 5% 11% 15%
Dyspepsia 1% 4% 8% 10%
Back Pain 3% 3% 5% 6%
Myalgia 1% 1% 4% 3%
Nasal Congestion 1% 2% 3% 3%
Flushing 1% 2% 3% 3%
Pain in limbs 1% 1% 3% 3%

The average retail cost for ten comparable
doses of the available PDE5 inhibitors is $103
($95.95-$108.33) for tadalafil, $105 ($102.95-
$108.34) for sildenafil, and $96 ($87.99-$103.03)
for vardenafil. 12

In clinical trials, tadalafil is well-tolerated
by about 70% of patients and appears to be a good
option for patients who suffer from ED. It has an
effective duration of 36 hours, which may provide
an advantage over the other available PDE5 inhibi-
tors, allowing it to be given once every 36 hours.
More trials are needed before any PDE5 inhibitor is
determined to be the drug of choice for ED.

1. NIH Consensus Development Panel on Impotence. Impo-
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AmMedAssoc 1993; 270: 8390.
2. Kubim M, Wagner G, Fugl-Meyer A R. Epidemiology
of Erectile Dysfunction. International Journal of Impo-
tence Research 2003; 15:63-71.
3. McKinlay J B. The Worldwide Prevalence and Epidemi-
ology of Erectile Dysfunction. International Journal of
Impotence Research 2000; 12:S6.
4. Rosen R, Kostis J. Overview of Phosphodiesterase 5 In-
hibition in Erectile Dysfunction. American Journal of
Cardiology 2003; 92(suppl): 9M-18M.
5. Patterson B, et al. Dose-normalized pharmacokinetics of
single-dose tadalafil (IC351) in healthy volunteers. Int J
Impot Res 2001;13 supplyl 5):S62. Abstract 14.
6. Patterson B, et al. The effect of intrinsic and extrinsic
factors on the pharmacokinetic properties of tadalafil
(IC351). Int J Impot Res 2001;13(suppl 5):S63. Abstract
7. Porst H, et al. Efficacy of Tadalafil for the Treatment of
Erectile Dysfunction at 24 and 36 Hours After Dosing: A
Randomized Controlled Trial. Urology 2003; 62: 121-

8. (C lihs (tadalafil) [package inset]. Indianapolis, IN;
Lilly; 2003.
9. Padma-Nathan H, McMurray JG, Pullman WE, et al. On-
demand IC351 (Cialis) enhances erectile function in pa-
tients with erectile dysfunction. Int J Impot Res
10. Tejada I, Anglin G, Knight JR, Emmick JT. Effects of
Tadalafil on Erectile Dysfunction in Men with Diabetes.
Diabetes Care 2002 Dec; 25;2159-2164.
11. Govier F, et al. A multicenter, randomized, double-blind,
crossover study of patient preference for tadalafil 20 mg
or sildenafil citrate 50 mg during initiation of treatment
for erectile dysfunction [Abstract]. Clinical Therapeutics
2003 Nov; 25(11) 2709-2723.
12. Prices were obtained 1/12/04 from three community

The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor

Pha rma Note Volume 19, Issue 4 January 2004


Volume 19, Issue 4 January 2004

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