Alprostadil cream in the treatment of erectile dysfunction: Clinical evidence and experience

Abstract

Erectile dysfunction (ED) is a very common disorder with a deep impact on quality of life on both patients and partners. Several options are available for treating ED: oral pharmacotherapy with phosphodiesterase 5 (PDE5) inhibitors currently represents the first-line option for many patients with ED. Alprostadil, a prostaglandin, has been marketed for many years as a urethral stick and an intracavernous injection for the treatment of ED. It is now available in the form of a cream (Vitaros/Virirec), a noninvasive treatment which combines an active drug (alprostadil, a synthetic prostaglandin E1) with a skin enhancer improving its local absorption directly at the site of action. Alprostadil has a favourable pharmacodynamic profile and is poorly absorbed in systemic circulation, which makes it suitable in a lot of circumstances and results in a reduced risk of adverse effects (AEs). Systemic AEs are reported in only 3% of the treated population. Clinical efficacy has been demonstrated in both phase II and III trials, showing a global efficacy up to 83% with the 300 μg dose in patients with severe ED, significantly better than placebo. Its fast onset of action and lack of interactions with other drugs makes alprostadil cream a possible first-line therapeutic option for some patients with ED: individuals who are reluctant to take systemic treatments or have AEs, patients who do not respond, cannot tolerate, or do not accept PDE5 inhibitor therapy, and patients treated with nitrates. Therefore, this new treatment for ED can be offered to patients and could help address the needs unmet by other treatments.

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Ther Adv Urol
2016, Vol. 8(4) 249 –256
DOI: 10.1177/
1756287216644116
© The Author(s), 2016.
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Therapeutic Advances in Urology
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Introduction
Erectile dysfunction (ED) is a common disorder,
with increasing incidence in men over 40 years of
age. The prevalence of ED has been estimated to
be between 2% and 10% in men aged between 40
and 50 years, between 30% and 40% in men aged
60–70 years, and more than 50% in men over the
age of 70 [Braun etal. 2000; Araujo et al. 2009;
Lewis etal. 2010].
Due to the increase in the healthy aging popula-
tion, ED could be considered as a public health
problem. Apart from pathophysiological implica-
tions of the disorder, several pathologies are also
associated with ED [cardiovascular (CV) disease,
diabetes, prostatectomy], further increasing the
proportion of individuals affected. ED strongly
contributes to an unsatisfactory sexual life, and as
a consequence, the quality of life of both affected
men and their partners is also greatly impaired.
Treatment of ED has been shown to have a posi-
tive effect on the quality of life and overall satis-
faction of both patients and their partners [Latini
etal. 2003].
Phosphodiesterase 5 (PDE5) inhibitors are first-
line on-demand therapy (level 1a and 1b evi-
dence) for ED [Hatzimouratidis et al. 2015].
However, this class of drugs is associated with
treatment failure in 11–44% of patients depend-
ing on the patient population under study
[Carvalheira et al. 2012]. In addition, PDE5
inhibitors have several pharmacological interac-
tions for which they are contraindicated, such as
patients taking nitrates. Compliance with PDE5
inhibitor treatment has been shown to decrease
Alprostadil cream in the treatment of
erectile dysfunction: clinical evidence and
experience
Béatrice Cuzin
Abstract: Erectile dysfunction (ED) is a very common disorder with a deep impact on quality
of life on both patients and partners. Several options are available for treating ED: oral
pharmacotherapy with phosphodiesterase 5 (PDE5) inhibitors currently represents the first-
line option for many patients with ED. Alprostadil, a prostaglandin, has been marketed for
many years as a urethral stick and an intracavernous injection for the treatment of ED. It is
now available in the form of a cream (Vitaros/Virirec), a noninvasive treatment which combines
an active drug (alprostadil, a synthetic prostaglandin E1) with a skin enhancer improving its
local absorption directly at the site of action. Alprostadil has a favourable pharmacodynamic
profile and is poorly absorbed in systemic circulation, which makes it suitable in a lot of
circumstances and results in a reduced risk of adverse effects (AEs). Systemic AEs are
reported in only 3% of the treated population. Clinical efficacy has been demonstrated in both
phase II and III trials, showing a global efficacy up to 83% with the 300 μg dose in patients with
severe ED, significantly better than placebo. Its fast onset of action and lack of interactions
with other drugs makes alprostadil cream a possible first-line therapeutic option for some
patients with ED: individuals who are reluctant to take systemic treatments or have AEs,
patients who do not respond, cannot tolerate, or do not accept PDE5 inhibitor therapy, and
patients treated with nitrates. Therefore, this new treatment for ED can be offered to patients
and could help address the needs unmet by other treatments.
Keywords:
alprostadil cream, clinical evidence, real life
Correspondence to:
Béatrice Cuzin, MD, MSc
Department of Urology and
Transplantation, E Herriot
University Hospital,
69437 Lyon Cedex, France
beatrice.cuzin@chu-lyon.fr
644116TAU0010.1177/1756287216644116Therapeutic Advances in UrologyB Cuzin
research-article2016
Review

Therapeutic Advances in Urology 8(4)
250 http://tau.sagepub.com
over time. In a mean follow up of 1–3 years, over-
all up to 49% of responders to sildenafil, vardena-
fil, and tadalafil reported that they had
discontinued their treatment [Carvalheira et al.
2012; Jiann et al. 2006]. Common reasons for
discontinuation were effect below expectations,
high cost, loss of interest in sex, and inconven-
ience of obtaining sildenafil [Carvalheira et al.
2012; Jiann etal. 2006]. Noneffectiveness was the
leading reason for discontinuation of sildenafil
treatment [Eardley etal. 2007].
The adverse affect (AE) profiles of PDE5 inhibitors
are generally similar. Common systemic AEs
include headache (5–15%), flushing (3–14%), dys-
pepsia (up to 10%), and nasal congestion (2–9%)
[Padma-Nathan et al. 2002; Kloner, 2002; Brock
etal. 2002; Belkoff etal. 2013]. Thus, men who are
not satisfied with PDE5 inhibitors may be offered
local treatment modalities (intracavernosal injec-
tion therapy, intraurethral alprostadil, vacuum
erection devices) which have been used as alterna-
tives or in combination with PDE5 inhibitors.
The available preclinical and clinical data regarding
clinical evidence and clinical experience with a
new alprostadil cream (Vitaros/Virirec, Apricus
Biosciences, San Diego, CA, USA) formulated
with a novel skin permeation enhancing drug deliv-
ery system, are discussed in the following sections.
Clinical evidence
Biology and mechanism
Alprostadil cream (Vitaros/Virirec) combines the
efficacy of alprostadil with an ‘easy to use’
formulation. Alprostadil is a synthetic analog of
prostaglandin E1 (PGE1), equivalent to naturally
occurring PGE1. Its mechanism of action involves
the binding to G protein coupled PGE1 receptors
localized on the surface of smooth muscle cells,
thus activating cAMP (cyclic adenosine
monophosphate), which in turn induces penile
vascular smooth muscle relaxation to provide
penile erection. In contrast to PDE5 inhibitors,
which require an erectogenic stimulus to activate
the nitric oxide/guanylatecyclase pathway, alpros-
tadil acts independently of the psychological and
neurological components of the entire process
leading to erection, thanks to its action as a direct
agonist. Vitaros/Virirec cream is a specific formu-
lation, which contains, together with alprostadil,
an enhancer, namely dodecyl-2-N,N-dimethyl-
amino propionate (DDAIP) HCl (an ester of
N-dimethylalanine and dodecanol), which tem-
porarily loosens tight junctions present in skin
epithelial cells, as a result of its interaction with
the polar region of the phospholipid bilayer on
the plasma membrane [Becher, 2004; Wolka
etal. 2004] (Figure 1). By increasing the motion
of lipid hydrocarbon chains and intercalating
within the skin ceramides, it improves the diffu-
sion of alprostadil through the skin. The formula-
tion is applied in drops directly to the meatus of
the glans penis, allowing for quick penetration of
the drug, directly at the site of action.
Through the use of a laser Doppler meter, it has
been reported that the microcirculation of the
glans improved rapidly after topical administra-
tion, reaching the levels observed in a physiologi-
cally normal erection. Within 10–12 min, full
rigidity of the penis is achieved, which lasts for
Figure 1. Permeation enhancer dodecyl-2-N,N-dimethylamino propionate (DDAIP) mechanism of action.
Adapted from Moncada and Cuzin [2015].

B Cuzin
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more than 1 h [Becher, 2004]. The fast and relia-
ble erectile response has been recently demon-
strated in phase III trials, in which it has been
shown that the majority of patients (n = 434)
receiving alprostadil topical cream 300 μg had a
time interval (from administration) to successful
penetration attempts of 5–30 min. In addition,
approximately 98% of the administered dose of
Vitaros/Virirec is retained in the fossa navicularis
of the penis, thus minimizing systemic diffusion of
the drug [Becher, 2004; Yeager and Beihn, 2005].
Data indicate that, with this formulation, alpros-
tadil is not systemically absorbed to a significant
extent and that it is rapidly metabolized, thereby
predicting low or absent systemic toxicity.
There are no known drug interactions between
Vitaros/Virirec and other medications and there
are no special warnings or precautions for drug–
drug interactions, food, or alcohol. The lack of
interference with food and alcohol is an advan-
tage for the cream formulation, as it eliminates
the need to coordinate the timing of meals around
sexual activity, in contrast to PDE5 inhibitors
whose efficacy, with the exception of tadalafil, is
reduced by heavy and fatty meals due to pro-
longed absorption [Mehrotra etal. 2007].
Outcomes of alprostadil cream in clinical trials
The efficacy and safety of alprostadil cream has
been demonstrated in phase II and III clinical tri-
als [Steidle etal. 2002; Campbell, 2005; Rooney
etal. 2009; Mulhall etal. 2013b]:
(1) Phase II studies have demonstrated signifi-
cant improvements in erectile function
(EF) after 6 weeks of treatment with
alprostadil cream in men with mild to
moderate (n = 161) or severe (n = 142)
ED. The primary efficacy parameter was
changed from baseline to final visit (after
10 drug doses in a 6-week period) in the
EF domain score of the International
Index of Erectile Function (IIEF).
Secondary efficacy parameters included
change from baseline to final visit in the
other domains of the IIEF and in the over-
all IIEF score, successful vaginal penetra-
tions based on Sexual Encounter Profile
(SEP), the Patient Self-Assessment of
Erection (PSAE), and Global Assessment
Questionnaire (GAQ) scores. In patients
with severe ED, the changes in EF domain
score and total IIEF scores from baseline
were significantly higher in the 300 μg
Vitaros/Virirec treatment group than the
placebo group (p < 0.01). These changes
were clinically meaningful. Moreover,
83% of patients with severe ED receiving
300 μg Vitaros/Virirec reported a signifi-
cant improvement in erections (GAQ)
compared with 26% in the placebo group
(p < 0.001). In the study, about 61% of
patients had CV disease and 49% had dia-
betes. A meta-analysis of the earlier two
phase II, multicentre, double-blind, dose-
ranging studies involving a total of 303
patients with ED confirmed the efficacy of
Vitaros/Virirec topical cream.
(2) The efficacy of alprostadil cream was con-
firmed in two phase III randomized con-
trolled trials conducted in men with
moderate to severe ED (mean IIEF EF
score: 13.6). The first study (n = 1732)
included patients with a mean age of 60
years (37% aged >65 years) with a wide
range of concomitant comorbidities (dia-
betes 22%, CVD 32%, prostatectomy
12%, hypertension 48%), treatments
(nitrates or α blockers 16%), and patients
who had previously failed to respond to
sildenafil (19%). After 12 weeks of treat-
ment, alprostadil cream 300 μg signifi-
cantly improved EF and intercourse ability
compared with placebo. As observed in
phase II studies, significant improvements
in all efficacy parameters (IIEF EF, SEP2,
and SEP3) were observed with alprostadil
cream compared with placebo. The major-
ity of the successful attempts took place
during the first 30 min following applica-
tion of alprostadil cream 300 μg.
Finally, the long-term (up to 9 months) efficacy
and safety profile of alprostadil cream has also
been demonstrated in an open-label study con-
ducted with 1161 patients (mean age 60 years)
with mild to severe ED (IIEF EF score ⩽25).
Most of these patients had participated in the
phase III trials. The majority of the patients
(93%) had a mean ED duration of at least 12
months. Patients were initially administered
alprostadil cream 200 μg that could be titrated up
or down to 300 or 100 μg for up to 9 months (two
doses per week). Significant improvements based
on the change from baseline in IIEF EF score
were observed after 6 months of treatment
(n = 119) with alprostadil cream 300 μg (score of

Therapeutic Advances in Urology 8(4)
252 http://tau.sagepub.com
21) compared with placebo (score of 11). As
observed in phase II and III studies, adjustment
to 300 μg alprostadil facilitated the greatest
improvement in EF, based on SEP2 and SEP3
responses [Mulhall etal. 2013b].
Concerning tolerance, results from a study con-
ducted with pooled data from these two phase II
studies (n = 303), alprostadil cream demonstrated
increased efficacy versus placebo in a dose-
dependent manner (50–300 μg) [Rooney et al.
2009; Mulhall etal. 2013a]. Most reported AEs
(65% local AEs plus 3% systemic AEs) were mild
or moderate, transient, and localized. As observed
in phase II studies, the majority of AEs were mild
to moderate, transient, and localized (Table 1).
No major differences compared with placebo
have been observed in terms of systemic AEs as
expected from a drug with a local site action
[Padma-Nathan and Yeager, 2006; Moncada and
Cuzin, 2015]. The incidence of local AEs, how-
ever, was higher among patients treated with
alprostadil (65%) compared with placebo (10%)
(Table 1) [Padma-Nathan and Yeager, 2006;
Moncada and Cuzin, 2015]. All local AEs were
mild or moderate and of short duration. In the
long term, the incidence of AEs decreased overall
(34%) [Mulhall etal. 2013b].
Results from the clinical studies demonstrate that
alprostadil cream can be considered as a valid
therapeutic option in patients with ED and the
product has been licensed in different countries
[Medicines Evaluation Board in the Netherlands,
2013; Takeda UK Ltd, 2014].
In summary, alprostadil is offered in a new for-
mulation, a cream that combines it with a novel
skin-permeation-enhancing drug delivery system.
The new topical formulation allows fast onset of
action, with reliable efficacy and no anticipated
interference with other drugs, food, or alcohol
consumption. It is easy to use, well suited for a
broad range of patients (e.g. those undergoing
other therapies) and, more importantly, with a
low incidence of unexpected systemic AEs.
Clinical experience
The efficacy and safety of alprostadil cream has
been demonstrated in clinical studies conducted
in large study populations [Padma-Nathan and
Yeager, 2006; Rooney etal. 2009; Moncada and
Table 1. Common adverse effects (AEs) for alprostadil cream 300 μg; results from clinical trials.
Placebo (n = 434) Alprostadil topical cream 300 μg (n = 434)
Systemic AEs
Patient, n (%)
Overall 3 (0.6) 13 (0.3)
Nervous system 1 (0.2) 11 (1.2)
Dizziness 1 (0.2) 5 (0.5)
Headache 1 (0.2) N/A
Hyperaesthesia 0 (0) 6
Skin and appendages 1 (0.2) 2 (0.5)
Rash 1 (0.2) 2 (0.5)
Local AEs
Patient, n (%)
Overall 51 (0.6) 279 (64.9)
Genital pain 2 (0.5) 76 (17.5)
Penile burning 26 (0.6) 100 (23)
Penile erythema 9 (2.1) 49 (11.3)
Partner, n (%)
Overall 13 (3) 28 (6.5)
Vaginal burning 8 (1.8) 19 (4.4)
Vaginitis 5 (1.2) 9 (2.1)
Padma-Nathan and Yeager [2006] and Moncada and Cuzin [2015].
N/A, not applicable.

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Cuzin, 2015] and clinical experience will help to
identify patients who could benefit most.
Indeed, a new treatment for ED can be offered to
patients that could help address their needs unmet
by other treatments:
(1) Current therapy with ED, usually consist-
ing of systemic treatment with PDE5
inhibitors, does not always reflect a
patient’s preference. Patients demand
easy-to-use treatments with a rapid onset
of action and no interference with food or
alcohol [Jannini etal. 2014; Moncada and
Cuzin, 2015].
(2) Several factors may limit the use of sys-
temic administration of PDE5 inhibitors
[Montorsi et al. 2010; Park et al. 2013].
Interactions with other drugs have been
reported that preclude the use of PDE5
inhibitors [Mehrotra etal. 2007; Schwartz
and Kloner, 2010]. In patients under treat-
ment with nitrates, the concomitant use of
PDE5 inhibitors can cause unpredictable
decreases in blood pressure, and they are
thus contraindicated in combination with
nitrates. Additive AEs have been reported
with the concomitant use of antihyperten-
sive drugs or α blockers. Interaction with
drugs inhibiting the P450 pathway, and
in particular cytochrome P450 3A4
(CYP3A4), which metabolizes PDE5
inhibitors, is well characterized. The use
of drugs known to inhibit this specific iso-
form (such as ketoconazole, erythromycin,
clarithromycin) can increase the circulating
levels of PDE5 inhibitors, and thus dose
reduction is required. In contrast, for drugs
known to induce CYP3A4 (such as pheno-
barbital, carbamazepine, and phenytoin), a
dose increase is required to counteract the
increased metabolic breakdown.
(3) Acceptable AEs are an important consid-
eration at the time of selecting treatment
for ED. In a study conducted to evaluate
the efficacy and safety of alprostadil for-
mulated for intracavernosal treatment,
penile pain was very commonly reported
(50%), followed by haematoma or ecchy-
mosis (8%), and prolonged erections (5%)
[Linet and Ogrinc, 1996]. The incidence
of systemic treatment-related AEs is high
with PDE5 inhibitors. Common AEs
include headache (13–16%), flushing and
dyspepsia (4–12%), back pain (7%), and
myalgia (6%) [Hatzimouratidis et al.
2015]. In contrast, common local AEs
with alprostadil cream include penile
burning sensation (25%) and penile ery-
thema (11%). Furthermore, AEs leading
to discontinuation were rarely reported
with alprostadil cream: 4.3% were reported
in clinical trials [Rooney etal. 2009] com-
pared with 12% with PDE5 inhibitors
[Jiann et al. 2006] and over 40% with
PGE1 intracavernous injections
[Hatzimouratidis etal. 2015].
(4) Furthermore, the results of a survey of
patients (n = 152) asked to express their
preferences for an ED treatment according
to the route of administration (systemic/
oral, injectable, intraurethral, or cream/
topical) showed that 53% of subjects
would select a cream as the first choice
[Moncada and Cuzin, 2015].
Thus, patients who may benefit the most include
treatment-naïve patients, patients who do not
respond, cannot tolerate, or do not accept PDE5
inhibitor therapy, and patients treated with
nitrates [Becher, 2004; Rooney et al. 2009;
European Medicines Agency, 2013]. So, alpros-
tadil cream could represent a new paradigm for
patients who are not satisfied with, cannot toler-
ate, or do not accept PDE5 inhibitor therapy or
other ED treatments
A second category could be difficult-to-treat patients
(those with diabetes, CV disease, prostatectomy,
hypertension). From the ‘clinical evidence’ section,
populations studied included patients who were not
candidates for treatment with PDE5 inhibitors
(nonresponders, those with contraindications),
patients with severe ED, and patients who were
difficult to treat (i.e. those who failed to respond
to previous PDE5 inhibitor therapy, specifically
sildenafil, those with stable CV disease, hyperten-
sion, or diabetes, those who had undergone prosta-
tectomy, and those aged > 65 years).
Clinical response was evaluated according to
medical history and severity of ED (Padma-
Nathan and Yeager, 2006; Rooney et al. 2009;
Moncada and Cuzin, 2015). Treatment with
alprostadil cream significantly improves EF in
patients with severe disease in a dose-dependent
manner (measured by IIEF EF, SEP2, and SEP3).
The proportion of patients in the phase II study
reporting significant improvements in the GAQ
score was up to 76% (200 μg; n = 35) and 83%

Therapeutic Advances in Urology 8(4)
254 http://tau.sagepub.com
(300 μg; n = 35) compared with 26% in the pla-
cebo group (n = 35) (Padma-Nathan etal. 2003].
From clinical experience, GAQ score (qualita-
tive) is meaningful. Indeed, instruments used to
measure patient-reported outcomes are recom-
mended by the US Food and Drug Administration
guidelines [McLeod etal. 2011]. There is a need
to provide evidence on outcomes based on quali-
tative (collecting input directly from patients and
clinical experts) and quantitative (use of a partic-
ular responder threshold as an indicator of mean-
ingful change from the patient’s perspective)
methods that can help to draw conclusions about
the statistical significance and clinical relevance
of the treatment. For example, considering the
IIEF questionnaire, an increase of four points is
considered clinically relevant [Rosen etal. 2011].
To evaluate treatment-related changes in terms of
clinically relevant improvement is therefore an
essential aspect towards understanding treatment
efficacy, interpreting the results across studies,
and managing patients effectively.
Post hoc analyses of the phase III clinical data
were performed by stratifying patients with dif-
ferent levels of disease severity and comorbidi-
ties. Patients were divided into five categories
according to medical history: CV disease, diabe-
tes, prostatectomy, sildenafil failure, and hyper-
tension. In addition, each category could be
divided into subcategories: mild, moderate, and
severe according to baseline ED severity. Changes
in the IIEF EF, SEP-Q2 (penetration success),
SEP-Q3 (maintenance success), IIEF EF final
score at least 26 (normalization of EF), and GAQ
scores were analysed. Interestingly, a high per-
centage of clinically significant improvements
were observed in patients in the 300 μg group
with comorbid CV disease or hypertension.
Figure 2 shows the percentage of patients with
clinically significant changes in IIEF EF [Figure
Figure 2. Percentage of patients with changes in the erectile function domain scores of the International
Index of Erectile Function in the placebo () and Vitaros/Virirec () groups with cardiac history, diabetes,
prostatectomy, and hypertension (a); percentage of patients with a positive Global Assessment Questionnaire
response in the control () and Vitaros/Virirec () groups for (b) specific populations (p < 0.0001 versus
placebo) and (c) global population (p < 0.001 versus placebo).
Adapted from Padma-Nathan et al. [2003] and Moncada and Cuzin [2015].

B Cuzin
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2(a)] and GAQ scores [Figure 2(b)] in subgroups
with different medical history. Clinically signifi-
cant improvements were seen in all three ED
subcategories with 50%, 40%, and 22% of
patients, respectively, with mild, moderate, and
severe ED showing a clinically relevant change in
the IIEF EF score [Buvat etal. 2012]. In patients
who failed to respond to sildenafil and in those
who previously used sildenafil, a consistent over-
all improvement in EF was observed, regardless
of ED severity [Mulhall etal. 2013b].
In conclusion, following its marketing authoriza-
tion by the European Health Authorities in 2013,
topical alprostadil (Vitaros/Virirec) has been
approved in more than 10 countries. It is an inno-
vative ED product, and has the potential to help a
large number of patients. Vitaros/Virirec is indi-
cated for patients with ED who are not responding
to PDE5 inhibitors, and in whom PDE5 inhibi-
tors are contraindicated or not tolerated. It is also
suitable in patients who are reluctant to take pills
for any reason, in patients with CV risk, and with
CV comorbidity treated with nitrates, and patients
with benign prostatic hypertrophy treated with α
blockers. Thus, Vitaros/Virirec is a therapeutic
option in ED, from mild to severe, that can fit
patients’ needs and expectations.
Conclusion
Nevertheless, the cream has not been compared
directly with other treatments and there is limited
information on long-term safety. However, in ani-
mals a recent publication has shown that repeated
vaginal exposure to Vitaros did not alter the pH,
microflora, or histology after 14 daily doses, sup-
porting the safety of Vitaros transference to the
female partner [Meier-Davis etal. 2015].
Postmarketing data representing ‘real life’ will be
crucial. Furthermore, the summary of product
characteristics recommends that a medical pro-
fessional should instruct each patient on proper
technique for administration of the product.
Finally, the route of administration for ED has
not been completely evaluated but is of interest
from a physiological point of view, and the field of
post-treatment ED recovery should be explored
(for example in ED with penile neuropathies).
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The author declares that there is no conflict of
interest.
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