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.

Keywords

alprostadil cream clinical evidence real life

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 population, ED could be considered as a public health problem. Apart from pathophysiological implications 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 positive effect on the quality of life and overall satisfaction of both patients and their partners [Latini et al. 2003].

Phosphodiesterase 5 (PDE5) inhibitors are first-line on-demand therapy (level 1a and 1b evidence) for ED [Hatzimouratidis et al. 2015]. However, this class of drugs is associated with treatment failure in 11–44% of patients depending on the patient population under study [Carvalheira et al. 2012]. In addition, PDE5 inhibitors have several pharmacological interactions for which they are contraindicated, such as patients taking nitrates. Compliance with PDE5 inhibitor treatment has been shown to decrease over time. In a mean follow up of 1–3 years, overall up to 49% of responders to sildenafil, vardenafil, 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 inconvenience 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%), dyspepsia (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 injection therapy, intraurethral alprostadil, vacuum erection devices) which have been used as alternatives 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 delivery 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, alprostadil 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 formulation, which contains, together with alprostadil, an enhancer, namely dodecyl-2-N,N-dimethylamino propionate (DDAIP) HCl (an ester of N-dimethylalanine and dodecanol), which temporarily 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 diffusion of alprostadil through the skin. The formulation 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.

Figure 1.

Permeation enhancer dodecyl-2-N,N-dimethylamino propionate (DDAIP) mechanism of action.

Through the use of a laser Doppler meter, it has been reported that the microcirculation of the glans improved rapidly after topical administration, reaching the levels observed in a physiologically normal erection. Within 10–12 min, full rigidity of the penis is achieved, which lasts for more than 1 h [Becher, 2004]. The fast and reliable erectile response has been recently demonstrated 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, alprostadil 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 advantage 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 prolonged 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 trials [Steidle et al. 2002; Campbell, 2005; Rooney et al. 2009; Mulhall et al. 2013b]:

Phase II studies have demonstrated significant 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 overall IIEF score, successful vaginal penetrations 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 significant 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 diabetes. 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.

The efficacy of alprostadil cream was confirmed in two phase III randomized controlled 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 (diabetes 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 treatment, alprostadil cream 300 μg significantly 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 majority of the successful attempts took place during the first 30 min following application 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 conducted 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 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 conducted 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).

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.

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, however, 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 formulation, 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 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:

Current therapy with ED, usually consisting 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].

Several factors may limit the use of systemic 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 treatment 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 antihypertensive 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 isoform (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 phenobarbital, carbamazepine, and phenytoin), a dose increase is required to counteract the increased metabolic breakdown.

Acceptable AEs are an important consideration at the time of selecting treatment for ED. In a study conducted to evaluate the efficacy and safety of alprostadil formulated for intracavernosal treatment, penile pain was very commonly reported (50%), followed by haematoma or ecchymosis (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 erythema (11%). Furthermore, AEs leading to discontinuation were rarely reported with alprostadil cream: 4.3% were reported in clinical trials [Rooney et al. 2009] compared with 12% with PDE5 inhibitors [Jiann et al. 2006] and over 40% with PGE1 intracavernous injections [Hatzimouratidis et al. 2015].

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, alprostadil cream could represent a new paradigm for patients who are not satisfied with, cannot tolerate, 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, hypertension, or diabetes, those who had undergone prostatectomy, 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% (300 μg; n = 35) compared with 26% in the placebo group (n = 35) (Padma-Nathan et al. 2003].

From clinical experience, GAQ score (qualitative) is meaningful. Indeed, instruments used to measure patient-reported outcomes are recommended by the US Food and Drug Administration guidelines [McLeod et al. 2011]. There is a need to provide evidence on outcomes based on qualitative (collecting input directly from patients and clinical experts) and quantitative (use of a particular responder threshold as an indicator of meaningful 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 different levels of disease severity and comorbidities. Patients were divided into five categories according to medical history: CV disease, diabetes, prostatectomy, sildenafil failure, and hypertension. 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 percentage 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 2(a)] and GAQ scores [Figure 2(b)] in subgroups with different medical history. Clinically significant 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 overall improvement in EF was observed, regardless of ED severity [Mulhall et al. 2013b].

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).

In conclusion, following its marketing authorization by the European Health Authorities in 2013, topical alprostadil (Vitaros/Virirec) has been approved in more than 10 countries. It is an innovative ED product, and has the potential to help a large number of patients. Vitaros/Virirec is indicated for patients with ED who are not responding to PDE5 inhibitors, and in whom PDE5 inhibitors 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 animals a recent publication has shown that repeated vaginal exposure to Vitaros did not alter the pH, microflora, or histology after 14 daily doses, supporting 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 professional 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).

Footnotes

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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