Clinical efficacy and safety of Vitaros©/Virirec© (Alprostadil cream) for the treatment of erectile dysfunction
Urologia 2015; 82(2): 84 - 92
Article Type: REVIEW
Article Subject: ANDROLOGY/andrologia
AuthorsIgnacio Moncada, Béatrice Cuzin
Erectile dysfunction (ED) is a very common disorder with a deep impact on patients and their partners. Several options are now available for treating ED; oral pharmacotherapy with phosphodiesterase-5 (PDE5) inhibitors currently represents the first-line option for many ED patients. Vitaros©/Virirec© is new topical, non-invasive treatment for ED that offers the combination of an active drug (alprostadil, a synthetic PGE1) with a skin enhancer that improves its local absorption directly at the site of action. Vitaros©/Virirec© has a favorable pharmacodynamic profile and is poorly absorbed in systemic circulation. This makes it suitable in any circumstances and results in a reduced risk of adverse events (AEs), being systemic AEs reported in only 3% of the treated population. Its 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 together with its favorable toxicity profile and lack of interactions with other drugs makes Vitaros©/Virirec© a first-line therapeutic option for patients with ED, particularly for individuals who are reluctant to take systemic treatments or with AEs. It may also have an important role in patients not responding to PDE5 inhibitors, particularly those with ED after radical prostatectomy.
- • Accepted on 11/02/2015
- • Available online on 03/03/2015
- • Published in print on 11/06/2015
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Erectile dysfunction (ED) can be defined as the consistent inability to obtain and maintain an adequate penile erection sufficient for a satisfactory sexual activity (1). It 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, 30 and 40% in men 60-70 years, and more than 50% in men over the age of 70 (2-3-4).
Due to the increase in healthy aging population, ED is becoming a serious 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 (5).
Treatment of ED has been shown to have a positive effect on the quality of life and overall satisfaction for both patients and their partners (6). The guidelines of the European Association of Urology recommend psychosexual counseling and phosphodiesterase-5 (PDE5) inhibitors as first-line treatment for ED (5). However, this class of drugs is associated with treatment failure in 11-44% of patients depending on the patient population under study (7). In addition, PDE5 inhibitors have several pharmacological interactions for which they are contraindicated, such as patients taking nitrates. Also, PDE5 inhibitors have numerous side effects that can cause treatment discontinuation, particularly headache, visual disturbances, muscular pain, and dyspepsia (8). Local treatment modalities (intracavernosal injection therapy, intraurethral alprostadil, vacuum erection devices) have been used as an alternative or in combination with PDE5 inhibitors.
Herein, we present the pharmacology, clinical efficacy data, and safety profile of Vitaros©/Virirec©, a new alprostadil cream formulated with a novel skin permeation enhancing drug delivery system.
Molecular mechanism and pathophysiology of erectile dysfunction
Penile erection is mostly governed by the tone of the penis smooth muscle (which represents roughly half of the volume of the corpus cavernosum) through its control of different hemodynamic events (9). Proper levels of agonists and receptors, calcium homeostasis as well as proper contacts between smooth muscle cells are key factors in controlling contractility. A concerted action of these factors is necessary to ensure penile erection and, in turn, any functional abnormality can lead to ED (1, 9). Nitric oxide (NO) represents the primary neurotransmitter involved in penile erection. Relaxation of arteriolar and cavernosal smooth muscle induced by NO produces dilation of arteries/arterioles, resulting in increased blood flow into the corporal sinuses, causing the cavernosal sinuses to expand while trapping arterial inflow and compressing subtunical small veins. This process called veno-occlusive mechanism impedes return of venous blood and maintains erection. In general, the relaxation of cavernosal smooth muscles can be considered as a kind of reset of the “contractile machinery.” In this context, a decrease in intracellular Ca++ concentrations is needed, which depends on the accumulation of the intracellular second messengers cAMP and cGMP and activation of ion channels. The general cascade leading to penile erection can be summarized as follows: following appropriate stimuli, there is neural and endothelial release of NO, entering the smooth muscle cell, activation of guanylatecyclase that catalyzes the conversion of GTP to cGMP thus lowering cytosolic Ca++ levels and triggering relaxation. A parallel pathway is activated by prostaglandins such as PGE1, which stimulate adenylatecyclase through the interaction with G protein coupled receptors (GPCRs), which in turn induces an increase in cAMP. An additional, important role is played by intracellular communications mostly mediated by connexins, which are gap junction proteins. Connexins ensure a sort of continuity between adjacent cells and allow the flow of ions and second messengers (1, 9).
ED can be classified as a psychogenic disorder, as an organic disorder (with neurogenic, hormonal, arterial, or drug-related causes), and, as is most frequent, a combination of both organic and psychogenic factors (1).
Several risk factors are implicated in the development of ED. In particular, a relation between ED and CV risk has been reported, and known CV risk factors such as hypertension, diabetes mellitus, dyslipidemia are also important risk factors for ED (1, 10). In addition, as persistence of ED has been shown to correlate with a subsequent cardiac event, persistent ED can be seen as a predictive sign of the occurrence of a CV event. From a mechanistic point of view, ED and CV diseases have been shown to have some common pathophysiological pathways. Other risk factors for the development of ED are metabolic syndrome, hypogonadism, obesity, other genitourinary diseases (prostatectomy for any reason), as well as depression, anxiety, stress, anger, sedentary life, and smoking habits.
ED has an important negative psychological impact and affects the relationships with partner, family, and friends, thus resulting in a reduced quality of life. These negative effects, however, can be overcome by effective therapy, as demonstrated in several studies (1).
Correct management of ED is important considering that responders to treatment report a significantly better quality of life and general health status. There are several therapeutic options for ED, and it is important to define the etiology of ED to treat the causes rather than the symptoms. For example, in case of ED associated with hormonal dysfunction, specific treatment of the hormonal defect can potentially cure ED. Another important consideration is the identification of lifestyle-associated risk factors, which, if modified, can ameliorate ED. Nonetheless, the majority of ED patients are treated with options that are not specific to the cause. Given the mechanisms at the basis of defects in penile erection, first-line systemic therapy involves the use of PDE5 inhibitors (11-13). These drugs act by inhibiting the ability of PDE5 to hydrolyze cGMP to increase blood flow in the arterioles, inducing smooth muscle relaxation and penile erection. They do not work as erection initiators, as they require sexual stimulation to facilitate erection. There are four selective inhibitors of PDE5 that are approved by both the EMA and FDA for ED: sildenafil tadalafil, avanafil, and vardenafil. These drugs have a variable peak of efficacy as well as differences in duration of action. They have all been demonstrated to be efficacious in a large proportion of patients during chronic treatment (1, 14). The response rate depends on the drug used and the patient’s characteristics; overall, a response rate of around 70% is generally achieved after 12-24 weeks of treatment (13). These drugs are normally “on-demand” and only tadalafil has been approved for daily dosing. For the majority of patients, the “on-demand” therapy is a preferred option in general.
Several factors may limit the use of systemic administration of PDE5 inhibitors (13, 15). First, a high-fat meal reduces the efficacy of short-acting PDE5 inhibitors, possibly due to decreased absorption (16). Interactions with other drugs have been reported that preclude the use of PDE5 inhibitors (8, 16). For example, 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 adverse events (AEs) have been reported with the concomitant use of antihypertensive drugs or alpha blockers. Interaction with drugs inhibiting P450 pathway, and in particular 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. On the contrary, for drugs known to induce CYP3A4 (such as phenobarbital, carbamazepine, and phenytoin), a dose increase is required to counteract the increased metabolic breakdown. Lastly, these drugs are associated with a number of common AEs such as headache, visual disturbances, flushing, dyspepsia, and muscular and back pain or nasal congestion, with frequencies that vary depending on the individual drug (1).
An alternative option is the use of intracavernous injections, provided that healthy vasculature is present. Several drugs can be employed including papaverine and alprostadil, while the latter is most widely used. This treatment modality is highly efficacious with a rapid effect on penile erection and a dose-dependent duration (17). Although this treatment has proven efficacy, its use is limited by the high rate of discontinuations, mostly due to the treatment modality (including fear of penile puncture). Nowadays, intracavernous injection can be offered as second-line treatment in patients not responding to systemic therapy. Alprostadil can also be administered intraurethrally through the use of a specific device that has been approved for the use in patients with ED. In this formulation, the drug is inserted in a pellet, directly in the urethra where it diffuses via vascular absorption to the corpora cavernosa. However, this therapeutic modality is considered less effective than intracavernous injection (17). Furthermore, together with the aforementioned contraindications for intracavernous administration, intraurethral treatment can also induce urethral pain and bleeding. There is thus a need for a new therapeutic paradigm that is able to offer reliable efficacy, satisfaction, increased compliance, and better tolerance.
A new formulation of alprostadil cream: Vitaros©/Virirec©
Alprostadil cream (Vitaros©/Virirec©) combines the efficacy of a well known drug (alprostadil) with an “easy to use” formulation that does not involve the use of systemic drugs or more invasive topical applications, which has the characteristics to meet all the above-mentioned needs for treatment of ED (17, 18). Alprostadil is a synthetic analog of prostaglandin E1, 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, 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 NO/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 (17-18-19) (
Mechanism of action of Vitaros©/Virirec©. Schematic mechanism of penile erection with a focus on second messengers: cGMP and cAMP. Alprostadil directly binds to G-protein coupled PGE1 receptors on the smooth muscle cell surface and activates the cAMP pathway resulting in relaxation of penile vascular smooth muscle and penile erection. Although PDE5 inhibitors require previous activation of the NO/guanylatecyclase pathway by erectogenic stimuli, alprostadil is a direct agonist that acts independently of the psychological and neurological components of the erection process. cGMP, cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate; NO, nitric oxide.
Vitaros©/Virirec© is available in a cream formulation, which ensures a rapid absorption of the drug at the site of action. In fact, this specific formulation contains, together with alprostadil, an enhancer, namely 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 (18, 20) (
Mechanism of action of the skin permeation enhancer DDAIP.HCl (ester of N-dimethylalanine and dodecanol). cAMP, cyclic adenosine monophosphate; NO, nitric oxide. Modified from (17).
Vitaros©/Virirec© has a favorable pharmacodynamic profile. Through the use of 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 (18). The fast, rapid, and reliable erectile response provided by Vitaros©/Virirec© 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 (
Onset of action of Vitaros©/Virirec©. The data presented are from two multicenter, placebo-controlled, double-blind, parallel-group phase III studies conducted on a large cohort of 1732 patients (mean age 60 years) with moderate to severe ED and concomitant medical conditions. Patients were randomly assigned to receive placebo or alprostadil topical cream in doses of 100, 200, or 300 μg for 12 weeks. The number of patients is shown for each time interval considering time from administration to successful penetration attempts for the 300 μg dose.
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 (16).
Clinical efficacy of Vitaros©/Virirec©
The efficacy and safety of Vitaros©/Virirec© has been studied in two phase II studies in patients with mild to moderate (N = 161) and severe (N = 142) ED (22). The primary efficacy parameter was changed from baseline to final visit (after 10 drug doses in a 6-week period) in the erectile function (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;
Changes in erectile function domain score from baseline to final visit (+-SD) in controls (■) and Vitaros©/Virirec©-treated patients (
Percentage of patients reporting improvement (GAQ) (p<0.001). Adapted from (22).
The efficacy of Vitaros©/Virirec© has also been confirmed in two multicenter, randomized, placebo-controlled, parallel-group, double-blind, phase III trials enrolling a total of 1732 patients with moderate to severe ED (mean baseline IIEF-EF 13.7) and a wide range of concomitant medical conditions and treatments (22% had diabetes, 32% had CV disease, 12% had underwent prostatectomy, 47% were hypertensive, and 16% were being treated with nitrates and alpha-blockers) (24). In these studies, ED patients were randomly assigned to receive placebo or Vitaros©/Virirec© at 100, 200, or 300 μg for 24 single doses over a 12-week period. The efficacy measures were changes in EF domain of the IIEF, vaginal penetration/attempt rate (SEP question 2), and intercourse completion to ejaculation rate (SEP question 3) between baseline and final visit. In addition, at the end of treatment, the percentage of patients reporting improvements in erection was assessed by the GAQ. The results corroborated the phase II results with a significant improvement in all efficacy parameters in Vitaros©/Virirec©-treated patients compared with placebo (
Last square mean change from baseline to endpoint in primary efficacy parameters in controls (n = 411) (■) and patients treated with 300 μg Vitaros©/Virirec© (N = 410) (
A number of 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: cardiac, 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 ≥26 (normalization of EF), and GAQ scores were analyzed. Interestingly, a high percentage of clinically significant improvements were observed in patients in the 300 µg group with comorbid cardiac disease or hypertension.
Percentage of patients with changes in IIEF-EF scores in the placebo (■) and Vitaros©/Virirec© (
The potential efficacy of Vitaros©/Virirec© in patients failing previous ED treatments is also documented by the data from a survey in which 152 patients with ED were interviewed. In that study, 53% of patients who had previously tried at least two different ED treatment modalities reported that Vitaros©/Virirec© was efficacious. These data strongly support the efficacy of Vitaros©/Virirec© in patients with different degrees of ED, in patients with a range of comorbidities, and in patients failing sildenafil therapy.
The efficacy of long-term treatment with Vitaros©/Virirec© was evaluated in a multicenter, open-label study in which the drug was administered during an initial 4-week period at the 200 μg dosage, and then adjusted to 100, 200, or 300 μg according to patient responsiveness for up to 9 months (two doses/week) (27). The majority of patients (75%) chose 300 μg Vitaros©/Virirec© as the final dose with a dosing frequency of one application every 4-7 days. ED improvement, based on changes in the IIEF-EF score, was significant for the 300 μg group (p<0.001), (
Long-term efficacy at 6 months
Safety and tolerability of Vitaros©/Virirec©
Alprostadil topical cream (Vitaros©/Virirec©) and the skin permeation enhancer DDAIP.HCl have been evaluated in several dose toxicity, irritation, and genotoxicity animal studies and shown to be devoid of genotoxic potential. In addition, topical administration of DDAIP.HCl does not induce local or systemic toxicity or tumorigenicity.
The available clinical data suggest that Vitaros©/Virirec© is safe and generally well tolerated. Indeed, in the overall phase II program, the vast majority (97%) of Vitaros©/Virirec©-related side effects were of mild or moderate in severity and short duration (<60 min) (22). Nearly, all these AEs were localized at the application site (i.e., genital pain, tenderness, and erythema). Approximately 2% of AEs were partner-related, and the majority of cases were related to mild, short-lasting (≤60 min post-intercourse) vaginal burning. Hypotension was uncommon and half of the reported cases were asymptomatic. No cases of prolonged erections were reported. The safety data from phase III studies substantiated the spectrum of AEs reported in phase II studies (24), with no treatment-related serious AEs. The most frequent AEs occurred locally at the site of application and resolved within 2 h; only 2.7% of patients withdrew from these studies because of treatment-related AEs.
Most common systemic adverse events following treatment with vitaros©/virirec© 300 μg
|Systemic side effects||Placebo (n = 434)||Vitaros 300 µg (n = 434)|
|Adapted from (24).|
|Patient n (%)|
|Total||3 (0.6)||13 (3.0)|
|Dizziness||1 (0.2)||5 (1.1)|
|Hyperesthesia||0 (0)||6 (1.4)|
|Rash||1 (0.2)||2 (0.5)|
Most common local (urogenital) adverse events in ed patients and partners after treatment with Vitaros©/Virirec© 300 μg
|Local side effects||Placebo (n = 434)||Vitaros 300 µg (n = 434)|
|Adapted from (24).|
|Total||51 (10.6)||279 (64.9)|
|Balanitis||3 (0.7)||20 (4.6)|
|Edema penile||1 (0.2)||6 (1.4)|
|Fullness genital||-||4 (0.9)|
|Genital pain||2 (0.5)||76 (17.5)|
|Penile burning||26 (0.6)||100 (23)|
|Penile erythema||9 (2.1)||49 (11.3)|
|Penile itching||1 (0.2)||5 (1.2)|
|Penile tingling||7 (1.6)||4 (0.9)|
|Penis disorder||2 (0.4)||15 (3.5)|
|Total||13 (3)||28 (6.5)|
|Vaginal burning||8 (1.8)||19 (4.4.)|
|Vaginitis||5 (1.2)||9 (2.1)|
Vitaros©/Virirec© topical cream has been used in clinical studies concomitantly with other drugs (steroidal and non-steroidal analgesics, anti-inflammatory drugs, anti-hypertensive drugs, diuretics, anti-hyperglycemic agents including insulin, anti-lipidemic drugs, multivitamins, and thyroid medication) and no apparent interference with its efficacy or safety has been reported, further supporting the favorable safety profile of this formulation (22-23-24).
Sexual health is considered to be a reflection of general health: male sexual dysfunction has a negative impact of quality of life of the patients and their partners. ED is the main sexual dysfunction affecting men of all age groups. Recent epidemiological data suggest that not only it is still underdiagnosed and undertreated but also men who suffer from ED are unsatisfied with their relationship, their physician, and with the available treatments. Although current therapy for ED most frequently consists of systemic treatment with a PDE5 inhibitor, this does not always reflect patient preference. Indeed, in a recent survey involving 152 patients with ED in which individuals were asked to express their preference for ED therapy according to the route of administration (systemic/oral medications, topical therapy/topical creams, injectable, and intra-urethral therapies), more than half selected a topical cream as the first choice (53%) (
Panel A: Ranking of patient preferences (first to fourth choice) of the ideal route of administration for therapy of ED. Survey of 152 patients with ED who were asked to rank their preferred route of administration therapy for ED. Panel B: Schematic representation of therapeutic choices in patients with ED.
In summary, Vitaros©/Virirec© can be considered a valid therapeutic option in any type of patient affected by ED. This new formulation of alprostadil cream combined with a novel skin permeation enhancing drug delivery system allows fast onset of action, with reliable efficacy in any circumstances, and no interference with food or alcohol consumption. It can be safely administered in men undergoing therapy for several comorbidities (α-blockers and antihypertensive drugs) and, more importantly, it is devoid of serious systemic AEs. Phase II and III clinical studies have documented its efficacy in improving EF. Vitaros©/Virirec© is safe and well tolerated. Most treatment-related side effects are mild or moderate in severity and of short duration (22), and nearly all AEs are localized at the application site (i.e., genital pain, tenderness, and erythema). Due to its favorable pharmacological properties, Vitaros©/Virirec© is indicated for all ED patients including those 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. Thus, Vitaros©/Virirec© is a therapeutic option in ED, from mild to severe, that can fit patient’s needs and expectations.