¹Wilshire Blvd, Beverly Hills, California, USA

²Department of Urology, Boston University School of Medicine, Boston, Massachusetts, USA

³The Urology Center of Florida, Ocala, Florida, USA

⁴Chicago Center for Clinical Research, Chicago, Ilinois, USA

⁵Newport Beach, California, USA

⁶Zonagen, Inc., The Woodlands, Texas, USA

Correspondence to: H Padma-Nathan, 9100 Wilshire Blvd # 360E, Beverly Hills, CA 90212, USA

The objectives of this study were to evaluate long-term safety and efficacy of phentolamine mesylate, an orally active, rapid-acting alpha-adrenergic receptor antagonist, for the treatment of men suffering from erectile dysfunction (ED). It was an open-label study involving more than 2000 patients. Men received phentolamine mesylate 40 mg or 80 mg (10 tablets/month) as needed for up to 13 months and self-assessed erectile performance using two validated questionnaires. Treatment with phentolamine mesylate was associated with increases in Erectile Function Domain score of the IIEF, successful vaginal penetrations, and in overall satisfaction. Most adverse events were mild or moderate in severity and consistent with the known pharmacodynamic properties of phentolamine. In conclusion, phentolamine mesylate is safe and effective in the long-term treatment of men with mild to moderate ED.

International Journal of Impotence Research (2002) 14, 266-270. doi:10.1038/sj.ijir.3900885

alpha adrenoreceptors; erectile dysfunction; International Index of Erectile Function; phentolamine mesylate; Sexual Encounter Profile; tolerability

Introduction

Erectile dysfunction (ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual activity.¹ According to this definition, as many as 30 million men in the USA have some degree of ED.²

Although there are two basic etiologies of ED (organic or psychogenic) the most common form of ED has a mixture of organic and psychogenic origins.³ Because of the complex etiology of ED, multiple approaches may be necessary to successfully treat the majority of individuals with the disorder.

Oral sildenafil citrate has gained widespread acceptance for the first-line treatment of ED.⁴ Another potentially promising oral treatment currently under clinical development is phentolamine mesylate (VasomaxÒ, phentolamine). Phentolamine, formulated as a rapidly disintegrating tablet, is a non-selective alpha-1, alpha-2 adrenergic-receptor antagonist. Peak serum concentrations of phentolamine are achieved within approximately 0.25 to 0.75 h after oral administration.⁵ The mean elimination half-life is approximately 2 h, and the duration of effect following administration is approximately 1-2 h.⁶

Goldstein et al have evaluated the efficacy and safety of oral phentolamine in a recently conducted phase III trial. Patients received 40 mg or 80 mg of oral phentolamine or placebo 30 min before attempting sexual intercourse. Statistically significant improvements were observed in the Erectile Function Domain (EFD) score of the International Index of Erectile Function (IIEF),⁷ in the proportion of men whom achieved successful vaginal penetration, and in maintenance of erection to ejaculation.

The objective of the present study was to evaluate the long-term safety and efficacy of phentolamine in men with mild to moderate ED.

Methods

Patients

Men enrolled in this open-label study had a history of ED of at least 6 months duration, and were engaged in a stable monogamous heterosexual relationship. All men and their partners provided written informed consent. Erectile function was mild to moderate as defined by an EFD score of 13 to £24 (range, 0 to 30).

Exclusion criteria included ED caused by untreated endocrine disease; history of radical prostatectomy; significant penile curvature; evidence of clinically significant hepatic or renal disease, coronary artery disease, nervous system diseases, uncontrolled psychiatric conditions, or postural hypotension; sitting or supine systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg; concurrent use of yohimbine, penile injection therapy, or vacuum devices; or a known intolerance to phentolamine.

Study design

The study was conducted at 37 sites in the USA. The institutional review board of each participating institution approved the protocols.

After an initial 40 mg in-office test dose of phentolamine to assess potential cardiovascular effects, subjects received 10-tablets/month during the study period, and recorded, with their partner, the outcome of an attempt at sexual intercourse in a sexual encounter diary. Patients not responding to 40 mg based on a global assessment question could up-titrate after 1 month to 80 mg. These patients received a 2´40 mg test dose, and those who tolerated the test dose were instructed to take two tablets prior to attempting intercourse. Men returned diary cards and received replacement medication at each subsequent visit.

Towards the end of the study, study duration was increased per protocol amendment from the original 12, to 13 months in order to collect full 1-y data on the 80 mg dose.

Patient methods and assessments

A complete medical history (ie concomitant medications), including physical examination, vital signs, electrocardiogram, and laboratory parameters was completed at study entry. Adverse events (collected at each visit), vital signs and laboratory parameters were monitored throughout the studies for safety assessment.

Efficacy was assessed with the self-administered IIEF and a Sexual Encounter Profile (SEP) questionnaire. The IIEF is a validated psychometric instrument and has been described elsewhere.⁷ Men also responded (affirmative/negative) to the following questions: 'Were you able to insert your penis into your partner's vagina?' (SEP Question 3), and 'Has the treatment you have been taking over the past study interval improved your erection'?

Statistical methods

All patients who received at least one dose of study drug were included in the safety analysis, whereas the efficacy cohorts consisted of those men who received at least one dose of study medication and had one or more efficacy measurements. Adverse events were classified according to the COSTART coding dictionary and summarized in tabular format. The primary efficacy parameter was the change from baseline IIEF score.

Results

Patient disposition

A total of 2478 men were enrolled between August 1997 and December 1998, of whom 475 were dropped as screening failures prior to receiving the test dose. A total of 2003 patients received the 40 mg test dose; 1927 patients received 40 mg phentolamine treatment; 727 patients proceeded to receive the 80 mg test dose at the end of month 1, and 691 patients received 80 mg phentolamine treatment. Demographic and baseline disease characteristics of the patient population are summarized in Table 1.

The most frequently used concurrent medications were heart and other cardiovascular system medications (beta-blockers, ACE inhibitors, calcium channel blockers, diuretics etc, 48%), antithrombotics (18%), analgesics (18%), antihyperlipidemics (16%), anti-inflammatories (16%), and diabetes mellitus medication (13%).

Four hundred and four (404, 20%) men completed the 12/13-month study. The majority of discontinuations occurred in the first 6 months of treatment and were attributed in part to: lost to follow-up (17%); lack of efficacy (16%); adverse events (16%); or at subject's request (13%).

Safety and tolerability

Following test dose administration, 4% (82/2003) of patients receiving the 40 mg test dose and 8% (60/727) of patients receiving the 80 mg test dose had adverse events, the majority of which were mild to moderate in intensity. Syncope was reported in 0.1% (2/2003) of patients (one patient at each dose level, both resolved without sequelae).

Oral phentolamine was generally well tolerated during the treatment period: 980 (51%) subjects reported one or more adverse events. The most common treatment-emergent adverse events (incidence 1%) are summarized in Table 2. The majority of adverse events were mild to moderate in intensity. With the exception of gastrointestinal adverse events (ie diarrhea, nausea, vomiting), dizziness and palpitations, no adverse events were dose related. Four patients (4/1927; 0.2%; 3 on 40 mg, 1 on 80 mg) reported syncope during treatment, all of which resolved without sequelae.

Two hundred and ninety-eight (298, 15%) discontinued from the study because of adverse events, including 9% during the 40 mg, and 18% during the 80 mg treatment period. The most common adverse events resulting in discontinuation included rhinitis (4%), vomiting (4%), nausea (3%), diarrhea (2%), headache (2%), dizziness (2%), and tachycardia (2%).

No patients reported serious adverse events (SAE) following the test dose. During the treatment phase, a total of 51 patients (2.6%) reported 64 SAEs, all but one were considered to be unrelated to the study drug (one report of congestive heart failure, unknown relationship to phentolamine intake). There were no deaths reported in the study.

Erectile function

The mean EFD score over time for this open-label study cohort is illustrated in Figure 1. In those subjects who received phentolamine 40 mg and 80 mg treatment for the full 12/13 months, the mean EFD score increased by 6.3±7.0 and 5.7±7.4 points, respectively. The first month data (40 mg) for the 80 mg dose group clearly shows that this group subsequently benefited from up-titration to the higher dose.

Improvement in EFD score was associated with significant increases in the percentage of successful vaginal penetrations (Table 3).

Regarding the other, secondary IIEF domains (orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), subjects treated with phentolamine (any dose) reported improvements from baseline to study end point in 'Overall Satisfaction' and 'Intercourse Satisfaction'. There was little or no effect of drug treatment on orgasmic function and sexual desire.

At study end point, 51% of men in the phentolamine mesylate 40 mg group and 38% of men in the 80 mg group reported improvement in their erections. In those men who completed phentolamine mesylate treatment in the trial, 87% reported improvement in erectile function.

Discussion

Oral therapy represents a convenient, noninvasive, first-line therapeutic option and preference for men with ED.^4,8 Oral sildenafil, although widely prescribed, is ineffective in approximately 27% of the population, and has been associated with a variety of adverse effects including headache, flushing, and visual disturbances,^4,8 and adverse interaction with nitrates and inhibitors of Cytochrome P-450 enzymes.^9,10 This leaves a large number of individuals who would benefit from an alternative oral therapy.

VasomaxÒ is an oral formulation of phentolamine, which has been proposed as a therapy for enhancing the natural response to sexual stimulation in men with mild to moderate ED. Phentolamine is a nonselective inhibitor of postsynaptic alpha-adrenoreceptors within the corpus cavernosum smooth muscle.¹¹ Peak levels of phentolamine mesylate are observed within approximately 30 min after oral dosing,^5,6 allowing for a spontaneous, natural sexual encounter.

The present trial was undertaken to evaluate the long-term safety and efficacy of phentolamine in men with mild to moderate ED. Almost 50% of patients in this trial were using cardiovascular or diabetes medications concomitantly, which is a reflection of the type of patients whom presents itself with symptoms of ED. An in-office test dose safeguarded the patients from experiencing unintended adverse cardiovascular events.

The majority of adverse events associated with phentolamine were mild to moderate in severity and included rhinitis, headache, nausea, vomiting, dizziness, and tachycardia. This study indicates that there is no increase in adverse events with increasing doses over time. No unexpected SAEs were encountered, and no deaths were reported.

There was an improvement in erectile function and in successful vaginal penetration for patients who completed this long-term study. This progressive improvement in erectile function suggests that the effect of phentolamine is durable over time. There was a clear benefit from switching from the 40 to the 80 mg dose for those patients who were not satisfied initially with the low dose formulation of phentolamine.

The high overall discontinuation rate in the study was due to a combination of factors, such as, the open-label design, the availability of and media attention on newly approved oral sildenafil, the demanding study requirements for the couples involved, the occurrence of adverse events, and the lack of efficacy. The latter may be an indication that, similar to what has been reported on sildenafil^4,8 not all ED patients respond to any, or to a specific type of oral treatment.

In conclusion, this study shows that oral phentolamine is a well-tolerated and effective treatment for mild to moderate erectile dysfunction.

Acknowledgements

We acknowledge the study coordinators, nurses, and the following investigators who participated in the Vasomax Study Group: Donald Gleason, Jay Young, Joel Kaufman, Marc Gittelman, Dean Knoll, Mitchell Wiatrak, Glen Wells, Gilberto Brito, Christopher Steidle, Jacques Susset, David Talley, Robert Feldman, Myron Murdock, Stacy Childs; Norman Zinner, Eugene Dula, Steve Koukol, Peter Knapp, Mark Immergut, Jeffrey Snyder, George Kornitzer, Arnold Belker, James Barada, John Byrne, Richard Harris, Gilbert McMahon, David Mobley, Stanley Bloom, Donald Kidd, Kevin Tomera, Steven Lamm.

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4 Goldstein I et al. Oral sildenafil in the treatment of erectile dysfunction. New Engl J Med 1998; 338: 1397-1404. MEDLINE

5 Becker AJ et al. Oral phentolamine as treatment for erectile dysfunction. J Urol 1998; 159: 1214-1216. MEDLINE

6 Data on file, Zonagen, Inc.

7 Rosen RC et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 822-830. Article MEDLINE

8 Goldstein I. A 36-week, open label non-comparative study to assess the long-term safety of sildenafil citrate (ViagraÒ) in patients with erectile dysfunction. Int J Clin Pract 1999; 102: ((suppl)) 8-9.

9 Schwartz I, McCarthy D. Sildenafil in the treatment of erectile dysfunction [letter]. New Engl J Med 1998; 339: 699-700. MEDLINE

10 Kloner RA, Zusman RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol 1999; 84: 11N-17N. MEDLINE

11 Traish A et al. Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res 1998; 10: 215-223. MEDLINE

Figure 1 Mean Erectile Function Domain score vs time from study entry in subjects who received phentolamine 40 mg (open bar) or 80 mg (solid bar). Data are plotted as the mean for those subjects who successfully completed the test dose and who received at least one treatment and follow-up measurement.* The Month 1 data on 80 mg shows the 40 mg dose result in this group of patients before up-titration to the higher dose (from Month 2 onwards).

Table 1 Patient demographics

Table 2 Number and percentage of most commonly (>1%) reported adverse events by treatment dose

Table 3 Percentage successful vaginal penetrations over time by treatment group