Clinical update on sildenafil citrate

Introduction

The timing of this edition's supplement containing papers on the pharmacokinetic and pharmacodynamic properties of sildenafil citrate (Viagra®, Pfizer) appears very apt. It comes at a time when sildenafil has been marketed in Europe for approximately 3 years and when there is increasing interest and focus on men's health. Indeed a recent edition of the British Medical Journal focused on the Men's Health Movement and related issues [1].

Several issues warrant updating and discussion. What has happened to sildenafil since it received regulatory approval in 1998? How has sildenafil been received in the market place? What further studies have been performed, and what more do we know about sildenafil than we did 3 years ago? Have the initial encouraging results of sildenafil effectiveness in clinical trials withstood the test of independent scrutiny? How have governments reacted to the arrival of what some consider to be a ‘lifestyle drug’? How safe is sildenafil? What future directions are PDE5 inhibitor research projects likely to take? What has the advent of sildenafil done for sexual medicine?

Development

At the time of regulatory submission in September 1997 in the United States, the pharmacokinetics, efficacy and safety of sildenafil had been studied in over 60 clinical trials, which enrolled over 5000 men. The phase III trials showed sildenafil to be an effective ‘on demand’ treatment of erectile dysfunction (ED) in men with a wide variety of associated medical conditions. Most of the efficacy trials recruited a wide variety of patients with ED, were placebo-controlled, with the double-blind treatment period usually lasting for 12 weeks or 24 weeks. Patients with stable cardiovascular disease (e.g. controlled hypertension, previous MI, stable exertional angina) were allowed in to the trials but the main exclusion criteria were patients with recent onset (<6 months of serious cardiovascular disease) and patients taking nitrates. The highest response rates to the global efficacy question were observed in men in whom the cause was thought to be predominantly psychogenic (sildenafil 84%; placebo 24%). Across the patients judged to have predominantly organic causes of ED, the overall response rate was 68%, but lower response rates were observed for patients with diabetes mellitus (59%) and in a nonselected group of patients post prostatectomy (43%). The placebo response rates were 19%, 16% and 15%, respectively. The efficacy of sildenafil was maintained in long-term studies (36–52 weeks) with only 5% of patients discontinuing treatment due to lack of efficacy. The main adverse events were headache and facial flushing, followed by indigestion and nasal congestion. Transient visual symptoms, mainly disturbances of colour vision, were reported predominantly at the 100 mg dose and temporally related to the time of peak plasma levels. The visual symptoms are almost certainly due to transient inhibition of PDE6, which is present in rods and cones. Across the whole clinical trial database, the incidence of serious adverse events was the same for sildenafil and placebo, and no serious adverse event was considered related to sildenafil therapy.

At the time of approval, the main contraindication to sildenafil therapy was coadministration with nitrates because both nitrates and sildenafil act on the nitric oxide/cGMP pathway, and the combination can lead to excessive vasodilatory effects [2, 3]. The other contraindications were related to patients in whom sexual activity was inadvisable or groups of patients in whom clinical experience with sildenafil was lacking (e.g. patients with recent myocardial infarction or stroke, severe liver failure, degenerative hereditary retinal conditions).

Since launch in the United States in April 1998, sildenafil has received regulatory approval in over 110 countries. Over 45 million prescriptions have been issued to over 15 million patients. Over 500 million tablets of sildenafil have been distributed worldwide. In addition to this large postmarketing clinical experience of the treatment of men with ED, there continue to be publications of many preclinical and clinical studies of sildenafil, some relating to sexual medicine, and others in unrelated disciplines such as cardiology, respiratory medicine, and reproductive medicine [4–24].

During the clinical development of sildenafil, six families of phosphodiesterase (PDE) were recognized. Sildenafil was highly selective for PDE5, with weak activity against PDE6. There are now a further five families identified (PDEs 7–11), but sildenafil has been shown to have no significant activity on any of these new enzymes [25]. Thus, all the clinical effects of sildenafil can be attributed to inhibition of PDE5 and PDE6.

With regard to clinical trials, most of the efficacy results are similar to those reported in the preregistration trials. Some of the later trials have demonstrated the efficacy of sildenafil in treating ED in patients with untreated symptoms of minor depression [26], multiple sclerosis [27], Parkinson's disease [28] and spina bifida [29] and in patients with prostate cancer treated with radiotherapy (external beam or local) [30–32]. There are also encouraging data indicating efficacy of sildenafil to treat patients post-prostatectomy [33, 34], post-heart transplant [35] and post-renal transplant [36]. With regard to long-term use of sildenafil, although one recent publication suggested that loss of efficacy with prolonged use might occur in some patients [37], other reports have indicated that the efficacy of sildenafil is maintained over periods of 1 year or longer [38, 39].

Over the last 12 months, some of the studies from the ongoing clinical trial programme in female sexual dysfunction have been completed [40]. A pharmacodynamic study in healthy women suggested that sildenafil could enhance vaginal blood flow in response to sexual stimulation [41]. A nonsponsored, placebo-controlled study from Italy indicated that sildenafil might improve sexual function in premenopausal women with sexual arousal disorder [42]. However, two larger Pfizer-sponsored, placebo-controlled trials recruiting women with female sexual arousal disorder (one recruiting patients who were premenopausal or perimenopausal and the other recruiting patients who were postmenopausal and not on hormone replacement therapy) failed to demonstrate any clinical efficacy relative to placebo [40]. The trials programme continues with further attempts to assess whether any particular subgroup of patients might benefit from this type of pharmacological agent. There is also ongoing independent research of the potential use of sildenafil in patients with pulmonary hypertension [43–45] and with certain types of infertility [24].

Postmarketing

Most of the post-registration Pfizer sponsored and independent clinical trials have described a similar safety profile to that reported in the pre-registration studies [19, 46–48]]. However, some safety issues (including concerns about cardiac adverse events such as myocardial infarction) have been raised post-marketing, and nearly all these concerns arise from two main sources. The first source of concern has arisen from reports of in vitro or animal studies usually performed with high concentrations or doses of sildenafil [49, 50]. However, the maximum free plasma concentration in men that can be achieved with therapeutic doses of sildenafil is approximately 40 nmol l⁻¹, and even if concomitant potent CYP3A4 inhibitors are coprescribed, free plasma concentrations rarely exceed 100 nmol l⁻¹[51].

The other main source of concern has been spontaneous reports of serious cardiac events. Given the large number of prescriptions of sildenafil, the immense publicity the treatment has received and the fact that most of the patients have risk factors for cardiovascular disease, it is not surprising that there have been reports of cardiac and other events in temporal association with sildenafil. The key question is whether the number and nature of the cases reported could represent a signal of some drug-related problem or whether they merely reflect the expected occurrence of such events in a predominantly middle-aged/elderly male population. A large variety of clinical studies have been undertaken to address this question, and of the studies reported to date, none has demonstrated a link between sildenafil and serious cardiovascular events [4, 10–21, 52, 53]. As an example, haemodynamic studies have shown that sildenafil does not increase the workload of the heart, even during severe physical activity [11], and a haemodynamic study in patients with severe coronary artery disease showed that sildenafil does not impair blood flow through stenosed coronary arteries [10]. At last year's annual meeting of the American Heart Association, Fox et al. reported the results of a large randomized, placebo-controlled trial in which patients with stable exertional angina and ED were exercised on a treadmill to the point of limiting angina [53]. Patients who had received 100 mg sildenafil 1 h before the stress test exercised about 5% longer than the patients randomized to placebo, and there were no serious adverse cardiac effects.

The sildenafil clinical trials database now includes over 10 000 man-years observation of patients treated with sildenafil, and the incidence of myocardial infarction, cardiac mortality and all-cause mortality continues to be the same for men treated with placebo and men treated with sildenafil.

Further important safety information comes from the results of the first phase of a Prescription Event Monitoring Study performed in the United Kingdom (UK) by Shakir et al. from the Drug Safety Research Unit, Southampton, and reported recently in the British Medical Journal [21]. This study collected adverse event data on over 5000 men with ED who were prescribed sildenafil in a general practice setting and who were followed for an average period of 5 months. The incidence of serious cardiac events and deaths was similar to that expected for an aged-matched male population in the UK. Moreover, there were no heart attacks, deaths or strokes reported during the first month of treatment, suggesting that resumption of sexual activity by men with ED is not associated with undue risk provided that the prescribing information is followed.

There have been some new adverse reactions reported since the launch of sildenafil. These findings include bloodshot eyes, eye pain and, rarely, priapism. In addition, patients with left ventricular outflow obstruction (e.g. hypertrophic obstructive cardiomyopathy) and patients with the degenerative condition Multiple System Atrophy with autonomic hypotension may be particularly susceptible to the modest hypotensive effects of sildenafil. There have been rare reports of hypotension and syncope in patients taking α-adrenoceptor blockers, but the significance of this is unknown. Importantly, the HIV protease inhibitors do raise plasma concentrations of sildenafil and prolongation of its pharmacological effects might be expected. Sildenafil dose adjustment (e.g. 25 mg starting dose) may therefore be advisable for many HIV-positive patients [51] although coadministration with ritonavir is not advised.

Reimbursement

How have patients, doctors and governments reacted to the advent of sildenafil? There seems little doubt that some patients are more willing to talk about sexual problems and are encouraged by the fact that pharmacological treatments for at least some sexual conditions are available. There is increasing awareness in the medical profession that ED can cause considerable embarrassment, loss of self-esteem and depressive symptoms in men and can lead to the break-up of sexual relationships. Many more doctors now feel able to broach the subject of erectile function and to manage the condition. However, many patients still find it difficult to get treatment for a variety of reasons, and many doctors are still uncomfortable in raising the subject of sexual function.

Governments in Europe, although acknowledging the efficacy and safety of sildenafil, have almost universally considered ED to be a condition that the health service systems cannot fully finance. A number of independent studies have reported that treatment of ED is cost effective [54, 55]. For example, the cost per quality-adjusted life year (QALY) is lower than many other treatments that are routinely reimbursed. However, reimbursement of sildenafil has been denied or limited to a minority of men with ED. In July 1999 the UK government introduced new legislation (schedule 11 grey list) restricting the NHS prescription of sildenafil and other pharmacological treatments for ED to men with a limited number of medical conditions (including diabetes but not cardiovascular disease or depressive symptoms). Patients with severe distress could only be treated with sildenafil if seen by a specialist. More recently, the UK government has reaffirmed the status quo. Both the original and the more recent Government decisions have led to considerable comments in medical articles [56–58]. The reimbursement status is not noticeably different in other parts of Europe.

Conclusions

The advent of sildenafil has had a considerable impact on the research and medical communities. It has led to increased interest in sexual medicine, both in academia, in clinical practice and in the pharmaceutical industry. There is a growing recognition that sexual disorders are relatively common, cause considerable distress to both partners in a relationship, are relatively easy to identify and can be studied in a clinical trial setting. There is far more interest in female sexuality and a growing recognition that the aetiology, diagnosis and treatment is far more complex than for some male sexual disorders. Several large pharmaceutical companies are searching for new treatments for male ED, female sexual arousal disorder and premature ejaculation.

In the future, we can anticipate a wider array of treatments for male erectile disorder and hopefully some breakthroughs in the treatment of other sexual disorders. It would be good if the increased awareness of the importance of sexual disorders and their treatment could lead to a greater proportion of medical school curriculum being devoted to this important but previously under-researched area of medicine. We should also await with interest future development arising from research of sildenafil in other areas of clinical medicine.