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AVANAFIL: the SECOND-GENERATION TREATMENT of ERECTILE DYSFUNCTION *Giovanni Corona,1 Mario Maggi,2 Emmanuele A

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AVANAFIL: the SECOND-GENERATION TREATMENT of ERECTILE DYSFUNCTION *Giovanni Corona,1 Mario Maggi,2 Emmanuele A AVANAFIL: THE SECOND-GENERATION TREATMENT OF ERECTILE DYSFUNCTION *Giovanni Corona,1 Mario Maggi,2 Emmanuele A. Jannini2,3 1. Endocrinology Unit 1, Maggiore-Bellaria Hospital, Medical Department, Azienda-Usl Bologna, Bologna, Italy 2. Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy 3. Endocrinology, Andrology, and Medical Sexology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy *Correspondence to [email protected] Disclosure: Giovanni Corona has received consultancy fees from Bayer, Besins, Otsuka, Eli Lilly, and Menarini. Emmanuele A. Jannini has received consultancies from Bayer, Bracco, Besins, GSK, Eli Lilly, Menarini, Pfizer, and Shionogi. Mario Maggi has received consultancy and speaker fees from Bayer, Eli Lilly, Menarini, Prostrakan, and Intercept. Support: The publication of this article was funded by The Menarini Group. The views and opinions expressed are those of the authors and not necessarily of The Menarini Group. Received: 23.03.16 Accepted: 18.07.16 Citation: EMJ. 2016;1[3]:61-69. ABSTRACT The main objectives of erectile dysfunction (ED) management are to control and reduce associated organic cardiovascular risk factors and to restore the capacity to obtain and maintain a rigid penile erection. Since oral phosphodiesterase (PDE)-5 inhibitors have a demonstrated efficiency in the number and duration of erections in patients with ED with a favourable benefit-to-risk ratio, they have been recommended in European guidelines as the first-line medical therapy for ED. In January 2016, we published a comprehensive review and meta-analysis on the safety and efficacy of avanafil, a novel second-generation PDE-5 inhibitor. This review aims to shed a special spotlight on the key aspects of this meta-analysis and to discuss how avanafil can provide an added value in the management of ED over first-generation agents. Keywords: Erectile dysfunction (ED), avanafil, phosphodiesterase (PDE)-5 inhibitors. INTRODUCTION of all the components involved in the erectile response including organic (the body), relational Erectile dysfunction (ED) is defined by the National (the couple), and intra-psychic (the mind).12-18 ED Institutes of Health (NIH) as the persistent inability may arise from the alteration of any one of these to achieve or maintain an erection sufficient for components (as a precipitating event) but sooner satisfactory sexual performance. This self-reported or later it will involve the other components in a condition is the main complaint in male sexual redundant way, having negative effects on quality medicine.1 The incidence of ED is 26 new annual of life, interpersonal relationships, and mood.9,19-24 cases per 1,000 men,2 for a worldwide ED prevalence Despite this evidence, it is important to recognise evaluated at 37–52% of adults aged ≥40 years that organic components and in particular old and that is projected to increase by 2025 to cardiovascular risk factors such as smoking,25,26 approximately 322 million.3 Of note, ED prevalence hypertension,27,28 diabetes,29,30 dyslipidaemia,27 and severity is strongly associated with age.4-11 obesity, and sedentary lifestyle,31,32 are major ED must be considered a multidimensional disorder contributors to the pathogenesis of ED. In fact, deriving from a general (or stepwise) perturbation arteriogenic ED, usually assessed through penile 60 EUROPEAN MEDICAL JOURNAL • August 2016 EMJ EUROPEAN MEDICAL JOURNAL EUROPEAN MEDICAL JOURNAL • August 2016 EMJ EUROPEAN MEDICAL JOURNAL 61 colour Doppler ultrasound, is associated with a comprehensive review and meta-analysis on the relevant increase in cardiovascular disease risk.33,34 safety and efficacy of avanafil, a novel second- generation PDE-5 inhibitor. This review aims to THE PHARMACOLOGICAL MANAGEMENT shed a special spotlight on the key aspects of this OF ERECTILE DYSFUNCTION meta-analysis and to discuss how avanafil can provide an added value in the management of ED The main objectives of ED management are over first-generation agents. to control and reduce associated organic cardiovascular risk factors and to restore the FIRST-GENERATION capacity to obtain and maintain a rigid penile PHOSPHODIESTERASE 5 INHIBITORS erection. Due to the great variability of underlying aetiologies and the subjective aspects of ED, Sildenafil (Viagra®) was approved by the European medical therapy depends on the patients’ (and their Medicines Agency (EMA) in 1998 as the first oral partners’) characteristics and comorbidities.10,35,36 PDE-5 inhibitor for ED and has been explored in a plethora of clinical trials.49,50 Market authorisations Androgens are considered the major hormonal for two other agents, vardenafil and tadalafil, were 37-40 regulator of penile physiology. Hypogonadism then subsequently granted by the EMA. The main is a frequent condition in subjects seeking medical characteristics of PDE-5 inhibitors are summarised 41 care for ED. Testosterone replacement therapy in Table 1.35,46,50-77 Adverse events (AEs) reported in hypogonadal men (total testosterone <12 nM) with first-generation PDE-5 inhibitors are generally is associated with significant increases in self- mild, mostly transient, and self-limited; the most 39,40 reported measures of erectile function. Hence, commonly-reported being headache, flushing, th according to the 4 International Consultation on dyspepsia, nasal congestion, and dizziness with Sexual Medicine (ICSM), testosterone assessment tadalafil also being associated to myalgia and must precede any pharmacological intervention of back pain.35,60,73,78-80 ED subjects.40 All PDE-5 inhibitors are contraindicated with the Oral pharmacological management with use of nitrates or NO-donor drugs due to the risk phosphodiesterase (PDE)-5 inhibitors is the of severe hypotension which can sometimes be first-line modality, before other methods, which life-threatening. PDE-5 inhibitors are to be used comprise penile self-injections with vasoactive with caution with non-selective alpha-blockers and drugs, intraurethral or intracavernosal alprostadil potent CYP3A4 inhibitors.81 In addition, precaution (a prostaglandin E1), vacuum-assisted erection is recommended for vardenafil in patients 10,35,36,42-44 devices, and penile prosthesis. Only oral taking Type 1A anti-arrhythmics (such as quinidine PDE-5 inhibitors that have been approved in or procainamide) or Type 3 anti-arrhythmics Europe will be discussed in this article. These drugs (such as sotalol or amiodarone) due to a possible act with a predominantly peripheral mechanism causal association with QT prolongation.82 potentiating the nitric oxide (NO) pathway. Sexual stimulation generates a local production AVANAFIL: A SECOND-GENERATION of NO which after binding to its intracellular PHOSPHODIESTERASE 5 INHIBITOR receptors, activates the enzyme guanylate cyclase, leading to increased levels of cyclic guanosine Drug Characteristics monophosphate (cGMP). cGMP can engage a number of downstream targets, leading eventually Avanafil (Spedra®) is the newest available PDE-5 to smooth muscle relaxation and penile erection. inhibitor having been approved by the EMA in PDE-5 inhibition, by blocking cGMP degradation, June 2013. It is a second-generation PDE-5 can therefore increase NO signalling and induce inhibitor along with lodenafil, mirodenafil, and smooth muscle relaxation.45-47 udenafil (the last two are marketed in South Korea) but is the only one approved in Europe to date.83,84 Oral PDE-5 inhibitors have a demonstrated efficiency in the number and duration of erections Avanafil has a demonstrated high potency with in patients with ED, with a favourable benefit-to- a 50% inhibitory concentration (4.3–5.2 nM).55-57 risk ratio, and hence they have been recommended This compound is highly selective for PDE-5 as in European guidelines as the first-line medical opposed to other PDE-5 inhibitors. In vitro studies therapy for ED.48 In January 2016, we published a evidenced less inhibition of PDE-1 (>10,000-fold; 62 EUROPEAN MEDICAL JOURNAL • August 2016 EMJ EUROPEAN MEDICAL JOURNAL EUROPEAN MEDICAL JOURNAL • August 2016 EMJ EUROPEAN MEDICAL JOURNAL 63 present in the heart), PDE-6 (120-fold, present Avanafil is available in Europe as 50, 100, in the retina), and PDE-11 (>10,000-fold, present or 200 mg oral tablets. The recommended dose in the testicles). Furthermore, approximately is 100 mg, taken as needed approximately 20,000-fold selectivity for the PDE-5 versus 15–30 minutes before sexual activity; sexual PDE-3 enzyme is found in the heart and blood stimulation is required for a response to treatment. vessels, which is important because PDE-3 is Based on individual efficacy and tolerability, the dose may be increased to a maximum dose of involved in control of cardiac contractility.85 200 mg or decreased to 50 mg. The maximum This high selectivity may confer and/or contribute recommended dosing frequency is once per day.51 to an improved safety profile over other PDE-5 inhibitors (Table 1).51-54 Table 1: Main characteristics and isozyme selectivity of phosphodiesterase 5 inhibitors. Sildenafil50,66-68 Vardenafil35,46,69-74 Vardenafil75-77 Tadalafil35,59-65 Avanafil51-58 Brand name Viagra® Levitra® Cialis® Spedra® Second- Generation First-generation generation Film-coated Film-coated Orodispersible Film-coated Galenic form Tablets tablets tablets tablets tablets Year of European market 1998 2003 2010 2003 2013 authorisation 50 mg (may be 100 mg increased to 10–20
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