130 SOP Conservative (Medical and Mechanical) Treatment of

Erectile Dysfunctionjsm_12023 130..171

Hartmut Porst, MD,* Arthur Burnett, MD, MBA, FACS,† Gerald Brock, MD, FRCSC,‡ Hussein Ghanem, MD,§ Francois Giuliano, MD,¶ Sidney Glina, MD,** Wayne Hellstrom, MD, FACS,†† Antonio Martin-Morales, MD,‡‡ Andrea Salonia, MD,§§ Ira Sharlip, MD,¶¶ and the ISSM Standards Committee for Sexual Medicine *Private Urological/Andrological Practice, Hamburg, Germany; †The James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, MD, USA; ‡Division of Urology, University of Western, ON, Canada; §Sexology & STDs, Cairo University, Cairo, Egypt; ¶Neuro-Urology-Andrology Unit, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France; **Instituto H.Ellis, São Paulo, Brazil; ††Department of Urology, Section of Andrology and Male Infertility, Tulane University School of Medicine, New Orleans, LA, USA; ‡‡Unidad Andrología, Servicio Urología Hospital, Regional Universitario Carlos Haya, Málaga, Spain; §§Department of Urology & Urological Reseach Institute (URI), Universiti Vita Saluta San Raffaele, Milan, Italy; ¶¶University of California at San Francisco, San Francisco, CA, USA

DOI: 10.1111/jsm.12023

ABSTRACT

Introduction. Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interper- sonal, family, and business relationships. Aim. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. Methods. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phos- phodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Results. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3–5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L- arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor mono- therapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethralPGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering

ISSM Standards Committee for Sexual Medicine Sub-Committee Male Sexual Dysfunction Chapter: Medical/Conservative Treatment in ED, Priapism, and Peyronie’s Disease

J Sex Med 2013;10:130–171 © 2013 International Society for Sexual Medicine Conservative Treatment of Erectile Dysfunction 131 from both ED and premature ejaculation. Porst H, Burnett A, Brock G, Ghanem H, Giuliano F, Glina S, Hellstrom W, Martin-Morales A, Salonia A, Sharlip I, and the ISSM Standards Committee for Sexual Medicine. SOP conservative (medical and mechanical) treatment of erectile dysfunction. J Sex Med 2013;10:130–171. Key Words. Erectile Dysfunction; Oral Drug Treatment; Phosphodiesterase Inhibitors; Intracavernous Self- Injection Therapy; Transurethral Alprostadil Therapy; Combination Therapies; Vacuum Device Therapy

Introduction Table 2 Age-dependent frequency of sexual activities in Germany and Japan [2,3]

exuality is a key domain in the lives of humans. German (Cologne) study Japanese study In the majority of partnerships, sexuality S Age No. of Sexually No. of Sexually remains the most important or at least a very (years) patients active patients active important bonding factor regardless of an indi- Total 4.489 9.880 vidual’s homosexual or heterosexual orientation. 30–39 Not reported 96% 679 96% Until recently, sex (which in this context refers 40–49 Not reported 92% 1.010 96% 50–59 Not reported 89% 883 92–95% both to an active sex life and interest in sexual 60–69 Not reported 84% 3.552 80–88% activities) is commonly associated in the public 70–79 Not reported 71% 2.308 55–70% domain with younger age groups, whereas sexual >80 Not evaluated 220 44% activities in elderly individuals (>70 or even 80 years) are considered in many cultures to be some- what uncommon or even strange. Therefore, in majority of older men, sexual activities play an the scientific literature, few representative data important role as a bonding factor for partnerships. exist regarding the importance of sex life in the Alternatively, many studies suggest that sexual elderly population. In a population-based cohort health is not maintained in many elderly men. study from Perth, Australia of 3,274 men, aged Declining sexual health is a process that usually 75–95 years, sexual life and activities were explored starts in the fifth decade and increases progressively via questionnaires from 1996 to 1999, from 2001 with age. This statement applies generally for all to 2004, and from 2008 to 2009 [1]. male sexual functions including sexual desire, A total of 2,783 (85%) provided data on their sexual arousal, erectile function, and ejaculatory/ sexual activity (Table 1). orgasmic capacity, as has been shown in a Norwe- In two previous studies from Germany and gian epidemiologic study (see Figure 1). Japan investigating sexual activities in age groups From a clinical standpoint, erectile dysfunction between 30 and 80 years of age, the frequency of (ED) is categorized in two major subtypes: (i) sexual activity (coitus, masturbation, erotic primary ED defined as ED that occurs from the movies, etc.) over the months prior to the study beginning of sexual activities and (ii) secondary or was between 70% and 96% (Table 2). acquired ED defined as ED that occurs after a These three large studies from three different period of normal sexual life in which erectile func- cultures provide convincing evidence that for the tion is intact. Many men experience erectile problems that Table 1 Results of a population-based cohort study from are clearly related to temporary life circumstances Perth, Australia, with 2,783 (85%) of 3,274 men, aged or problems. These erectile problems disappear 75–95 years, providing data on sexual life and activities once the temporary circumstances are resolved. In from 1996–1999, 2001–2004, and 2008–2009 [1] these cases, consultation with a physician is not Yes needed. Item responses In contrast to these temporary erectile prob- Sex at least somewhat important 48.8% lems, a man experiencing longer-lasting ED of At least one sexual encounter in the past 12 months 30.8% greater than 3–6 months should seek professional Satisfied with frequency of sexual activity 56.5% help and undergo a thorough medical evaluation Sex less often than preferred 43% both because of the increasing risk of partnership

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Table 3 Prevalence of male sexual disorders in the elderly U.S. population [4]

Sexual disorder 57–64 years 65–74 years 75–85 years Premature ejaculation 29.5% (23.4–35.7%) 28.1% (23.4–32.9%) 21.3% (13.2–29.3%) Delayed/absent ejaculation/orgasm 16.2% (11.9–20.5%) 22.7% (17.5–27.9%) 33.2% (25.0–41.5%) Erectile dysfunction 30.7% (25.3–36.9% 44.6% (38.7–50.5%) 43.5% (34.5–52.4%) problems and the likelihood of underlying and Risk Factors for ED principally treatable medical risk factors/diseases In patients > 40 years of age, ED is significantly contributing to the onset or progression of associated with cardiovascular risk factors such as ED. diabetes, hypertension, coronary artery disease (CAD), dyslipidemia, atherosclerosis, and meta- Epidemiology bolic syndrome [8–11; Table 4]. In addition many ED and premature ejaculation (PE) are the most epidemiological studies have provided convincing common male sexual disorders (Table 3). The evidence that men with BPH and LUTS show an prevalence of these disorders is similar. In contrast significantly increased risk of both simultaneous to PE, ED is clearly age dependent with a steep erectile dysfunction and ejaculatory disorders increase beyond the fifth decade. In age [12]. The increased risk of cardiovascular risks/ groups < 50 years, the reported prevalence rates events in men with ED compared with age- for ED range between 9% and 39% (<20% in matched men without ED has been demonstrated most series). In men > 70 years of age, the preva- repeatedly, most notably, in a meta-analysis lence of ED increases to between 40% and 80% reviewing 12 prospective cohort studies with a depending on the populations investigated [6]. total of 36,744 participants [9]. The overall com- For standardization of clinical trials, categori- bined relative risks for men with ED compared zation of ED severity was based on the Interna- with the reference group were the following: 1.48 tional Index of Erectile Function (IIEF) using a (95% confidence interval [CI]: 1.25–1.74) for car- scoring system from 1 to 30 in the erectile func- diovascular disease (CVD); 1.46 (95% CI: 1.31– tion domain (EF) of the IIEF [7]. ED is subdi- 1.63) for coronary heart disease; 1.35 (95% CI: vided into mild (IIEF-EF score 17–25), moderate 1.19–1.54) for stroke, and 1.19 (95% CI: 1.05– (IIEF-EF score 11–16), and severe ED (IIEF-EF 1.34) for all-cause mortality. Sensitivity analysis score 1–10) with an IIEF-EF score of between 26 restricted to studies with control for conventional and 30, indicating a normal erectile function. cardiovascular risk factors yielded similar results. The IIEF has been tested only for heterosexual No evidence of publication bias was observed. activities over the prior 4 weeks. It has not been Therefore, the manifestation of ED must abso- tested in sexually inactive men or in homosexual lutely be considered a marker (warning sign) for men. occult CAD with a significant likelihood of later

Figure 1 Decline of male sexual func- tion related to age as evaluated by the Brief Sexual Function Inventory. Results of a Norwegian epidemiologi- cal study (reprinted with permission from [5])

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Table 4 Etiology and risk factors of erectile dysfunction (ED)

Psychogenic factors Psychosexual development in childhood/adolescence (special negative experiences, etc.) Sexual orientation problems? Partnership problems?

Lifestyle factors and individual health conditions Permanent stress factors? (private/business life) Sedentary lifestyle? Nicotine? Alcohol abuse? Drug addictions?

Cardiovascular risk factors Hypertension (including antihypertensive medications with potential negative impact on erectile function) Dyslipidemia Coronary artery disease Peripheral arterial occlusive disease Diabetes mellitus (types 1 and 2)

Endocrine factors Hypogonadism (primary/secondary) Hyperprolactinemia (microprolactinoma/macroprolactinoma or drug induced) Thyroid disorders (hypothyroidism/hyperthyroidism)

Iatrogenic ED Drug induced (drugs with a negative impact on central and peripheral erectile functions including hormones—hyperprolactinemia and hypogonadism) Postoperative (pelvic, perineal, urethral, and penile surgery → radical prostatectomy, cystectomy rectum resection/amputation, aorto-iliac vascular surgery (aneurysms) Postradiation (prostate cancer, bladder cancer, and rectum cancer)

Medical/metabolic disorders Renal insufficiency Hepatic insufficiency Dyslipidemia

Urological disorders Benign prostate hyperplasia (BPH) and lower urinary tract symptoms (LUTS) Chronic prostatitis

Respiratory disorders Chronic obstructive pulmonary disease Sleep apnea

Neurologic disorders

Cerebral, spinal, and peripheral affections: central (brain) diseases such as multiple sclerosis, cerebrovascular atherosclerosis, Parkinson’s disease, dementia, etc. Somatic and autonomic polyneuropathy Pudendal nerve lesions (“vulnerable perineum”)

Penile/cavernous factors

Cavernous myopathy and fibrosis (veno-occlusive dysfunction) Peyronie’s disease or penile fracture

Posttraumatic ED

Brain/spinal cord injuries Pelvic fractures, urethral ruptures, straddle traumas, and penile injuries

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PatientPatient presentingpresenting withwith aa sexualsexual problem problem

Clinical Investigations

No/low risk Moderate risk High risk

Immediate Stabilization/ treatment Cardiovascular treatment of assessment and of the the sexual risk restratification cardiovascular Figure 2 Princeton II Consensus problem situation Conference Algorithm for the cardio- vascular risk management of the ED patient (modified after [10]). Dysfunction in dependence of T- Because of the proven link between ED and CAD periodical cardiovascular cutoff levels (N = 2.794 [13]). CAD = risk evaluation and management for all ED patients strongly recommended coronary artery disease; ED = erectile dysfunction major cardiovascular events [10,11]. In the Italian Several well-designed studies provide convincing Cobra study, comprising 162 men with CAD, evidence that in untreated hypogonadal men, documented by catheter angiography, the onset of responsiveness to phosphodiesterase type 5 ED occurred in 71% of the study population with (PDE5) inhibitors is substantially impaired and a mean interval of 25 months before myocardial can be significantly increased by testosterone. infarction or angina symptoms occurred [11]. Adding T-replacement therapy to PDE5 inhibitor In summary, there is level 1a evidence that ED therapy can convert PDE5 inhibitor nonre- in men > 40 years is associated with an increased sponders to PDE5 inhibitor responders especially all-cause mortality primarily due to increased car- in men with T levels < 300 ng/dL or 10.4 nmol/L diovascular mortality (fatal myocardial infarction [14–16]. or cerebral insult). Therefore, each man > 40 years In a subset of untreated hypogonadal men with with chronic ED should be considered a potential ED, T substitution alone may restore impaired cardiovascular risk patient and investigated sexual functions, especially libido and erection accordingly. [16–18]. According to several well-designed The Princeton II Consensus Conference on the studies, the threshold T value below which ED cardiovascular risk management of any ED patient becomes evident is <300 ng/dL [19] (see Figure 4). is shown as an algorithm in Figure 2 [10]. For low libido disorder, the T-threshold values were 15 nmol/L (432 ng/dL). In conclusions on ED and simultaneous hypogo- ED and Hypogonadism nadism, testosterone plays a key role in the main- The incidence of hypogonadism in men with ED tenance of men’s sexual functions and sexual depends both on age and the total testosterone (T) health. Depending on the plasma T levels, cutoff values, which are used for the definition of hypogonadal men develop libido, erectile, or hypogonadism. As a rule, between 20% and 40% ejaculatory/orgasmic disorders. The respective of men > 40 years and suffering from ED have threshold levels below which sexual symptoms hypogonadal T values (see Figure 3). become evident are about 15 nmol/L (432 ng/dL) for libido and 8–10.4 nmol/L (230–300 ng/dL) for Treatment of Hypogonadism in Patients with ED ED. T-replacement therapy in hypogonadal men Hypogonadal men with ED should be offered with sexual disorders should start first followed by T-replacement therapy because it is well estab- specific ED medications such as PDE5 inhibitors. lished that ED-specific medications are less effec- Recovery of sexual functions takes usually 4–12 tive if applied to men with untreated T deficiency. weeks depending on the sexual symptoms in ques-

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Figure 3 Prevalence of androgen deficiency in men with erectile dys- function in dependence of T-cutoff levels (N = 2.794 [13]). ED = erectile dysfunction tion. Responsiveness to specific ED medications is approved PDE5 inhibitors have the same mode/ substantially disturbed in untreated hypogonadal site of action: they inhibit the enzyme PDE5 com- men if T values are <300 ng/dL (10.4 nmol/L). petitively, thereby blocking the cleavage of its There is level 1b evidence that T-replacement physiological target substance 3′5′-cGMP (cyclo- therapy in hypogonadal men can convert nonre- guanosine monophosphate). The PDE5 enzyme is sponders to PDE5 inhibitors to responders. found in high concentrations in the entire uro- genital system and especially in the cavernous bodies [22] (Figure 5). Medical Treatment of ED In general, above a certain threshold concentra- Oral Drug Therapy of ED tion of the key mediator for erection—3′5′- PDE5 Inhibitors cGMP—the physiological cascade of erection is triggered and erection occurs. The formation of Mechanism of Action. PDE5 inhibitors are widely 3′5′-cGMP in the cavernous tissue is triggered considered as first-line therapy for ED [20,21]. All after parasympathetic nerve stimulation resulting in nitric oxide (NO) release and guanylate cyclase activation. The enzyme PDE5 regulates hydrolysis of 3′5′-cGMP. By lowering its concentration, erec- tion subsides. It is believed that in men with erectile problems, regardless of whether their underlying etiology is psychogenic or organic, intracavernous 3′5′-cGMP concentrations are principally below the threshold level above which erection occurs. By inhibiting the enzyme PDE5 via a PDE5 inhibitor, 3′5′-cGMP cannot be further hydrolyzed, resulting in achieve- ment of the threshold concentration above which erection is triggered [23] (see Figure 6). Regarding the mechanism of action of PDE5 inhibition, it is logical that PDE5 inhibitors need Figure 4 Threshold values for the manifestation of different the substrate 3′5′-cGMP to exert any efficacy clinical symptom (N = 434 [19]). BMI = body mass index regarding erectile function. As 3′5′-cGMP is only

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generated after adequate sexual stimulation, it is obvious that PDE5 inhibitors need prior sexual stimulation to develop clinical efficacy and to support the onset and maintenance of a rigid erection. PDE5 inhibitors prevent breakdown of 3′5′- cGMP resulting both in achieving the 3′5′-cGMP threshold concentration despite impairment of 3′5′-cGMP formation and in achieving suprath- reshold 3′5′-cGMP concentrations with subse- quent maintenance of a rigid erection. In summary, after adequate sexual stimulation, PDE5 inhibitors elevate the concentrations of the mediator 3′5′-cGMP above the threshold level that is needed to trigger erection. This mechanism works in the majority of ED etiologies except those in which severe damage/injury of the para- sympathetic cavernous nerves prevents NO release, guanylate cyclase activation, and 3′5′- cGMP formation, such as after major pelvic cancer surgery with resection of the cavernous nerves at both sides or diseases with severe autonomic neu- ropathy such as diabetes.

Pharmacokinetics Figure 5 Quantitative expression, by real-time RT-PCR, of PDE5 mRNA in (A) human and (B) rat male urogenital The pharmacokinetic profile of a drug is deter- tissues. (A) Data are expressed as PDE5 mRNA mined by many steps between the drug’s entry molecules/mg total RNA Ϯ SEM obtained according to a into the body and its elimination. Two key phar- standard curve method for absolute quantitation. (B) Data macokinetic parameters related to the speed of are expressed as mean Ϯ SEM of arbitrary units (a.u.) cal- absorption are TMax, which is defined as the time culated according to the comparative Ct method and using the b2-microglobulin as reference gene for normalization. n, needed to reach CMax (the maximum plasma con- number of analyzed samples. *P < 0.05 vs. human kidney; centration), and T1/2 (half-life time), which is °P < 0.001 vs. human corpus cavernosum (CC); **P < 0.01 defined as the time it takes for the fall of the vs. rat CC (reprinted with permission from [22]). plasma concentrations of a drug to half of its CMax mRNA = messenger RNA; PDE5 = phosphodiesterase type values. In the clinical setting, the TMax corresponds 5; RT-PCR = real-time polymerase chain reaction; SEM = standard error of mean quite well with the speed of clinical efficacy (onset of

Cerebral Sex Centers Erotic stimuli Stimulatory Neurotransmitters (Visual, tactile, imaginary) Figure 6 Physiology of erection and Dopamine, NO, Oxytocin + impact of PDE5 inhibitors on erection NE (partly), Serotonin (partly) (from [23]). ACH = Acetylcholine; alpha-MSH, Vasopressin, ACTH ACTH = Adrenocorticotropic hormone; ATP = Adenosine triphosphate; 3′5′- + + + cAMP = cyclic adenosine monophos- + Parasympathetic phate; 3′5′-cGMP = cyclic guanosine nerves NANC ACH Nerve monophosphate; eNOS = endothelial eNOS NO VIP O2 + L - Arginine NO + Citrulline nitric oxide synthase; GTP = G -Protein + + Guanosine triphphosphate; MSH = Guanylate cyclase Adenylate cyclase Melanocyte stimulating hormone; NANC = non adrenergic, non cholin- GTP 3´5’-cGMP ATP 3´5’-cAMP ergic; NE = Norepinephrine; NO = 5-GMP - Phosphodiesterase V-Inhibitors: Nitric oxide; VIP = Vasoactive intesti- Sildenafil, Tadalafil, Vardenafil, other nal polypeptide

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Table 5 Pharmacokinetics of the three phosphodiesterase type 5 inhibitors: sildenafil, tadalafil, and vardenafil (Cialis®, Levitra®, and Viagra® labels)

Onset of action (minutes) Duration of efficacy >50% patient (hour) (% succesf.

Drug TMax (minutes) Earliest response T1/2 (hour) coitus) CMax (ng/mL) Sildenafil 100 mg 70 (30–120) 14 20 3.82 Ϯ 0.84 8 (85%) 327 Ϯ 236 Tadalafil 20 mg 120 (30–720) 16 30 17.5 36 (59% and 62%) 378 Vardenafil 20 mg 40 (15–180) 11 25 3.94 Ϯ 1.31 8 Ϯ 2 (69%) 20.9 Ϯ 1.83

erection) and the T1/2, with the duration of clinical sure, heart rate, and vision). The pharmacody- efficacy. namic interactions of any drug are influenced by As illustrated in Table 5, all three drugs show the number of molecules available in the target similar earliest onset of action times with vardena- organ and the affinity of the compound for the fil being slightly most rapid. The Tmax and CMax of target molecule in question. For example, it has sildenafil and vardenafil are clearly dependent on food been reported that the proportion of high-affinity intake. After intake of a high-fat (59% fat) meal, a components for the PDE5 catalytic site of vard- delay in TMax of 60 minutes and a reduction in CMax enafil is 85% compared with 50% for sildenafil of 29% was observed with sildenafil (Viagra® U.S. and 60% for tadalafil [27]. High-affinity compo- label; Pfizer Corp, New York, NY, USA). Similar nents of a PDE5 inhibitor show a considerably data apply for vardenafil ([24], Levitra® U.S. label; longer dissociation time from the target molecule. Bayer Healthcare, Leverkusen, Germany). On the This explains why vardenafil showed in clinical use other hand, no food interaction has been reported a clearly longer duration of efficacy than it would for tadalafil, even with a high-fat meal [25,26]. be suspected by its half-life time [28].

Pharmacodynamics Intrinsic and Extrinsic Factors The term pharmacodynamics covers all actions of Renal and Hepatic Insufficiency. Special dose adjust- a drug on the different body organs/tissues and in ments must be made in patients with renal and turn on their functions (for example, blood pres- hepatic insufficiency (see Table 6).

Table 6 Pharmacodynamic characteristics of the three PDE5 inhibitors (source: U.S. labels for Cialis®, Levitra®, and Viagra® as of July 2005)

Parameter/condition Sildenafil Tadalafil Vardenafil CYP 3A4 inhibitors* Start dose 25 mg Max. dose 10 mg/72 hours Max. 2.5 mg/day CYP 3A4 inhibitors† Start dose 25 mg Max dose 10 mg/72 hours Max. dose: 2.5 mg/72 hours Max. dose 25 mg/day Age > 65 years Start dose 25 mg No dose adjustment Start dose 5 mg Severe renal failure (creat. Start dose 25 mg Max. dose 5 mg No dose adjustment clearance < 30 mL/minutes) Mild/mod. hepatic failure (Child Start dose 25 mg Max. dose 10 mg Start dose 5 mg Pugh A/B) Max. dose 10 mg Blood pressure drop syst./diast. 8.4/5.5 mm Hg 1.6/0.8 mm Hg 7/8 mm Hg Alpha blockers Interval of 4 hours Stable alpha-blocker therapy Stable alpha-blocker therapy recommended recommended. Start dose recommend. Start dose 5mg 10 mg Antihypertensives (all drug No interactions of clinical No interactions of clinical No interactions of clinical classes) relevance relevance relevance Alcohol intake (0.5–0.6 g/kg) No additional hypotensive effect No additional hypotensive effect No additional hypotensive effect Contraindications Nitrates and NO donors‡ Nitrates and NO donors Nitrates and NO donors Safe interval for nitrate 24 hours 48 hours 24 hours medication in emergencies

*CYP 3A4 inhibitors: erythromycin, ketoconazole, itraconazole: up to 3- to 10-fold increases of the plasma concentrations of the respective PDE5 inhibitors, cimetidine (56% increase of sildenafil plasma concentrations, not valid for vardenafil, tadalafil not reported) †CYP 3A4 inhibitors: protease inhibitors ritonavir, indinavir, saquinavir: increase of plasma concentrations of the respective PDE5 inhibitors between onefold and fivefold for tadalafil and 16-fold for vardenafil CYP 3A4 inducers: rifampin: decrease of PDE5 inhibitor plasma levels up to 88% (reported for tadalafil) ‡Nitrates and NO donors: All short- and long-acting nitrates containing drugs including recreational drugs such as “poppers” as well as molsidomine and nitroprusside natrium containing medications NO = nitric oxide; PDE5 = phosphodiesterase type 5

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Bleeding Time. Both with aspirin 150 mg and war- CYP 3A4 Inhibitors. Erythromycin, ketoconazole, farin, no increase in bleeding time was observed and itroconazole have been reported to cause up with the PDE5 inhibitors. After heparin, sildenafil to 3- to 10-fold increases of the plasma concen- showed an additive effect on bleeding time in trations of PDE5 inhibitors. Cimetidine has been rabbits, but this interaction trial was not con- reported to cause a 56% increase of sildenafil ducted in humans. plasma concentrations, but this effect has not been found with vardenafil (interaction CVD. Patients with CVD can be particularly sen- between cimetidine and tadalafil has not been sitive to the systemic actions of PDE5 inhibitors reported). and may need reduced doses. This includes patients Protease inhibitors ritonavir, indinavir, and with left ventricular outflow obstruction (aortic and saquinavir have been reported to cause an increase subaortic stenosis), recent (<6 months) myocardial of plasma concentrations of onefold to fivefold for infarction, stroke, life-threatening arrhythmias, tadalafil and 16-fold for vardenafil. and hypotensive (blood pressure < 90/50 mm Hg) and hypertensive (blood pressure > 170/ CYP 3A4 Inducers. Rifampin has been reported to 110 mm Hg) blood pressure values. decrease tadalafil plasma levels up to 88%. Priapism. In conditions/drugs with a known risk of Efficacy of PDE5 Inhibitors priapism such as sickle cell disease, leukemia, and General Considerations on PDE5 Inhibitors multiple myeloma, PDE5 inhibitors must be used For a better understanding of differences among with special precautions because of the concern and comparisons between the three widely avail- that the drugs may heighten this risk. able PDE5 inhibitors, some terms have to be explained: Drug Interactions Alpha Blockers. Both sildenafil 25 mg and tadalafil IC50: IC50 (Inhibitory concentration) is defined as 20 mg used simultaneously with doxazosin 4 mg the concentration of a PDE5 inhibitor, which is resulted in symptomatic postural hypotension required to reduce the activity of PDE5 by (Viagra® U.S. label; Cialis® U.S. label; Eli Lilly 50%. The IC50 value provides an overview of Comp., Indianapolis, IN, USA). Tamsulosin the clinical efficacy of a PDE5 inhibitor. Gen- 0.4 mg with either tadalafil 20 mg or vardenafil erally speaking, the lower the IC50 value, the 5 mg did not show any clinically relevant influence more potent and therefore more effective a on the blood pressure. Vardenafil 5 mg used simul- compound is for inhibiting this enzyme. The taneously with terazosin 10 mg resulted in symp- IC50 values vary greatly among the available tomatic hypotension. This effect was not observed PDE5 inhibitors as is illustrated in Table 7 [33]. when both drugs were taken 6 hours apart ([29], In the clinical setting, the IC50 translates to the Cialis® U.S. label; Levitra® U.S. label). Tadalafil dose used to reach the same clinical efficacy. 20 mg used with alfuzosin 10 mg did not result in The higher the IC50, the higher the dose needed clinically significant hemodynamic interactions to reach the same clinical efficacy as compared [30]. with a competitive PDE5 inhibitor with a lower IC50. Nitrate-/NO-Donor Interactions. All three PDE5 Clinical efficacy: Regarding the clinical efficacy of a inhibitors showed clinically relevant interactions PDE5 inhibitor, several tools are used in clinical with nitrates. The most threatening of these inter- trials: actions is severe hypotension, which can be lethal General Assessment Question: “Has the treatment if not recognized and managed properly ([31,32], you have been taking improved your erec- Cialis®, Levitra®, and Viagra® U.S. labels). tions?” Although this efficacy tool does not Therefore, all three PDE5 inhibitors are abso- really tell whether the patient is able to attain lutely contraindicated for patients using nitrate an erection sufficient for sexual intercourse, medications. this relatively weak efficacy measure has been The time interval considered to be safe between widely used especially by pharmaceutical the administration of a PDE5 inhibitor and a companies because usually it yields the nitrate medication is 24 hours for the shorter- highest success rates. acting sildenafil and vardenafil and 48 hours for IIEF: The International Index of Erectile the longer-acting tadalafil (Cialis®, Levitra®, and Function (IIEF) was originally developed to Viagra® U.S. labels). evaluate the clinical efficacy of sildenafil

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Table 7 Selectivity profile and IC50 values of the three PDE5 inhibitors: sildenafil, tadalafil, and vardenafil. Adapted from Gbekor et al. [33]

Selectivity ratio of the PDE5 inhibitors for some clinically important phosphodiesterases

IC50 values (mmol) Ratio to PDE5 PDE isoform Sildenafil Tadalafil Vardenafil Sildenafil Tadalafil Vardenafil PDE5 0.0035 0.0067 0.00014 1 1 1 PDE1 0.281 >30 0.07 80 >4.450 500 PDE3 16.2 >100 >1.0 4.63 >14.800 >7.140 PDE6 0.037 1.26 0.0035 11 187 25 PDE11 2.73 0.037 0.162 780 5 1.16

PDE5 potency: vardenafil > sildenafil > tadalafil PDE selectivity For PDE6: tadalafil > vardenafil > sildenafil For PDE11: vardenafil > sildenafil > tadalafil IC50 = Inhibitory concentration of a drug that inhibits the target enzyme, here PDE5, by 50%; PDE = phosphodiesterase

(Viagra®). It became the most accepted and On-Demand (Pro Re Nate [P.R.N.]) Therapy with used efficacy tool worldwide for ED drugs. It PDE5 Inhibitors comprises 15 questions, which cover five The efficacy of the on-demand or p.r.n. use of PDE5 domains of sexual function. These domains are inhibitors was investigated in large scale trials erectile function, orgasmic function, sexual worldwide both in mixed ED populations and in desire, sexual satisfaction, and overall satisfac- subpopulations such as patients with diabetes and tion. Each question has six possible response after nerve sparing radical prostatectomy (see options with scoring between 0 (worst) and 5 Table 8). Tointerpret Table 8 correctly, it has to be (best result) [7]. Questions 1–5 have six emphasized that SEP 2 and 3 diary data were only response options from score 0 if there was no available in the tadalafil and vardenafil trials, sexual activity over the last 4 weeks to score 5 whereas in the early sildenafil trials SEP 2 and 3 if erection/sexual intercourse was always were not yet used. All three PDE5 inhibitors pro- successful. vided impressive efficacy data in a variety of ED IIEF-EF: For the evaluation of the erectile effi- subpopulations including patients with diabetes, cacy of a drug, the IIEF-EF domain, com- patients with neurological disorders such as spinal prising questions 1–5 and 15 of the IIEF, cord injuries and multiple sclerosis, patients after represents the strongest efficacy tool. A radical prostatectomy (provided they have under- score > 25 indicates normal erectile function. gone a nerve sparing procedure), patients with Sexual Encounter Profile (SEP): The SEP is a five- hypertension or CAD, and patients with renal question patient diary, which is completed by insufficiency or after kidney transplantation. the patient after each sexual encounter. The The efficacy of all PDE5 inhibitors is clearly SEP comprises the following questions: less in special ED subpopulations such as after Question 1: Were you able to achieve at least radical prostatectomy and diabetes mellitus in some erection (some enlargement of the which either the autonomic parasympathetic penis)? innervation (cavernous nerves) to the penis or the Question 2: Were you able to insert your penis functional capacity of the cavernous bodies (veno- into your partner’s vagina? occlusive dysfunction in diabetes or untreated Question 3: Did your erection last long enough hypogonadism) is clearly impaired (Table 8). for you to have successful intercourse? Long-Term Efficacy/Satisfaction Question 4: Were you satisfied with the hard- Long-term studies (2 years) have shown that effi- ness of your erection? cacy is maintained over a long period and that Question 5: Were you satisfied overall with there is no loss of efficacy, i.e., no tachyphylaxis, this sexual experience? among the three PDE5 inhibitors: sildenafil, tad- SEP question 3 (ability to complete sexual alafil, and vardenafil [42–44]. In addition, in intercourse) is considered the most rigorous and experimental research studies, no upregulation of most frequently used efficacy measure in clinical PDE5 in the penis was observed with the long- ED trials. acting PDE5 inhibitor tadalafil [45]. Chronic

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Table 8 Efficacy of the three PDE5 inhibitors in a variety of ED populations

Sildenafil/placebo (50/100 mg) Tadalafil/placebo (10/20 mg) Vardenafil/placebo (10/20 mg) ED population GAQ (%) SEP 2/3 (%) GAQ (%) SEP 2 (%) SEP 3 (%) GAQ (%) SEP 2 (%) SEP 3 (%) Mixed 82/24 66/20 81/35 Not reported 75/32 80/30 Not reported 75/39 (N = 1,600–1,787)* (N = 1,112)† (N = 601)‡ 85/28 81/52 67/33 (N = 804)§ Diabetes 56/10 48/12 64/25 57/30 48/20 72/13 64/36 54/23 (N = 268)*,¶ (N = 216)** (N = 452)†† BNSP RRP No controlled multicenter 62/23 54/32 41/19 65/13 48/22 37/10 studies (N = 303)‡‡ (N = 427)§§

*Viagra® (sildenafil citrate) U.S. label (LAB-0221-2.4, July 2005) †Brock et al. [34] ‡Porst et al. [35] §Hellstrom et al. [36] ¶Rendell et al. [37] **Saenz de Tejada et al. [38] ††Goldstein et al. [39] ‡‡Montorsi et al. [40] §§Brock et al. [41] BNSP RRP = bilateral nerve sparing retropubic radical prostatectomy; ED = erectile dysfunction; GAQ = General Assessment Question; PDE5 = phosphodiesterase type 5; SEP 2/3 = Sexual Encounter Profile 2/3

PDE5 inhibitor therapy also improved other Reasons frequently mentioned for early discon- sexual domains such as orgasmic function and tinuation of PDE5 inhibitor therapy are listed in overall satisfaction with the sexual experience and Table 9. quality of life [46]. In addition, improvement of depressive symptoms [46] and increases in Nonresponders to PDE5 Inhibitors partner satisfaction with sexual life were repeat- Considering all the data of clinical trials with edly reported with the use of PDE5 inhibitors PDE5 inhibitors, between 30% and 40% of a [47–49]. mixed ED population of patients do not suffi- First-Dose Success ciently respond to the maximum dose of the PDE5 Large cohort studies were able to show that even inhibitor. As mentioned above, responsiveness to with the very first dose of a PDE5 inhibitor, the PDE5 inhibitors depends on the underlying etiol- overwhelming majority of patients could be suc- ogy of ED and is clearly less favorable in all ED cessfully treated, e.g., 87% SEP 2 rates (successful etiologies, which are associated with either vaginal penetration) for vardenafil 10 mg [50] and damage to the penile autonomic nerve supply or 79% SEP 2 rates for tadalafil 20 mg [51]. linked to veno-occlusive dysfunction. However, it has also been shown in clinical trials Real nonresponders mostly have severe end-organ that it takes the majority of couples between three failure, which means that the cavernosal tissue has to eight attempts (2–8 weeks) before the maximum lost a considerable portion of its functional smooth efficacy of either PDE5 inhibitor is reached musculature [56]. In the clinical setting, these [35,52]. PDE5 inhibitor nonresponders show severe veno- Treatment Adherence/Discontinuation Rates The advent of PDE5 inhibitors has revolutionized Table 9 Reasons for early discontinuation of sildenafil the management of ED. Many experts expected therapy (N = 726, response rate to sildenafil = 67%, that with easy oral administration of a small pill, discontinuation rate of sildenafil responders = 53%; the high discontinuation rates previously observed source: Jiann et al. [54]) with intracavernosal injection therapy would dis- Reasons for dropout (several options possible) N (%) appear. However, against all expectations, this was Efficacy below expectations 104 (42.3) not the case. Even with the ease of oral drug High cost 93 (37) therapy, unexpectedly high drop-out rates were Loss of interest in sex 75 (30.5) Inconvenience in obtaining sildenafil 71 (28.9) reported ranging between 45% and 78% after Recovery of erectile ability 37 (15) 6–24 months, depending on the population being Partner reluctance 36 (14.6) treated and the specialization of the physicians Side effects 29 (11.8) Other reasons 59 (24) prescribing the pill [53–55].

J Sex Med 2013;10:130–171 Conservative Treatment of Erectile Dysfunction 141 occlusive dysfunction with many of them also differences of PDE5 inhibitors: Onset of action failing to respond to intracavernosal injection of and maximum efficacy of sildenafil and vard- vasoactive drugs such as alprostadil or trimix com- enafil are clearly dependent on food intake bination. This veno-occlusive dysfunction, also and content. known as venous leak or cavernous insufficiency, is Maximal efficacy, i.e., time to maximal plasma frequently associated with severe impairment of concentrations of tadalafil, shows a broad the penile arterial blood supply, also known as individual range between 30 and 720 minutes. “arteriogenic” ED. In rare individuals, best efficacy may not occur According to an international expert panel, the until 12 hours after dosing. definition of a nonresponder to oral pharmaco- 2. Optimal treatment of concomitant diseases: therapy for ED is as follows [57]: Optimal diabetes control mirrored by gycosy- lated hemoglobin [61] or treatment of hyper- “Any patient who, after four successive or closely timed trials of the maximum tolerated dose of the medication, tension with more erection protective drugs in accordance with the regulatory agency’s guidelines such as angiotensin receptor blockers, sartans, with respect to timing relative to meals, alcohol inges- tion, use of concomitant medications and adequate or the beta-blocker nebivolol [8] may improve sexual stimulation, is unable to achieve or sustain responsiveness to PDE5 inhibitor therapy. In adequate penile rigidity until completion of sexual addition, treatment of hypercholesterolemia performance.” with statins such as atorvastatin may improve erectile function per se due to the fact that “Pseudo-nonresponders” statins decrease low-density lipoprotein Many so-called nonresponders may be rescued (LDL) levels and subsequently reduce the through appropriate counseling regarding specific negative effect of oxidized LDL on endothe- drug-related pharmacokinetics/dynamics, change lial function [62] or may increase the efficacy of sedentary lifestyle, adequate treatment of con- of PDE5 inhibitors if given simultaneously comitant diseases, and/or exchange of concomi- [63]. tant medications in favor of more erection 3. Treatment of concomitant hypogonadism: It has protective drugs (see antihypertensives). The defi- been shown that testosterone regulates the nition of a real nonresponder is justified if no expression of PDE5. Hypogonadal men have success is seen under the following conditions: a poorer response to PDE5 inhibitors [64] and The use of at least four tablets with the highest also other erectogenic drugs. Several studies dose of any PDE5 inhibitor at four different occa- have provided evidence that many hypogo- sions under optimal conditions (appropriate sexual nadal ED patients, originally unresponsive to stimulation and appropriate interval between PDE5 inhibitors, can be rescued by adding tablet intake and sexual activity, with sildenafil and T-replacement therapy [14–17,65,66]. These vardenafil under fasting conditions for 2 hours and findings especially apply to patients with total with tadalafil keeping an interval of at least 2 hours T values of <300 ng/dL (<10.4 nmol/L) [14]. between intake and sexual activity to guarantee 4. “High-dose” (overdosing) PDE5 inhibitor maximal plasma concentrations and maximal effi- therapy: High-dose PDE5 inhibitor therapy, cacy). In individual cases according to literature i.e., doubling the maximal dose, resulted in a reports, it has been observed that after PDE5 24% salvage rate of ED patients (N = 54) pre- inhibitor administration the following measures/ viously unresponsive to 100 mg of sildenafil actions were able to salvage “pseudo- [67]. According to the principal author’s per- nonresponders” to PDE5 inhibitors and convert sonal experience, this may also apply to vard- them to responders. enafil and tadalafil in some individual patients especially in unresponsive diabetics. 5. Shifting patients to another PDE5 inhibitor: Measures to Improve Responsiveness to Shifting of real nonresponders from sildenafil PDE5 Inhibitors to vardenafil resulted in a rescue/success rate 1a. Recounseling of the patients/couples in the appro- of 12% [68]. According to the principal priate use of PDE5 inhibitors [58–60]: Early author’s personal experience with more than adjustment of dosing to the highest doses 7,000 patients on PDE5 inhibitors, only a resulted in salvage rates of up to 60%. small minority (5–8%) of real nonresponders 1b. Reeducation regarding the pharmacokinetic/ to one PDE5 inhibitor are satisfactorily dynamic characteristics and the individual rescued by another one.

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precise specificity. All currently available PDE5 inhibitors have some inhibitory effects on other PDE enzymes as well. Because these enzymes are widely distributed in our body, the inhibition of PDE5 and other isotypes cause special organ-/ tissue-related undesired effects. The typical side- effect profiles of sildenafil, tadalafil, and vardenafil are shown in Table 10. Whereas headache, flushing, dyspepsia, and rhinitis are typical side effects for all three PDE5 inhibitors, back pain and myalgia are more com- Figure 7 Nonresponders to the highest dose of tadalafil monly reported with tadalafil. In contrast, color 20 mg on demand could be converted to responders by vision disturbances are nearly exclusively observed once a day tadalafil 10 mg (reprinted with permission from with sildenafil because of its partial inhibition of [69]). SEP 3 = Sexual Encounter Profile 3 PDE6, an enzyme located in the retina, and responsible for brightness sensitivity and color discrimination. 6. Daily dosing of PDE5 inhibitors: Daily dosing of The side-effect profiles of sildenafil, vardenafil, tadalafil [69] or sildenafil [70] for several and tadalafil as reported in the most recent U.S. months in patients previously unresponsive to label revisions are shown in Tables 11–13. on-demand therapy at maximum doses sal- vaged more than 50% of failures. Although Cardiovascular Safety of PDE5 Inhibitors in salvage was proven in these preliminary small Clinical Trials series for tadalafil and sildenafil, it can be Shortly after gaining regulatory approval of the assumed that this concept may apply also for PDE5 inhibitor sildenafil in the United States, other PDE5 inhibitors, in particular in patients with severe organic ED (Figure 7). Table 10 Frequent (>2%) side effects of the three phosphodiesterase type 5 inhibitors: sildenafil, tadalafil, and vardenafil (sources: Padma-Nathan et al. [72], Kloner Preference Studies Between Marketed et al. [73], and Brock et al. [34]) PDE5 Inhibitors Sildenafil [72] Vardenafil [73] Tadalafil [34] Several sponsored and independent nonsponsored Side effects (N = 5,918) (N = 2,203) (N = 804) studies have investigated whether patients/couples Headache 14.6% 14.5% 14% prefer one PDE5 inhibitor over others after Flush 14.1% 11.1% 4% patients tried sildenafil, vardenafil, and/or tadalafil Dyspepsia 6.2% 3.7% 10% over a reasonably long period of time. A recent Rhinitis 2.6% 9.2% 5% Back pain 0% 0% 6% review of the literature from 2000 to 2010 on this Color visual 5.2% 0% 0% topic concluded that preferences of the patients/ disturbances couples were the following [71]: Vardenafil: 12–20% Sildenafil: 8–30% Table 11 Side-effect profile of sildenafil (Viagra®) (source: Viagra®, U.S. label LAB-0221-11.1, revised Tadalafil: 52–65% January 2011): adverse events reported by Ն2% of The reasons for preference of tadalafil were patients treated with Viagra® and more frequent on drug than placebo in Pro Re Nate (PRN) flexible dose phase mainly because of the longer duration of action II/III studies that increased patients’ freedom and spontaneity Viagra® Placebo in sexual life. In general, the authors found a con- Adverse event (N = 734) (N = 725) sistency in patients’ preference for tadalafil over Headache 16% 4% sildenafil or vardenafil across the studies reviewed. Flushing 10% 1% Dyspepsia 7% 2% Safety and Drug-Related Adverse Events of Nasal congestion 4% 2% Urinary tract infection 3% 2% PDE5 Inhibitors Abnormal vision 3% 0% The side-effect profile of the PDE5 inhibitors is Diarrhea 3% 1% mainly related to its mechanism of action, i.e., Dizziness 2% 1% Rash 2% 1% inhibition of the PDE5 enzyme and their lack of

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Table 12 Side-effect profile of tadalafil (Cialis®): treatment-emergent adverse events reported by Ն2% of patients treated with tadalafil (10 or 20 mg) and more frequent on drug than placebo in the eight primary placebo-controlled phase III studies (including a study in patients with diabetes) (source: U.S. label 2007)

Percentage of patients reporting event Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 20 mg Adverse event (N = 476) (N = 151) (N = 394) (N = 635) Headache 5% 11% 11% 15% Dyspepsia 1% 4% 8% 10% Back pain 3% 3% 5% 6% Myalgia 1% 1% 4% 3% Nasal congestion 1% 2% 3% 3% Flushing* 1% 2% 3% 3% Pain in limb 1% 1% 3% 3%

*The term flushing includes facial flushing and flushing. concerns about its cardiovascular safety profile and mass media regarding the cardiovascular were expressed in the mass media, after some safety of these agents prompted their manufactur- unexpected deaths were linked to its use. The gen- ers to invest in a comprehensive clinical research erally negative perception in the public domain program evaluating safety. As shown in Table 14, all trials demonstrate the risk for myocardial infarction and death per 100 Table 13 Adverse events reported by Ն2% of patients patient years among those exposed to PDE5 treated with vardenafil (Levitra®) and more frequent on inhibitors was not greater than that associated with drug than placebo in fixed and flexible dose randomized controlled trials of 5, 10, or 20 mg of vardenafil (Levitra®) placebo. In addition, several trials in patients with (source: U.S. label 2007) CAD were able to confirm that PDE5 inhibitors do not have any detrimental effect on cardiovascu- Percentage of patients reporting event lar safety, a finding that also applied to patients Vardenafil using antihypertensive agents. Moreover, many Placebo (Levitra®) Adverse event* (N = 1,169) (N = 2,203) patients currently receiving nitrates can stop their use on the recommendation of a cardiologist, Headache 4% 15% Flushing 1% 11% without experiencing adverse cardiovascular con- Rhinitis 3% 9% sequences, allowing subsequent use of a PDE5 Dyspepsia 1% 4% inhibitor [77]. Accidental injury 2% 3% Sinusitis 1% 3% In this context, it once more should be empha- Flu syndrome 2% 3% sized that concomitant use of any nitrates or NO Dizziness 1% 2% donors (molsidomine and others) containing Increased creatine kinase 1% 2% Nausea 1% 2% medications and PDE5 inhibitors is absolutely contraindicated because of the potential danger of *All the events listed in the table above were deemed to be adverse drug reactions with the exception of accidental injury. life-threatening hypotension.

Table 14 Cardiovascular safety of the three PDE5 inhibitors: sildenafil, tadalafil, and vardenafil)

Tadalafil treated Demographics Sildenafil* Vardenafil†,‡ Tadalafil (controlled trials)§ patients in all trials§ Study drug Placebo Active Placebo Active Placebo Active Active No. of patients 3.627 5.148 793 1.812 2.118 5.228 10.480 Mean age (years) 54 54 57 57 55 55 Not reported Hypertension 28% 26% 35% 26% 27% Not reported Diabetes 26% 22% 30% 20% 20% Not reported CAD 10% 11% 7% Not reported Not reported Dyslipidemia 12% 13% 24% 16% 15% Not reported MI/insult rate per 100 patient years 0.84 0.80 0.4 0.05 0.41 0.26 0.33 Cardiac death per 100 patient years 0.19 0.23 0% Not reported 0.12

*Mittelman et al. [74] †Kloner et al. [73] ‡Reffelmann et al. [75] §Kloner et al. [76] CAD = coronary artery disease; MI = myocardial infarction; PDE5 = phosphodiesterase type 5

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Special Safety Issues with PDE5 Inhibitor Use Table 15 Efficacy results of vardenafil ODT trials: mean scores, differences between placebo and vardenafil ODT Ocular Safety [82] In recent years, reports in the lay press that PDE5 inhibitors may cause blindness due to the POTENT I study POTENT II study so-called nonarteric anterior ischemic optic neuropa- Vardenafil Vardenafil thy (NAION) made patients and physicians Efficacy Placebo ODT Placebo ODT unsure about the safety of these medications. IIEF-EF 14.4 21.5 15.0 22.9 Interestingly, the U.S. Food and Drug Adminis- SEP 2 46.7 73.7 48.8 76.1 SEP 3 26.7 64.9 30.7 69.6 tration (FDA) reports that no causal connection between the cases reported and the use of PDE5 POTENT I: study conducted in Europe and South Africa POTENT II: study conducted in the United States, Canada, Mexico, and inhibitors exists; the PDE5 manufacturers were Australia IIEF-EF = International Index of Erectile Function-erectile function domain; requested to include in their new label warnings ODT = orodispersible tablet; SEP 2/3 = Sexual Encounter Profile 2/3 about a higher likelihood for developing NAION among the following: age > 50 years, heart disease, diabetes, hypertension, high cholesterol, Vardenafil Orodispersible Formulation nicotine use, and certain eye problems. Several recent review articles based on the analyses of Just recently, a new formulation of vardenafil was databases pertaining safety came to the conclu- introduced in the market called vardenafil orodis- sion that there is no causal link between sildenafil persible tablet (ODT) 10 mg. This vardenafil and cardiovascular events nor are there any new ODT is applied on the tongue without the need safety risks relating to cardiovascular events, pri- of water or any other fluid and provides a rapid apism, NAION, hearing loss, or drug interac- disintegration within the mouth before swallow- tions [78]. However, basic recommendations were ing [82]. The two international studies conducted given that despite the absence of a proven link with that new ODT formation showed a similar between PDE5 inhibitor use and serious ocular efficacy and safety profile as compared with the disorders, physicians should continue to advise oral vardenafil film-coated tablets 10 mg with patients to stop the use of a PDE5 inhibitor and SEP 3 data (completion of sexual intercourse) seek immediate medical attention in the event success at 65% and 70% (Table 15, [82]). The key of a sudden loss of vision as a safety measure pharmacokinetics of vardenafil ODT 10 mg as [79]. compared with the film-coated tablets are sum- marized in Table 16 and showed longer TMax and Hearing Safety lower CMax data for the ODT formulation but Because some cases of sudden hearing loss were 20–44% higher area under the curve, indicating a linked to the use of PDE5 inhibitors, although no higher bioavailability [83]. Whether this higher causal relationship has been demonstrated, the FDA requested a label revision stating that patients taking sildenafil, tadalafil, or vardenafil Table 16 Pharmacokinetic parameters of vardenafil and and experiencing a sudden hearing loss should its N-desethyl metabolite (M-1) after single or multiple doses of vardenafil orodispersible tablet (ODT) (without immediately stop taking the drug and seek prompt water) or a single dose of vardenafil film-coated tablet medical attention. (FCT) 10 mg in fasting patients with erectile (after Heinig et al. [83]) Reproductive Safety Vardenafil Vardenafil Because tadalafil may have an inhibitory effect on 10 mg ODT 10 mg FCT PDE11, an enzyme related in part to spermato- Men aged < 65 years genesis, concerns have been raised about the Single dose (N = 20) Day 4 Day 1 reproductive safety of this drug. In this context, AUC (mg ¥ hour/L) 29.97/48.1 23.52/57.6 two 6-month studies with 10 and 20 mg of tad- CMax (mg/L) 7.187/52.9 8.167/75.2 T1/2 (hour) 4.361/38.1 4.471/29.8 alafil once a day (OAD) given to 421 healthy men TMax (hour, median range) 1.25 (0.75–2.50) 0.75 (0.50–1.50) for 6 months [80] and a 9-month placebo- Men aged Ն 65 years controlled study with 20 mg of tadalafil covering Single dose (N = 14) Day 4 Day 1 AUC (mg ¥ hour/L) 42.16/42.6 34.88/32.1 three spermatogenesis cycles and conducted in CMax (mg/L) 8.891/60.2 11.00/54.6 253 healthy men were performed. They did not T1/2 (hour) 5.952/27.5 6.179/28.3 show any adverse effects on spermatogenesis TMax (hour, median range) 0.875 (0.50–3.00) 0.75 (0.50–3.00) [80,81]. AUC = area under the curve

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Figure 8 Historical comparison: SEP 3 question tadalafil once a day and on demand [84]. ED = erectile dysfunc- tion; SEP 3 = Sexual Encounter Profile 3 bioavailability of the vardenafil ODT formulation As illustrated in Figure 8, a historical compari- translates into any clinical advantage (longer son of data from 16 placebo-controlled trials with duration of efficacy) over the existing oral vard- tadalafil taken on demand for the treatment of ED enafil formulation remains to be shown in clinical and the results of the first large multicenter trial studies. with tadalafil OAD shows that 5 mg of OAD tad- alafil provides comparable efficacy to 20 mg of tad- alafil taken on demand ([84], data on file with Lilly Daily Dosing of PDE5 Inhibitors Corp.). Tadalafil OAD In pharmacokinetic studies with OAD tadalafil, Since 2009, tadalafil (Cialis®) has been approved steady state was attained by day 5, and accumula- for daily application (OAD) in doses of 2.5 and tion (1.6-fold) was consistent with the T1/2. From 5 mg as an alternative treatment regimen to day 5 of OAD tadalafil, plasma levels are 1.6 on-demand or p.r.n. dosing. In many countries higher as compared with the respective single dose worldwide, including most countries of the Euro- [25]: pean Union, only 5 mg of tadalafil OAD is mar- OAD tadalafil 2.5 mg ª 4–5 mg single-dose on keted. In the most recent “EAU Guidelines on demand Male Sexual Dysfunctions,” OAD tadalafil has OAD tadalafil 5 mg ª 8 mg single-dose on been officially listed as a first-line treatment of ED demand together with on-demand treatment with PDE5 OAD tadalafil 10 mg ª 16 mg single-dose on inhibitors [21]. Because of its long half-life with demand 17.5 hours as compared with PDE5 inhibitors with a half-life of about only 4 hours (i.e., sildenafil and First-Dose Success with Tadalafil OAD vardenafil), tadalafil is at present the only PDE5 Pharmacokinetic studies have proven that with inhibitor that has been approved worldwide for daily dosing of tadalafil after 5 days, a steady state daily dosing therapy. of plasma concentrations is reached equal to 1.6 Several studies have evaluated both the efficacy times a single dose [25]. In this context, a recent and safety of OAD tadalafil in doses between clinical study was able to show that from day 2, 2.5 and 20 mg and in different ED populations tadalafil OAD resulted in significant efficacy that (broad spectrum, diabetes, and lower urinary tract increased over the next 5 days ([88], Figure 9). symptoms [LUTS]/benign prostatic hyperplasia [BPH]). Both in short-term (3 months) and long- Safety of Tadalafil OAD term trials up to 2 years, tadalafil OAD was effec- As shown in Table 13, the side-effect profile of tive in the treatment of ED of various etiologies tadalafil OAD 5 mg is comparable to that of tad- even at the 2.5-mg dose without signs of tachyphy- alafil 20 mg p.r.n. Tadalafil OAD may have an laxis or increased drug-related adverse events improved side-effect profile compared with [84–87]. on-demand use, although this tendency did not

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Figure 9 Cumulative dose response with tadalafil OAD 2.5 and 5 mg in a prospective study [88]. OAD = once a day

show statistical significance with historical com- showing a 73% change rate from baseline regard- parisons from pooled data of tadalafil on-demand ing SEP 3 data and a 44% shift rate to normal trials (Table 17). erectile function (IIEF-EF < 25) for the highest udenafil dose (75 mg) investigated ([89], Table 18). Udenafil Once Daily Dosing Side-effect rates with daily dosing of udenafil were In August 2011, the results of the first daily dosing low with flushing (6.8%), headache (3.4%), and trial with udenafil, a new PDE5 inhibitor with a nasal congestion (1.7%) at the highest udenafil half-life time of about 13 hours, were published, dose.

Table 17 Historical comparison of treatment-emergent adverse events: once a day tadalafil vs. on-demand tadalafil (Porst et al. [84])

Once a day On demand

Events occurring in Ն3% of any Placebo Tadalafil 5 mg Tadalafil 10 mg Tadalafil 10 mg Tadalafil 20 mg treatment group N = 54 N = 109 N = 105 N = 441 N = 1,730 Headache 7% 6% 11% 10% 15% Dyspepsia 4% 6% 11% 6% 7% Back pain 4% 4% 10% 5% 5% Upper abdominal pain 0% 3% 9% 1% 1% Myalgia 0% 3% 7% 3% 3% Pain in limb 0% 4% 3% 2% 3% Flushing 0% 3% 3% 3% 3% Nasopharyngitis 4% 3% 1% 6% 2% Discontinuations due to adverse events 2% 3% 6% 2% 3%

PCT PRN = pooled data from 16 placebo-controlled studies (data on file with Lilly Corp.)

Table 18 Changes of secondary efficacy outcome variables after 12 weeks in the first udenafil daily dosing trial [89]

Placebo Udenafil 25 mg Udenafil 50 mg Udenafil 75 mg (N = 59) (N = 59) (N = 60) (N = 59) SEP 2 (%) 11.95 22.10 27.90* 39.11* SEP 3 (%) 23.46 42.09* 51.41* 73.50* GAQ (%) 35.60 69.50* 75.00* 88.10* Shift to normal IIEF-EF 13.60 30.50* 40.00* 44.10*

Values are changes of percentage of positive responses from baseline after 12-week treatment. P values were calculated using chi square or Fisher exact tests for comparison of subject numbers and analysis of variance for comparison of mean values. *P < 0.001 GAQ = General Assessment Question; IIEF-EF = International Index of Erectile Function-erectile function domain; SEP 2/3 = Sexual Encounter Profile 2/3

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Table 19 Prostatic and plasma concentrations of In summary, all currently marketed PDE5 phosphodiesterase type 5 inhibitors in patients with lower inhibitors have shown in randomized placebo- urinary tract symptoms due to benign prostatic hyperplasia [97] controlled trials significant efficacy improving LUTS symptoms as assessed by the IPSS [90–94], Plasma Prostate Prostate/ comparable to that of alpha blockers (Level of concentration concentration plasma (ng/mL) (ng/g) ratio Evidence 1). In addition, daily dosing of tadalafil was able to improve both ED and LUTS given Udenafil 436.7 Ϯ 39.1 2,028.6 Ϯ 360.8 4.4 Tadalafil 305.8 Ϯ 41.1 385.7 Ϯ 83.8 1.3 that both diseases are frequently present in the same patient ([93]; Figure 10). In the United States and the countries of the European Union, tadalafil Men with ED and Simultaneous LUTS/BPH OAD is approved for the treatment of both In the past years, several placebo-controlled conditions—ED and/or BPH. studies with daily dosing of both short-acting PDE5 inhibitors (i.e., sildenafil and vardenafil) and Selectively Marketed PDE5 Inhibitors long-acting PDE5 inhibitors (tadalafil and udena- fil) provided convincing evidence that daily dosing Several PDE5 inhibitors have been investigated in of PDE5 inhibitors results in relief of LUTS randomized controlled trials (RCTs) and have symptoms due to BPH, as assessed by the Interna- shown similar efficacy and safety profiles to tional Prostate Symptom Score (IPSS) score. sildenafil, tadalafil, and vardenafil. Improvements in the IPSS score after PDE5 Avanafil (VIVUS, Inc., Mountain View, CA, inhibitors were found to the same extent in terms USA) is a very short-acting PDE5 inhibitor with a of IPSS improvement as has been reported with TMax of between 0.5 and 1 hour and a T1/2 of <1.5 uroselective and nonselective alpha blockers hours [98]. In a large multicenter trial with a total [90–96]. of 646 patients allocated to either placebo or In this context, it has been demonstrated that avanafil 50, 100, or 200 mg, respectively, all doses after oral administration, both tadalafil and udena- of avanafil were significantly superior (P Յ 0.001) fil concentrations were significantly higher in the in all main end points being investigated such as prostatic tissue as compared with the maximum SEP 2, SEP 3, and IIEF-EF domain score [99]. In plasma levels and that both PDE5 inhibitors addition, the authors evaluated the window of effi- significantly increased cyclo adenosine monophos- cacy and reported that avanafil in as early as 15 phate (cAMP) and cyclo guanosine monophos- minutes and >6 hours after dosing is effective [99]. phate (cGMP) concentrations ([97], Table 19). Side effects were the same as established for other On October 7, 2011, the U.S. FDA approved PDE5 inhibitors. tadalafil (Cialis®) OAD for the treatment of men Similar results were found in a recently pub- who have both ED and the signs and symptoms of lished multicenter, randomized, double-blind, BPH. In addition, the FDA also approved tadalafil placebo-controlled, fix-dosed phase III clinical OAD for the separate indication for the treatment trial with 100 and 200 mg of avanafil involving 200 of the signs and symptoms of BPH (Figure 10). patients with ED from South Korea [100].

Figure 10 Tadalafil once a day signifi- cantly improves ED and LUTS/BPH symptoms in men suffering from both conditions [93]. ANCOVA = analysis of covariance; BPH = benign prostatic hyperplasia; ED = erectile dysfunc- tion; IIEF-EF = International Index of Erectile Function-erectile function domain; IPSS = International Prostate Symptom Score; LUTS = lower urinary tract symptoms

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Table 20 Pharmacokinetics of new phosphodiesterase similar to sildenafil, vardenafil, and tadalafil with type 5 inhibitors SEP 3 data in diabetics of 53% (udenafil 100 mg), Avanafil* Mirodenafil† Lodenafil‡ Udenafil§ and 63% (udenafil 200 mg) vs. 22% after placebo 100 mg 10 mg 160 mg 100 mg [103,106] have been reported.

TMax (hour) 0.5–1.5 1.25 1.2 1–1.5 In a published review of available udenafil, data < T1/2 (hour) 1.5 2.5 2.4 11–13 from five RCTs totaling 1,109 patients [107] *Limin et al. [98] showed that udenafil had greater efficacy than †Paick et al. [101] ‡Glina et al. [102] placebo in the change from baseline for the §Kim et al. [103] IIEF-EF score (mean difference 5.65, 95% CI 4.41–6.89, P < 0.00001). Most adverse events were either mild or moderate in severity, and no Considering the TMax of avanafil that is dis- serious adverse events were observed in these tinctly shorter than the other PDE5 inhibitors on trials. The most common drug-related adverse the market and the available data from clinical events were flushing and headache (udenafil vs. trials in terms of onset of action, it seems that placebo, 5.6% vs. 1.8% and 3.1% vs. 0%, respec- avanafil reports the quickest onset of action (see tively) [107]. Table 20). Avanafil has been recently (April 27, Udenafil was recently investigated in a daily 2012) approved by the FDA as Stendra® in the dosing trial using doses of 25, 50, and 75 mg or United States. placebo, respectively [89]. Patients taking 50 or Lodenafil (Helleva; Cristalia Pharmaceuticals 75 mg of udenafil reported better IIEF domain Ltd., Itapira, Brazil), also a short-acting PDE5 scores than placebo (Figure 11). inhibitor with TMax of 1.2 hours and T1/2 of 2.4 In conclusions on PDE5 inhibitors, at present, all hours, is approved for the treatment of ED in PDE5 inhibitors represent a first-line choice for Brazil. Two multicenter trials in a broad-spectrum the majority of all ED patients and their partners, ED population have provided SEP 3 data as shown regardless of the underlying ED etiology, and are in Table 21 [102,104]. recommended in all guidelines of urological soci- The lodenafil data show both efficacy and safety eties as first-line therapy (Level of Evidence 1). profiles comparable to sildenafil, tadalafil, and Their use in more than 100 million men worldwide vardenafil [102,104]. has shown convincing evidence of their acceptance, Mirodenafil (SK Chemicals, Seoul, South efficacy, and safety profile. In general, all PDE5 Korea), a short-acting PDE5 inhibitor with TMax of inhibitors are successfully used on an on-demand 1.25 hours and T1/2 of 2.5 hours, is available in (p.r.n.) basis. Tadalafil OAD low-dose use has been South Korea and has shown impressive efficacy approved in some markets for up to 3 years and has data in a variety of clinical trials with SEP 3 results provided similar efficacy and safety as compared of 68.9% after mirodenafil 100 mg vs. 22.3% after with the on-demand use of all other available PDE5 placebo (P < 0.0001) in a Korean diabetic ED inhibitors. (Level of Evidence 1) Tadalafil OAD population [101,105]. represents an effective, safe, and attractive alterna- Udenafil (Dong-A PharmTech Co. Ltd, Seoul, tive to the p.r.n. dosing, taking away the need to South Korea) is the only long-acting drug among schedule sexual activities and thus allowing a spon- the new PDE5 inhibitors with TMax of 1–1.5 hours taneous and natural sex life. Udenafil has also and T1/2 of 11–13 hours. The drug is licensed as shown both efficacy and safety in a daily dosing Zydena® in South Korea, Russia, and other coun- regimen but is not yet approved for chronic dosing. tries of the previous Russian Federation. In a In addition in men suffering from both ED and variety of clinical trials, efficacy and safety data LUTS, tadalafil OAD is able to treat both condi-

Table 21 Results of two different randomized, placebo-controlled, and double-blind lodenafil trials

*SEP 3 baseline *SEP 3 after †SEP 3 baseline †SEP 3 after Placebo 23.3 Ϯ 27.6% 33.6 Ϯ 42.3% 20.2 Ϯ 32.3% 29.7 Ϯ 38.1% Lodenafil 20 mg 32.3 Ϯ 38.9% 51.2 Ϯ 41.7% Not tested Not tested Lodenafil 40 mg 39.7 Ϯ 44.7% 46.7 Ϯ 41.1% 19.6 Ϯ 34.3% 50.8 Ϯ 44.4% Lodenafil 80 mg 17.2 Ϯ 29.5% 74.3 Ϯ 36.3% 20.8 Ϯ 33.2% 66.0 Ϯ 39.3%

*Glina et al. [102] (P < 0.05 for difference to placebo) †Glina et al. [104] (P < 0.01 for difference to placebo) SEP 3 = Sexual Encounter Profile 3

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Figure 11 Results of the various IIEF domains in the randomized, placebo- controlled, double-blind once daily dosing trial with udenafil 25, 50, and 75 mg [89]. IIEF = International Index of Erectile Function tions successfully with one pill (Level of Evidence induced CC relaxation was inhibited by 1) and has recently received the official approval for mechanical removing of the endothelium and by both indications in several markets worldwide. blocking NO synthesis or signaling via guanylate cyclase and cGMP formation [109]. In contrast, inhibition of cGMP degradation strongly Oral Therapies Other than PDE5 Inhibitors increased yohimbine activity. In an experimental Yohimbine chemical castration model, conducted in rabbits Yohimbineis the main alkaloid from the bark of the by chronic treatment with a long-lasting Gona- tree called Coryanthe johimbe K. Schum (yohimbehe dotropine Releasing Hormone (GnRH) agonist, tree), particularly growing in Central Africa. The the relaxant yohimbine activity was also alkaloid was first isolated from the bark of the decreased but completely restored by androgen yohimbehe tree (hence the name) by L. Spiegel in supplementation [109]. These experimental data 1896. The bark of this tree is still used today as the indicate that yohimbine’s efficacy in ED is not raw material for the various yohimbine prepara- only due to its inhibitory effects on the tions. First information on its use combined with presynapticalpha1-adrenoceptor activity in the papaverine to treat ED was published in 1923 [108]. cavernous smooth muscle cells but also includes Until the launch of sildenafil and the other PDE5 an impact on NO and cGMP formation involv- inhibitors, yohimbine was the most prescribed sub- ing endothelium and endothelial nitric oxide stance worldwide for the treatment of ED. synthase (eNOS) activity which again is test- osterone dependent. Pharmacological Profile The sites of action of yohimbine are the following: Pharmacokinetics and Dosage Yohimbine hydrochloride is orally well absorbed Central: Unlike alpha adrenoceptors, cerebral 1 and has a plasma half-life of between 0.25 and 2.5 alpha adrenoceptors mediate erection- 2 hours. However, the effects triggered by yohim- inhibiting impulses. Yohimbine facilitates erec- bine, which can be traced back to an increase in tion in part through a central level. plasma norepinephrine, may last for more than 13 Peripheral: Yohimbine directly blocks alpha 2 hours. Only about 1% of yohimbine appears in the adrenoceptors that dominate in the penile arter- urine, indicating a predominantly hepatic clear- ies. It is believed to counteract the vasoconstric- ance [110]. tion induced by norepinephrine/epinephrine Doses described both in trials and in the litera- release and in turn the reduction in blood flow. ture ranged commonly from 5 to 15 mg three Endothelium and androgen-dependent NO forma- times a day [111]. tion: Experimental studies aimed at exploring yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC) have provided Efficacy evidence that yohimbine interferes with NO The efficacy and safety of yohimbine have been release from the endothelium: yohimbine- analyzed in numerous studies, some of them with

J Sex Med 2013;10:130–171 150 Porst et al. a placebo-controlled, double-blind, prospective A high-dose, prospective, randomized, double- design. The efficacy rates ranged from no effect to blind, and placebo-controlled study with 5 g of 71% as compared with 40% for placebo in nonor- L-arginine per day for 6 weeks was conducted in ganic impotence. A meta-analysis of seven large 50 patients (aged 55–75 years) with organic, com- yohimbine studies, which met strict quality crite- plete ED (unable to perform coitus) for at least 6 ria, showed a superiority of yohimbine vs. placebo. months [115]. This study resulted in a success rate Based on these data, the authors concluded that (sexual intercourse possible) of 31% in the there is a rationale for the use of yohimbine in L-arginine group compared with 12% in the suitable ED patients [111]. The Clinical Guide- placebo arm. It was interesting to note that signifi- lines Panel on Erectile Dysfunction of the Ameri- cantly higher urine concentrations of the stable can Urological Association (AUA) concluded that NO metabolites NO2 and NO3 were measured in the data currently available on yohimbine do not the L-arginine responders than in the nonre- allow it to be recommended as standard treatment sponders, although the responders had lower urine in ED, particularly not in organic etiologies, and concentrations of NO3 prior to treatment. Thus, this statement of the AUA ED Guideline Panel the question arises as to whether supraphysiologic was not changed with the 2005 update [112]. doses of L-arginine given over a long period of Apart from its use in ED yohimbine has also time can lead to a permanent improvement in cav- been reported effective in orgasmic disorders, i.e., ernous function in some ED patients. No side delayed ejaculation or orgasm [113]. effects were observed except a fall in maximal blood pressure of 10% in some patients, which did Side Effects and Contraindications not result in clinical symptoms. The common side effects observed with yohim- Just recently, the results of a double-blind, bine can mostly be traced back to its partially placebo-controlled study with Prelox® (Horphag increased sympathetic activity: anxiety, nausea, Research Ltd, Geneva, Switzerland; commercially restlessness, agitation, sleeplessness tachycardia, available L-arginine product in some European palpitations, diarrhea, and manic symptoms. In countries) in 124 patients (aged 30–50 years) with addition, yohimbine is reported to either increase moderate ED over an investigational period of 6 or more infrequently decrease blood pressure, months were published [116]. The IIEF-EF which may be clinically relevant if hypertensive improved after Prelox® from a baseline mean patients are taking this medication. In cases of (standard deviation) score of 15.2 (6.6) to 25.2 severe CVD such as unstable angina or recent (2.1) after 3 months and to 27.1 (2.1) after 6 myocardial infarction, difficult to treat hyperten- months of treatment. sion and severe psychiatric diseases, as well as The corresponding figures in the placebo severe hepatic impairment, should be considered group were from baseline 15.1 (7.0) to 19.1 (3.0) contraindications for yohimbine use. and 19.0 (3.1) after 3 and 6 months, respectively. In conclusions on yohimbine, if yohimbine has any The effects with Prelox® were statistically sig- potential indications for use in ED management, it nificant compared with placebo (P < 0.05). It is would be among nonorganic ED. In these notable that these efficacy data for Prelox® show patients, yohimbine may be used for a maximum of an increase of mean IIEF-EF score of 11.9. This 2 months either as a regular regimen (3 ¥ 5– exceeds the improvements in IIEF-EF score of 10 mg/day) and has shown in a review a superiority about 8–10, which were achieved in clinical trials to placebo (Level of Evidence 1b). Apart from ED, with the highest doses of PDE5 inhibitors. These yohimbine has shown a limited efficacy in the exceptional results with Prelox® must of course medical treatment of delayed ejaculation. be reproduced in other large multicenter RCT studies in order for L-arginine (here L-Arginine Prelox®) to be accepted as first-line therapy for L-arginine is the precursor of NO synthesis ED. (Figure 6). Zorgniotti and Lizza conducted a In conclusions on L-arginine, at present, no rep- placebo-controlled study with 2,800 mg of resentative and reliable data from multicenter L-arginine per day in 20 impotent men for 2 well-designed randomized trials are available pro- weeks. Of the 15 men who completed the study, six viding evidence of significant efficacy of reported an improvement in their ability to L-arginine in a broad-spectrum ED population. achieve an erection and nine experienced no The trials published on L-arginine and its effects improvement [114]. in ED are at best a Level of Evidence 2b that

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The Impact of PGE1 (Alprostadil) on Erectile Function

PGE1 NANC-Nerve - EP + stimulation Endothelial cell Rec. - + converting Ang Ienzyme Ang II + + + Inhibition NA-release EP-receptor AT -receptor alpha -receptor AT1-receptor 2 1 Gs -Protein + Adenylate Zyklase L- type + - Figure 12 Sites of action of PGE1 ++ ++ Ca ATP 3´5-cAMP Ca - - [23]. AT1 = Angiotensin 1; AT2 = Ca++ Ca++ Angiotensin 2; 3’5’-cAMP = cyclo channel adenosine monophosphate; EP = E- Contraction Relaxation Contraction Prostaglandin; NA = Noradrenaline; NANC = non adrenergic non cholin- ergic; PGE1 = Prostaglandin E1

L-arginine may work in ED patients of not closely investigated the efficacy of topical application on specified ED etiology. the glans penis to reach the corpus cavernosum [117]. Drugs used in small trials with very limited Apomorphine SL number of patients were minoxidil solution, nitro- With Apomorphine SL, a central dopamine- glycerin ointment, and papaverine gel. None of receptor agonist, a comprehensive clinical phase these drugs was neither investigated in larger trials I–III developmental program was conducted, nor reached market approval mainly because of finally resulting in the official approval of Apomor- limited efficacy. phine sublingual tablets 2 and 3 mg (Ixense®, Tokyo, Takeda Pharma, Japan; and Uprima®, Topical Therapy with Prostaglandin E1 (PGE1, Abbott Laboratories, Abbott Park, IL, USA) in Synonymous Alprostadil) Europe 10 years ago. Because of its significantly inferior efficacy as compared with that of PDE5 Sites of Action of PGE1 inhibitors, the drug was withdrawn from the Euro- PGE1 induces relaxation of corpus cavernosum pean market. Because Apomorphine SL is, to the smooth musculature through binding at knowledge of the authors, at present not marketed E-prostaglandin receptors and activating the and therefore not officially available in pharmacies membrane bound adenylate cyclase, resulting in in any major regions of the world such as America, an increase of intracellular concentrations of Asia, and Europe, no further details on Apomor- cAMP in the cavernous tissue [118]. Further con- phine are provided in this standard operation pro- sequences of the PGE1-mediated relaxation of cedures (SOP) on ED. human corpus cavernosum are the activation of Maxi K channels, resulting in hyperpolarization Topical Therapy and changes in transmembrane Ca2+ flux [119]. Several drugs have been investigated in the past for These effects are complemented by PGE1- topical application such as ointment/gel either on induced inhibition of the release of noradrenaline the glans penis or the penis shaft skin. The chal- from sympathetic nerve endings [120] and the sup- lenge with topical therapy is to reach the level of pression of angiotensin II secretion in the cavern- the CC, i.e., agents applied on penile skin have to osal tissues [121] (Figure 12). permeate fascial layers and the tunica albuginea, which means thick layers of collagen. In view of Topical Alprostadil (Synonymous PGE1) the proven existence of venous communications With a special topical PGE1 preparation, two between CC and glans penis, some studies have large randomized placebo-controlled double-blind

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erythema (11.3%) and resolved in the majority within 2 hours. Partners complained in 4.4% of vaginal burning and in 2.1% of vaginitis. In conclusions on topical PGE1, compared with oral PDE5 inhibitor therapy with IIEF-EF changes between four and nine depending on dose and study population, topical alprostadil cannot be considered an effective monotherapy for ED (Level of Evidence 1b). Topical PGE1 may be useful in combination therapy with oral drugs if they show limited efficacy; however, data on com- Figure 13 Integrated analysis of two phase III trials with bination therapies with topical PGE1 (Vitaros, topical alprostadil (PGE1): SEP 3 data [122]. PGE1 = prostaglandin E1; SEP 3 = Sexual Encounter Profile 3 Apricus Bio, San Diego, CA, USA) are not avail- able. Topical PGE1 is produced by the U.S.-based trials with doses of 100, 200, and 300 mg of alpros- NexMed Inc., a wholly owned subsidiary of tadil were conducted and the integrated results Apricus Biosciences, with its special NexACT® were published some years ago [122]: a total of drug delivery technology and has recently been 1,732 patients (21% diabetes, 44% hypertension, filed for approval in some countries. It is approved 12% radical retropubic prostatectomy [RRP], in Canada. 21% CAD, and 16% nitrate- or alpha-blocker Transurethral Alprostadil (PGE1) with Medicated medication) received either placebo (N = 434) or Urethral System for Erection (MUSE®) topical alprostadil cream at 100 (N = 434), 200 A new alprostadil preparation using a transurethral (N = 430), or 300 mg(N= 434). The mean application with a small applicator for single use changes of the IIEF-EF domain scores from base- was introduced in 1994 and later on after succesful line to end point were -0.7, 1.6, 2.5, and 2.4 points phase II/III clinical development program mar- for each group, respectively (P < 0.001). Scores on keted as MUSE® (MEDA Pharma GmbH, SEP questions 2 and 3 improved slightly but sig- Wangen-Brüttisellen, Switzerland). Although the nificantly for all drug treatment groups compared transurethral application route seemed at first with placebo (P < 0.001, Figure 13, Table 22). glance to be preferable to intracavernosal self- Adverse events were mainly limited locally to the injection therapy, this new medical therapy pro- application site with penile edema (1.4%), genital vided limited efficacy data especially in direct pain (17.5%), penile burning (23%), and penile comparative trials with intracavernously injected alprostadil (e.g., Caverject®, Edex®, and Viri- Table 22 Efficacy end points of alprostadil topical cream dal®), as is shown in Table 23. MUSE® is applied studies: results of an integrated analysis of two into the moistened urethra through the external multicenter trials in 1,732 patients [122] orifice directly after emptying the bladder Alprostadil Topical Cream (Figure 14). Placebo 100 mg 200 mg 300 mg Typical frequent side effects of MUSE® are (N = 411) (N = 418) (N = 410) (N = 410) penile/urethral pain between 25% and 43% and IIEF-EF Baseline 14.0 13.6 13.6 13.6 End point 13.3 15.3 16.1 16.1 Table 23 Review of the literature: efficacy rates of Mean change -0.7 1.7 2.5 2.5 transurethral alprostadil (MUSE®) vs. self-injection P value* 0.001 <0.001 <0.001 therapy with alprostadil (Caverject®, Viridal®, and Edex®) SEP 2 (from Porst and Adaikan [123]) Baseline 55.9 53.4 52.9 49.9 End point 51.2 56.6 58.2 57.5 No. of Mean change -4.7 3.2 5.3 7.6 Author patients MUSE® i.c. alprostadil P value* 0.001 <0.001 <0.001 SEP 3 Ghazi, 1998 [124] 125 48% (61) 79% (98) Baseline 29.4 31.3 27.6 28.7 Werthman, 1997 [125] 100 37% 89% End point 30.3 38.9 41.9 38.5 Porst, 1997 [126] 103 43% (44) 70% (72) Mean change 0.8 7.6 14.3 9.8 Shabsigh, 1998 [127] 106 27% 66% (buckling test) P value* 0.001 <0.001 <0.001 Shabsigh, 2000 [128] 68 53% 83% (at home use) Flynn, 1998 [129] Literature 45% >70% *Least square difference relative to placebo from ANCOVA review ANCOVA = analysis of covariance; IIEF-EF = International Index of Erectile Function-erectile function domain; SEP 2/3 = Sexual Encounter Profile 2/3 MUSE = Medicated Urethral System for Erection

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Figure 14 Technique of transurethral PGE1 application with MUSE®. PGE1 = prostaglandin E1 urethral bleeding (around 5%). Infrequent adverse about a soft (cold) glans syndrome, which some- events are dizziness because of blood pressure fall times occurs after insertion of a penile implant or (1–5%) and even the occurrence of syncope as a clinical entity. between 0.4% and 3% [123]. Of importance, in order to achieve the best effi- Vasoactive Drugs Used for Intracavernosal cacy with MUSE® and to avoid transurethral Self-Injection Therapy bleeding, a correct technical application is essen- In general worldwide, the following vasoactive tial, i.e., to insert MUSE® directly upon micturi- drugs are/were used both for diagnostic and thera- tion with the urethra still being moist. peutic purposes in the management of ED: The efficacy of MUSE® may be enhanced by simultaneous application of a constriction band PGE1 (synonymous alprostadil) (trade names: on the penis’ base to avoid fast drainage of the Caverject®, Edex®, and Viridal®) [127–129] medication through the penile veins. Papaverine (several generics available worldwide) Successful salvage of nonresponders to mono- Combination of papaverine/phentolamine—bimix therapy either with sildenafil or MUSE® by com- (trade name: Androskat®: only in some Euro- bination of both methods was reported by several pean countries available) authors [130,131]. Trimix (synonymous triple drug): mixture of PGE1/ Successful use of transurethral alprostadil in papaverine/phentolamine (worldwide, no com- men with the so-called soft (cold) glans was reported mercial product available; this combination is in 23 out of 28 men after insertion of a penile often reconstituded by pharmacists on an indi- implant [132]. vidual prescription basis) In conclusions on transurethral PGE1 (MUSE®), Combination of vasoactive intestinal polypeptide (VIP) transurethral alprostadil therapy with MUSE® and phentolamine (trade name: Invicorp®, only has shown significant efficacy in a variety of ED available in Europe on patient named prescrip- populations as compared with placebo (Level of tion basis) Evidence 1a), but because of its inferior efficacy both with regard to PDE5 inhibitors and intrac- PGE1 (Synonymous Alprostadil), Papaverine, avernosal self-injection therapy, transurethral Combination of Papaverine/Phentolamine alprostadil therapy with MUSE® must be consid- ered a niche therapy in ED. The main indications Diagnostic Use for MUSE® are patients who are nonresponsive The above-mentioned vasoactive drugs are used to PDE5 inhibitors due to damage of the auto- for diagnostic purposes to investigate cavernosal nomic penile nerve supply (radical prostatectomy, relaxation capacity and in combination with penile cystectomy, and trauma) or in combination with Doppler/duplex to investigate the penile vascular PDE5 inhibitors in the so-called poor responders system. When used for diagnostic purposes (only to oral therapy. Another rare indication for tran- marketed drugs considered), the response rates surethral PGE1 are those patients complaining (complete erection) were highest for PGE1 with

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Table 24 Efficacy of vasoactive substances in the diagnosis of ED. Literature review of evaluable publications (from Porst [133])

No. of Substance Dose (min/max) Publications patients Responders Papaverine 30–110 mg 19 2,161 61% (987 out of 1,616) Papaverine/phentolamine 15 mg/1.25 mg 13 3,016 68.5% (2,065 out of 3,016) 60 mg/2 mg PGE1 (alprostadil) 5 mg–40 mg 27 10,353 72.6% (7,519 out of 10,353)

ED = erectile dysfunction; PGE1 = prostaglandin E1 about 73% efficacy and lowest for papaverine with alprostadil sterile powder (Viridal®/Edex®) were about 61% efficacy ([133], Table 24). very high, ranging between 91% and 96%, once a patient was successfully introduced to intracaver- Therapeutic Use nosal self-injection therapy [135]. Depending on both the availability and the physi- The injection frequency in various PGE1 self- cian’s personal preference/experience, the injection studies ranged between two and four per outcome of self-injection therapy in a representa- month [135–138]. tive number of patients was reported in the litera- The satisfaction rates with intracavernosal self- ture with papaverine, the mixture of papaverine/ injection therapy with PGE1 compared with that of phentolamine, or with PGE1. oral drug therapy were evaluated in a study among In this context, only with PGE1 two well- previous PDE5 inhibitor failures. In an analysis designed prospective long-term trials with comprising 596 patients with a mean age of 62.1 follow-up of 4 and 5 years, respectively, were pub- years, mean duration of ED of 61 months, and mean lished in the literature [135,136]. duration of PGE1 ICI treatment of 35 months, the authors reported the following results [138]: Before introduction to intracavernosal self- PGE1 (Alprostadil—Caverject®, Viridal®, and injection therapy, 43% of patients had taken at Edex®) least one PDE5 inhibitor and 81% discontinued The common doses used with PGE1 depend on this therapy because of treatment inefficacy. The the underlying ED etiology and the residual relax- overall satisfaction rate with ICI was 78.3% and ant capacity of the cavernous bodies. In this ICI met expectations each time in 78.6% of context in a longitudinal study (N = 1.687), it has patients and at least half the time in 90% of been shown that men with a poor response to patients; 86% of the patients would recommend intracavernosal PGE1 testing had both a higher ICI to friends. Patients reported improvements in prevalence of hypogonadism-related symptoms their sex life (70.1%), relationship with their and signs along with lower T levels and a higher partner (50%), quality of life (44.8%), and confi- incidence of major adverse cardiovascular events, dence in attempting sexual intercourse (80.3%). with a hazard ratio of 2.745 (P < 0.05) [134]. Both The mean number of injections was 4.4 per prevalences of diabetes and metabolic syndrome month. Most patients (81.1%) found the injections were inversely related to intracavernosal injection easy to use. The mean score for pain on injection (ICI) test response [134]. Doses used in ED usually was 2.09/10 and for pain on erection was 2.15/10. range between 5 and 40 mg, with the most Three-quarters of patients (73.1%) thought that commonly used doses between 10 and 20 mg their partners were satisfied with ICI [138]. [135–138]. Table 25 Number of successful injections resulting in In patients after pelvic surgery (RRP and cys- sexual intercourse in the prospective European trial with tectomy), the initial dose should be chosen at 5 mg alprostadil sterile powder (source: Porst et al. [135]) because of the higher risk of priapism and in No. of total No. of successful patients after cavernous nerve injury the use of Year follow-up injections injections Percentage PGE1 is associated with pain, which occurs less First year 6,935 3,937 91 often with papaverine/phentolamine combinations Second year 3,937 3,691 94 or trimix solutions. Third year 3,233 3,050 94 As shown in Table 25, the individual long-term Fourth year 2,781 2,679 96 Total 16.886 15.713 93 success rates in the European prospective trial with

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In another study, patients’ satisfaction rates with PGE1-induced erections at home were 67.3% [137]. In both multicenter long-term trials with PGE1 (alprostadil sterile powder and Alprostadil Alfadex), patients’ self-esteem as well as patients’ and partners’ satisfaction with sex life increased significantly [135,136,139].

Return of Spontaneous Erections A return or improvement of spontaneous erections while on intracavernosal self-injection therapy with PGE1 demonstrates a wide range with studies reporting between 37.3% and 85% [137,140]. Although many patients on intracavernosal self- injection therapy report an improvement of spon- taneous erections, only a minority of patients can give up this therapy because they are considered cured [141].

Papaverine/Phentolamine Combination (Androskat®) The mixture of papaverine/phentolamine also often referred to as bimix is commercially available and approved as Androskat® in several countries worldwide, especially in Europe. Androskat® is marketed in 2-mL ampoules containing 15 mg of papaverine and 0.5 mg of phentolamine per 1 mL, i.e., a total content of 30 mg of papaverine + 1mg

of phentolamine per ampoule. As a rule of thumb, 6 hours Fibrosis Pain Elevated liver enzymes the efficacy of one ampoule of Androskat® is com- > parable to 10 mg of alprostadil and two ampoules of Androskat® to 20 mg of alprostadil ([133], Table 24).

Side Effects of Injectable Vasoactive Drugs A review of the side-effect profile of intracavern- osal vasoactive drugs is provided in Table 26. Priapism may occur with any vasoactive drug No. of publications Priapism and usually in the early initiation phase when the appropriate dose for intracavernosal self-injection therapy is being determined. The occurrence of priapism depends on the prostaglandin E1 following: = 1. the drug itself, 2. the dose used, 3. the underlying ED etiology.

Priapism often occurs with papaverine and the Side effects of vasoactive drugs in ED. Review of the literature (Porst [133]) combination of papaverine/phentolamine rather erectile dysfunction; PGE1 than with PGE1 monotherapy. It is more often = PapaverinePapaverine/phentolaminePGE1 (alprostadil) 2,263 22 2,745 1,527 10 15 7.8% (122 out of 1,561) 0.36% (10 out 7.1% of 12.4% (92 2,745) (288 out out of of 1,300) 1,843) 11.6% 0.8% (141 (18 out out of 5.7% of 1,215) (60 2,180) out of 1,056) 5.4% (43 out of 7.2% 799) (40 out of 558) 4% (18 out of 452) 0% 1.6% (5 out of 314) observed in cases of neurogenic ED, especially Table 26 SubstanceED N

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Table 27 Penile fibroses in prospective long-term intracavernosal self-injection trials with alprostadil (prostaglandin E1) [135,136]

No. Follow-up Fibrosis Nodules Severe Pts. (months) total Plaques Deviations fibros. Alprostadil St. Powder (Caverject®-USA) 683 18 7.5% (51) 22 8 21 Alprostadil St. Powder (Caverject®-Europe) 848 6 4% (34) Not published 511 18 5.1% (26) Alprostadil Alfadex (Viridal®-Europe) 162 48 11.7% (19) 10 6 3 after spinal cord injury or pelvic surgery. In such therapy are not based on objective side effects and patients, lower initiation doses should be used. discomfort. Patients leaving the program were Fibrosis manifests as palpable penile nodules/ usually less motivated, less satisfied with the plaques or in severe cases as cavernousal fibrosis. It quality of pharmaco-induced sexuality, consider occurs much more often after the use of papaver- the effort to inject to be too substantial, and had ine containing injectables such as the combination not achieved improved self-esteem [143]. of papaverine/phentolamine, and trimix than after PGE1 monotherapy. In the majority of cases, fibrotic changes mani- Combination of Papaverine/Phentolamine/PGE1 fest as nodules/plaques and in 25–60% penile (Triple Drug, Synonymous Trimix) curvature is present. The follow-up of fibrotic In 1990, Goldstein et al. first reported the triple- changes, occurring both in the 4-year European drug combination of papaverine/phentolamine/ multicenter study with Alprostadil Alfadex PGE1 [144]. Since this publication, a variety of (Viridal®/Edex®) and in the 5-year U.S. trial reports on the efficacy of this drug combination with alprostadil sterile powder (Caverject®), has been published using a wide range of doses (see showed that between 33% and 47% of these Table 24 and 28). The trimix combination is rec- nodules/plaques heal spontaneously ([135,136], ommended for patients unsuitable for PGE1 injec- Table 27). tion due to poor response, pain, or cost. A direct Penile pain depends on the following: comparative study investigated the efficacy of 1. the drug itself, equivalent doses of alprostadil monotherapy to the 2. the underlying ED etiology, triple-drug combination [152] (Table 29). In this 3. the injection technique. trial, more patients expressed a preference for the trimix combination as compared with PGE1 Pain occurs more frequently after PGE1 and in (alprostadil) monotherapy (Table 30). neurogenic patients, especially after pelvic surgery. The major disadvantage of the trimix drug com- Elevated liver enzymes have only been reported bination is that up to now no marketed preparation in papaverine-containing preparations. exists worldwide; patients or pharmacists need to reconstitute this combination on an individual Drop-Out Rates basis, which can be somewhat complicated and Reviewing both prospective long-term self- cumbersome. injection trials with PGE1, the drop-out rates According to personal reports, the trimix com- were 55% after 18 months in the alprostadil bination is superior to alprostadil monodrug effi- sterile powder (Caverject®) trial [136] and 54% cacy in patients with veno-occlusive dysfunction after 2 years and 67% after 4 years in the Alpros- (the so-called venous leak) and in patients after tadil Alfadex (Viridal®/Edex®) trial [135]. Drop- pelvic surgery for reducing penile pain, which is out rates were less than in the prospective common in patients using alprostadil mono- multicenter transurethral PGE1 (MUSE®) trial, therapy. The most common high-dose trimix pre- with 57% after 3 months and 75% after 15 scribed contains 40 mg of alprostadil + 30 mg of months [142]. papaverine + 1 mg of phentolamine, which can In a smaller study, with 86 patients, who had easily be reconstituted from two ampoules of been on self-injection therapy for at least 3 Caverject® and one ampoule of Androskat®. months, 69 patients (80%) continued and 17 Because the application of trimix has a higher (20%) discontinued the treatment. After inter- risk for priapism than alprostadil monotherapy, viewing the patients in this study, the authors came the initiation dose of trimix should be accordingly to the conclusion that dropouts from self-injection lower with stepwise up-titration.

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Table 28 Various dose combinations with trimix combinations have been reported in the literature (from Porst and Adaikan [123])

Trimix stock solution Injection Reference Papaverine per mL PGE1 per mL Phentolamine per mL volume (mL)

Bennett et al., 1991 [145] 17.6 mg 5.9 mg 0.59 mg 0.25 Govier et al., 1993 [146] 22.5 mg 8.3 mg 0.83 mg 0.36 Israilov et al., 2002 [147] 19.4 mg 16.4 mg 1.6 mg NA Marshall et al., 1994 [148] 12 mg 9 mg 1 mg 0.1–0.8 Shenfeld et al. 1995 [149] 4.5 mg/0.5 mL 5 mg/0.5 mL 0.25 mg/0.5 mL 0.5 Mulhall et al., 1999 [150] 30 mg 10 mg 1 mg NA 30 mg 25 mg 2 mg NA Montorsi et al., 2002 [151] 150 mg 30 mg 5 mg 0.18–0.21 300 mg 100 mg 10 mg 0.18–0.21 300 mg 200 mg 20 mg 0.18–0.21

NA = not applicable; PGE1 = prostaglandin E1

Some patients may experience clinically symp- therapy. Trimix is associated with a much higher tomatic blood pressure decreases when taking risk of priapism, especially at higher doses, and has high-dose trimix (20–40 mg of PGE1/20–40 mg of a higher rate of cavernousal fibrotic changes with papaverine/1–2 mg of phentolamine). mid- and long-term use, compared with alprostadil In conclusion on PGE1/papaverine/phentolamine monotherapy (Level of Evidence 2a). A major dis- (trimix), the trimix combination is a very effective advantage of trimix is the lack of a marketed prepa- alternative to PGE1 monotherapy. It is indicated in ration and the need for reconstitution, which can be patients with cavernous insufficiency (venous leak) especially cumbersome for some patients. and postradical pelvic surgery, and in patients who often experience penile pain with alprostadil mono- Combination of VIP and Phentolamine (Invicorp®) The combination of vasoactive intestinal polypep- Table 29 Equivalent efficacy doses of alprostadil powder (Caverject®) and papaverine/phentolamine/PGE1 tide (VIP) and phentolamine in a larger series of combination (triple-drug solution) in 68 patients [152] patients with ED was first published in 1992 [153]. Thereafter, the mixture of VIP/phentolamine, in Papaverine (mg)/ Alprostadil powder phentolamine doses of 25 mg/1 mg or 25 mg/2 mg, was intro- (PGE1 [mg]) (mg)/PGE1 (mg) duced commercially as Invicorp®. It was available 4 1.47/0.05/0.49 with a very user-friendly automatic injection 8 3.2/0.1/1.1 device for single use (Senetek, Napa, CA, USA) 12 4.6/0.15/1.55 and approved in some countries (Denmark, UK, 16 6.8/0.22/2.27 20 7.6/0.25/2.5 and New Zealand) [154,155] (Table 31). Although the VIP/phentolamine combination had promise, PGE1 = prostaglandin E1 due to its former self-injection prototype device and relatively high efficacy, it was never marketed Table 30 Intraindividual comparative study of alprostadil globally after the successful introduction of PDE5 powder (Caverject®) and papaverine/phentolamine/PGE1 inhibitors. (triple-drug solution) [152]

Papaverine/ Alprostadil phentolamine/ No Table 31 Response rates to VIP/phentolamine powder PGE1 preference (Invicorp®) with in-office testing in combination with visual (PGE1 (triple-drug (both the sexual stimulation [155] Caverject®) solution) same) N Responder Responder Overall assessment 23% 46% 31% 289 (Ø VIP 25 mg/ VIP 25 mg/ better ED etiology 58,5 years) phentol 1 mg phentol 2 mg Improved rigidity 22% 37% 41% Erection maintenance 19% 37% 44% Arteriogenic 72 59.7% 80.6% better Diabetes 62 64.5% 85.5% Reproducibility better 15% 35% 50% Neurogenic 3 100% Orgasm/ejaculation 0 0 100% Mixed 152 63.8% 82.9% better Total 289 63.3% 83.1%

PGE1 = prostaglandin E1 ED = erectile dysfunction; VIP = vasoactive intestinal polypeptide

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Figure 15 Correct technique of self- injection therapy (original source: Pharmacia Upjohn, former Caverject® manufacturer, now Pfizer Corp., New York, NY, USA)

A comparative study of PGE1 (Caverject®) and Forskolin, a direct activator of adenylate cyclase. VIP/phentolamine (Invicorp® autoinjection Chlorpromazine, an alpha1-adrenergic receptor device) was conducted over a longer interval in blocker, is used in some countries in combina- over 40 men who were performing self-injection tion with papaverine (bimix) instead of phento- therapy with PGE1 (Caverject®). At that time, lamine. In a comparator trial with 50 patients, over 80% of the patients preferred Invicorp® the efficacy of the combination of papaverine because of its convenient delivery mode (at that and chlorpromazine, as compared with the time a single use autoinjection device was provided combination of papaverine and phentolamine, with Invicorp®) and the more natural sensation of yielded similar efficacy responses [157]. the erection as compared with PGE1 (Porst, unpublished data). In 2004, Senetec/USA outlicensed Invicorp® Technique and Complications of to Ardana, a small pharmaceutical company based Self-Injection Therapy in Edinburgh/Scotland. To date, Invicorp® still has not been officially In order to overcome patients’ resistance and to marketed but can be prescribed in Europe on a decrease potential complications from self- patient named basis as an injectable ampoule. injection therapy, a thorough education on the However, it is no longer offered with the patient- proper injection technique with the use of friendly autoinjection device, which was dropped ultrathin needles is mandatory (Figure 14). due to cost. According to personal experience, it takes at least two instruction sessions before the patient gains enough confidence to administer the technique Other Vasoactive Drugs Tried or Used for correctly and to avoid potential injection compli- Self-Injection Therapy cations (see Figures 15 and 16). Several other vasoactive drugs have been used for intracavernosal self-injection therapy but received Spring-Loaded Injector for Intracavernous little or no marketing support: Self-Injection Therapy Moxisylyte (thymoxamine) (Viatris, Mérignac, Spring-loaded self-injection devices are available, France) is an alpha-adrenoceptor blocker with a which insert the needle into the corpus caverno- preference for alpha1 adrenoceptors. The drug sum with a touch of a button. Some patients, was marketed as Icavex® with moderate success especially those who are needle phobic, find the for intracavernous self-injection therapy in use of this “automatic” injector much more France but withdrawn some years later because acceptable than inserting the needle manually. of small market share [156]. Whether the needle is inserted into the corpus Linsidomine (SIN-1), the biologically active cavernosum manually or “automatically,” the metabolite of the NO-donor molsidomine. patient still must push the plunger of the needle Nitroprusside-natrium, also belonging to the class down to inject the liquid solution into the corpus of NO donors. cavernosum. Potassium-channel openers: PNU 83757, a new The most frequent side effects encountered potassium channel opener. with self-injection therapy are the following:

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Potential of Malinjection in Correct Intra Self-Injection Technique sinusoidal Injection

1.subcutaneous injection 4.intraseptal 2.intratunical injection injection

3.intratrabecular 5.intraurethrale injection injection

Figure 16 Correct technique and malinjection possibilities of self- injection therapy [123]

Prolonged erections/priapism—the frequency of this about half of the patients, fibrotic changes are complication has been shown to be clearly followed by the development of penile curva- drug-and-dose dependent (see Table 26). Pri- tures that may require surgical correction. apism episodes lasting longer than 6 hours Penile hematoma/bruising is the most often reported must be treated by intracavernosal injection of side effect with intracavernosal self-injection a sympathomimetic agent (e.g., etilefrine, phe- therapy and occurred between 33% and 47% of nylephrine, or adrenaline) and/or evacuation of the time in the 4-year European long-term trial the entrapped blood with a butterfly needle. [135]. Hematomas occurred more frequently in This is especially required if the patient pre- those patients who developed fibrotic changes, sents with erections longer than 6 hours. The pointing to the role of postinjection technique. 6-hour time limit has been established in order In some patients, a dark coloring of the penile to prevent irreversible ischemic damage to the skin due to hemosiderin deposits may follow cavernosal tissues (see also manuscript SOP on repeated hematoma occurrence. priapism). Rare complications reported with self-injection Fibrosis of the cavernosal tissue is dependent on the therapy include the occurrence of infections/ drug used and on the patients’ ability to cor- abscesses, needle breakage requiring surgical rectly inject (see Table 26). On follow-up of removal, and the development of cavernous fibrotic changes occurring in the 4-year Euro- thrombosis with involvement of the pelvic veins pean multicenter study with alprostadil and subsequent fatal pulmonary embolism (Viridal®/Edex®) and in the 5-year U.S. trial [159]. (Caverject®), it was demonstrated that between 33% and 47% of these nodules/plaques healed spontaneously ([135,136], Table 27). Special Populations/Features Regarding In another study, on the outcome of fibrotic Self-Injection Therapy changes related to self-injection therapy in 44 Patients on Anticoagulants patients, 52% (N = 23) of the patients showed According to the literature, intracavernosal self- spontaneous improvement despite the majority injection therapy can be performed in men (91%) continuing with intracavernosal self- on warfarin-containing anticoagulants without injection therapy [158]. The tendency for spon- increasing the risk of bleeding/ecchymosis [160]. taneous disappearance of fibrotic changes can be augmented by temporary discontinuation of self-injection therapy for 2–4 months, followed Transplant Patients by reeducation of the patient as to the correct The literature has not indicated any increased self-injection technique (see Figure 16). In risk with self-injection therapy in patients

J Sex Med 2013;10:130–171 160 Porst et al. having received kidney or heart transplants surgery). The trimix combination is highly effec- [161]. tive, usually higher than PGE1 monotherapy, but is burdened by a higher rate of priapism and penile Diabetics fibrotic, Peyronie’s like changes (Level of Evi- Observations in the literature indicate that ED dence 3a). patients with diabetes are at increased risk to Papaverine monotherapy is not recommended develop fibrosis and pain with self-injection because of high toxicity (liver and cell toxicity with therapy [162]. subsequent cavernosal fibrosis) and greater risk of In conclusions on intracavernosal self-injection priapism and fibrotic changes (Level of Evidence therapy with vasoactive drugs, since the successful 3a). introduction of effective oral drug therapy with The major risk of self-injection therapy occurs PDE5 inhibitors, intracavernosal self-injection at the initiation phase, with the chance of priapism therapy with vasoactive drugs has diminished in and fibrotic changes developing over time. Pri- popularity for the management of ED and is not apism occurs more frequently in papaverine- even considered a viable option by the majority of containing combinations compared with PGE1 physicians treating patients with ED at present. To monotherapy or VIP/phentolamine. Priapism date, intracavernosal self-injection therapy is the must be treated by at least 6 hours after adminis- most effective and reliable medical therapy we can tration, by intracavernosal injection of an alpha- offer to our ED patients. Major obstacles to accep- adrenoceptor agonist, such as epinephrine (must tance of intracavernosal self-injection therapy are be diluted accordingly!) and phenylephrine or the procedure itself and needle phobia. Keys to etilefrine, depending on what drug is more avail- success of self-injection therapy are a careful and able in that part of the world. sensitive approach to the patient/couple on the Fibrotic changes are treated by temporary sus- correct application technique and the use of pension of self-injection therapy for 3–4 months, ultrathin needles (27–30 g), which contributes to followed by a thorough reeducation on the correct reduction of pain and injection-related complica- self-injection technique, with a chance for sponta- tions and which translates to higher acceptance neous recovery of 30–50%. rates. Intracavernosal self-injection therapy may be PGE1 (alprostadil) monotherapy is considered also considered in combination with oral drug the standard vasoactive agent with three different therapy (PDE5 inhibitors) for patients where marketed products (Caverject®, Edex®, and Viri- monotherapy fails to produce satisfying erections dal®) available worldwide in relative patient- (Level of Evidence 3b). friendly dual-chamber injection devices. The efficacy and safety of PGE1 (alprostadil) Vacuum-Erection Devices (VEDs)/Vacuum monotherapy have been proven in two interna- Constriction Devices (VCDs) tional long-term (4 and 5 year) trials (Level of Evidence 2b). The concept of vacuum device therapy in the Two alternatives to PGE1 monotherapy, the treatment of ED dates back to the American phy- VIP/phentolamine (Invicorp®) combination, sician John King, who described in 1874 a method which can be prescribed on an individual patient of improving erections by a small vacuum pump. basis in some European countries, and the com- After being granted various patents for vacuum bination of papaverine/phentolamine (bimix— device therapy both in Germany and in the United available in some European countries, as States, the American entrepreneur Geddings Androskat®), may be effective for those patients Osbon obtained permission from the FDA to experiencing pain after PGE1. Both combinations produce a vacuum device that was subsequently were effective and safe in midterm trials (6–12 named Erec-Aid® in 1982. In that same year, months) (Level of Evidence 3a). The trimix com- Nadig et al. published the first report on efficacy bination (PGE1/papaverine/phentolamine)— and safety of VEDs [163]. no trade marketed product available worldwide must be reconstituted individually by a General Indications for VEDs pharmacist—may be considered as a reserve medi- One of the major advantages of VED is that it can cation for those patients in whom PGE1 mono- be successfully applied to men with nearly all eti- therapy (up to 40 mg) is either ineffective or too ologies of ED. Therefore, VED is considered a painful (which occurs in patients after pelvic first-line therapy option for ED populations in

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Figure 17 Technique of vacuum device therapy with the conventional “two-piece” Osbon Erec-Aid® system [169] most current recommendations/guidelines for the shortened penis after reconstructive surgery [167] management of ED [21,164]. to avoid postoperative, severe penile fibrosis and Although a VED can be offered to every ED shortening, similarly after removal of an infected patient, the acceptance for mechanical ED therapy penile prosthesis [168]. is somewhat poor. It is especially successful in elderly patients in long-term partnerships with Technique of VED occasional intercourse attempts. VEDs share a common mechanism of action: a Vacuum therapy can also be used in combina- plastic cylinder, whose lower rim is made airtight tion with other ED therapies such as oral drug by application of a lubricant gel, is applied over the therapy (e.g., PDE5 inhibitors), transurethral or penis in a standing position and then firmly intracavernosal injection therapy, or even with sex pressed against the pubic bone (Figure 17). After- therapy if the patient/couple is dissatisfied with ward, a vacuum is created manually, via a pump, another monotherapy [165,166]. which is either separately connected to the cylin- der with a tube or is directly integrated and battery Special Indications for VEDs operated on the top of the cylinder (Figure 18). Besides common ED, special indications in which A major disadvantage of VED therapy is that VEDs have been successfully used are in men after induced erections are not natural by look or feel. Peyronie’s disease surgery. The VEDs stretch the First, the rigid erection achieved by creating a

Figure 18 Modern vacuum device (Osbon-Esteem®) with cylinder inte- grated pump either mechanically or battery operated

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Table 32 Outcome of VCD therapy—overviews of the literature (source: Glina and Porst [169])

Mean age Follow-up Author Device N Evaluable (years) (months) Satisfaction Nadig, 1987 [170] Osbon Erec-Aid® 302 81% (244) ? up to 72 83% Witherington, 1989 [171] Osbon Erec-Aid® 15,000 10% (1,517) 64 8.6 92% good erections Blackard, 1993 [172] Osbon Erec-Aid® 47 96% (45) ? ? 42% Derouet, 1993 [173] Osbon Erec-Aid® 90 100% 32–75 ? 37% Baltaci, 1995 [174] Osbon Erec-Aid® 61 80% (49) ? 12.8 67% Lewis, 1997 [175] Osbon Erec-Aid® 34,777 17% (5,847) ? 1974–1992 65–83% Meinhardt, 1993 [176] Post-T VED 74 100% 55 3 weeks 30% Fedel, 1995 [177] Innovital 100 40% 52.4 6 90% Cookson, 1993 [178] ? 216 53% (115) 65 29 84% Graham, 1998 [179] ? 323 100% 61 2 weeks 23% Droupy, 1998 [180] ? 53 (RRP) 55% (29) 66.5 27 52% Opsomer, 1998 [181] ? 170 ? 66 48 55%

Post-T VED = post-testosterone vacuum-erection device; RRP = radical retropubic prostatectomy; VCD = vacuum constriction device vacuum within the cylinder can only be main- ers, such as the Innovital System, Post-T, VED, tained by a rubber constriction ring, which of and the Synergist System (Table 32). course cannot be concealed. The rubber constric- When analyzing the data of VED therapy, there tion ring must be rolled onto the cylinder prior to is a striking discrepancy between sold VEDs and the vacuum maneuver and is then rolled onto the eligible patients for follow-up. So, for example, in base of the penis after creating the vacuum and the large series published by Witherington and erection to prevent venous drainage and detumes- Lewis, only 10–17% of all VED buyers were con- cence. Generally, the application duration of the sidered or eligible, which is in sharp contrast to all constriction ring is limited to 30 minutes by the other ED therapies [171,175]. VED manufacturers to avoid ischemic damages of In those series, in which a majority of the the cavernosal tissue. Sometimes, two constriction patients were eligible for follow-up, 40–60% dis- rings need to be applied to maintain a rigid erec- continued VED therapy. The generally low accep- tion if one ring is insufficient. tance of VED therapy was also shown in the series Compared with naturally occurring erections, by Graham et al. among 1,236 new ED patients VED-induced erections are perceived as different who were subjected to full diagnostic workup and by the couple because the constriction ring applied to whom all available therapeutic modalities were to the base of the penis, the proximal third of the offered only 323 (27%) requested a 2-week trial of cavernous bodies, i.e., the crura, is uninvolved in VED, with only 74 (6% of the total population) the VED-induced erection. This noninvolvement opting for a VED prescription [179]. of the crura in the penis in VED-induced erections In a German VED series, it was obvious that the causes some degree of instability at the penis’ base, acceptance rate of VED was markedly higher in occasionally requiring manual assistance while nonresponders to pharmacotherapy compared inserting the penis into the vagina. with responders (45% vs. 22%) [173,182]. The VED-erect penis appears more cyanotic in The role and importance of VED in penile color and is perceptibly cooler by the partner rehabilitation therapy after radical prostatectomy because the cavernous bodies are filled with low was recently discussed in detail [183]. The authors oxygenated blood. This is in contrast to natural pointed to the fact that VED may be successfully erections occurring through arterialized and used in combination therapy with PDE5 inhibi- highly oxygenated blood, and thus makes the erect tors, injection therapy, and transurethral therapy. penis feel warmer. It could also be used to prevent penile shrinking Worldwide, a variety of manufacturers has mar- after RRP or reconstructive penile surgery for keted VED, with the Osbon VED being the Peyronie’s disease. market leader. Therefore, among the relatively sparse litera- Contraindications to VED ture on VED, most deal with the outcome of the Provided the Princeton II Consensus Conference Osbon VCD devices (Osbon Erec-Aid® and Algorithm (see Figure 2) is considered, the only Osbon Esteem®). Only a few smaller series have real contraindications to VED are patients with a been published with devices of other manufactur- history of recurrent prolonged erections/priapism

J Sex Med 2013;10:130–171 Conservative Treatment of Erectile Dysfunction 163 and those with severe bleeding disorders. For acceptance- and long-term use rates are relatively patients on anticoagulants such as coumadin and low (Level of Evidence 2b). Major reasons for warfarin, a prospective trial demonstrated that these low acceptance and usage rates are both the bleeding complications, such as hematoma and very mechanical procedure linked to VED- petechiae, in patients using VED did not exceed induced erections and their unnatural feeling due those observed in the general urological popula- to the filling of the cavernous bodies with poorly tion [160]. VED therapy is also contraindicated in oxygenated blood, making the penis appear cyan- patients with severe penile curvature, either con- otic and feel cooler than natural erections. Because genital or acquired (Peyronie’s disease), because of the discharge of the seminal fluid is restricted in the potential risk of penile fracture while establish- many patients due to the constriction ring, which ing the vacuum in the cylinder. is necessary to maintain the erection, VEDs are not an option for those couples desiring to con- Side Effects of VED ceive by natural means. Relatively frequent side Relatively frequent side effects of VED therapy effects linked to VED are penile bruising/ are penile bruising, petechiae, and extensive hematoma, which often occur in the initiation hematoma or pain. phase but are not more commonly found in A common side effect of VED is the blockade of patients using anticoagulants. In special situations, seminal fluid discharge while the constriction ring VED may be used in combination with oral drug is applied, which may cause ejaculatory discomfort therapy and transurethral or intracavernosal injec- in some patients [171,175]. tion therapy to increase efficacy (Level of Evidence Rare or anecdotal complications with the use of 3b). Successful application of VED has been sug- VED are the onset of Peyronie’s disease, skin gested for penile stretching after surgical recon- necrosis, and urethral bleeding [169]. struction for Peyronie’s disease to avoid penile Occasionally, chronic use of VED may result in scarring/fibrosis and shortening and after removal hyperpigmentation of the penile skin due to of an infected penile implant. repeated skin bruising with subsequent hemosid- erin deposition. In this regard, it is important to Combination Therapies advise patients to use only prescription devices. Other devices may have no pressure control or Combination therapies have been reported in the safety valves to release the pressure. literature for patients who fail monotherapy to produce a satisfactory erection. Acceptance and Discontinuation Rates of VED Although VED therapy must be considered very PDE5 Inhibitors + Self-Injection Therapy effective in producing erections sufficient for Successful salvage therapy in nonresponders vaginal penetration, many couples discontinue (N = 93, mean 53.5 years, range 24–77) to mono- vacuum-erection therapy over the long term. The therapy (here either high-dose alprostadil or main reasons pertain to the very mechanical and trimix, respectively) was reported with the combi- therefore “unsexy” procedure to create an erec- nation of sildenafil (100 mg) and trimix [186]. Of tion, which finally results in an unnatural per- these 93 patients failing successful injection ceived erection and subsequent lack of acceptance therapy at home, 32 (34%) successfully responded for both the patients and their partners [184]. to sildenafil monotherapy 100 mg. Of the remain- Once the couples have adapted their sex life to ing 61 patients, 29 (47%) responded to combina- the use of VEDs, a significant increase in fre- tion therapy with sildenafil 100 mg and trimix. quency of intercourse, sexual arousal, coital Thirty-two (53%) did not and were defined as orgasm, and sexual satisfaction has been reported nonresponders, even with combination therapy. [185]. A minority of patients (8–16%) reported on the PDE5 Inhibitors + Transurethral PGE1 return of spontaneous erections with the long- Of 214 patients treated for ED, with transurethral term use of VED [174,175,178,180]. PGE1 (MUSE®) or sildenafil up to 100 mg, 65 In conclusions on VED, among all options, VED (30%) were not fully satisfied was reported with the can be considered as the safest and most inexpen- firmness of their erections using either mono- sive form of ED treatment. Although VED effi- therapy. Sixty (92%) out of the 65 patients claimed cacy rates are comparable to both PDE5 inhibitors satisfaction with combination therapy. Question- and intracavernosal self-injection therapy, the naire scores for erectile function were 23.1 Ϯ 2.0

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(114%) for combination therapy vs. 19.2 Ϯ 1.8 American Medical Systems, Coloplast, Timm (77%) and 15.2 Ϯ 1.6 (41%) for sildenafil and Medical, Shionogi Pharma, and Reflexonic alprostadil monotherapies, respectively (P < 0.05). LLC. There were no significant differences in responses G. Brock: Advisory board and speaker bureau for between the two groups. The men also reported Lilly, Pfizer, Bayer Healthcare, J&J, GSK, improvement in intercourse and overall satisfaction Coloplast, and AMS; stock holdings for Lilly, [130]. J&J, and Pfizer. Sixteen patients (mean 56 years, 11 post-RRP H. Ghanem: Speaker for Elli Lilly, Pfizer, and and 5 with other organic ED) failing both 100 mg Bayer Healthcare. of sildenafil and 1,000 mg of MUSE® monothera- F. Giuliano: Consultant and speaker for Lilly, con- pies underwent combination therapy with 100 mg sultant and investigator for Bayer Healthcare. of sildenafil and 500 mg of MUSE®. Using this S. Glina: Speaker for Lilly, Pfizer, Bayer Health- combination treatment, all patients were able to care, and Cristalia; investigator for Lilly and have successful intercourse after 3 months [131]. AmGen; consultatnt for Lilly. W. Hellstrom: American Medical Systems— Vacuum Device Combination Therapies consultant or advisor; Auxilium—meeting Successful augmentation of the erectile response participant or lecturer, consultant or advisor, after self-injection of a papaverine 30 mg/ investigator; Coloplast—consultant or advisor, phentolamine 1 mg combination (bimix) with investigator; Cook—consultant or advisor, VED was observed in a pilot study with 22 men lecturer; Endo—consultant or advisor, investi- [166]. In a similar study including 10 men who did gator, lecturer; Johnson & Johnson—consultant not show satisfactory response to either intracav- or advisor, meeting participant or lecturer, ernosal injection of a combination of 60 mg of investigator; Lilly, USA—consultant or advisor, papaverine + 30 mg of PGE1 or after application of lecturer; Medtronic—consultant or advisor, a VED, the combination of both modalities < investigator, meeting participant or lecturer; resulted in a significantly (P 0.0001) better NIH—board member, officer, trustee; Slate response, measured by penile buckle pressure, Pharmaceutical—lecturer, advisor, investiga- than either monotherapy alone [165]. tor; Theralogix—board member, officer, In conclusion on combination therapies for ED, trustee; VIVUS—advisor/consultant, investiga- although the literature lacks data from prospective tor, lecturer. and well-designed studies in a representative A. Martin-Morales: Investigator, speaker, and number of patients, combination therapies in ED consultant for Bayer, Lilly, AMS, and Coloplast. patients must be considered routine practice in the A. Salonia: Speaker and consultant for Bayer management of ED. It is documented that between Healthcare. 20% and 40% do not respond to either mono- I. Sharlip: Speaker and consultant to Pfizer and therapy. A variety of combination strategies exists, Lilly; speaker for Endo. which may fit couples’ needs for a satisfying sex life. According to their own experiences, the limiting Corresponding Author: Hartmut Porst, MD, Private element of combination therapies is not lack of Urological/Andrological Practice, Neuer Jungfernstieg efficacy or safety, but expense. All the previous 6a, 20354 Hamburg, Germany. Tel: +49-40-34-61-84; listed treatments in combination therapies may cost Fax: +49-40-35-11-17; E-mail: [email protected] the patients up to US $100–$200 per month, depending on the choice of therapy and frequency of sexual intercourse. Nevertheless, physicians should be aware of these combination options in Statement of Authorship order to counsel patients appropriately (Figure 19). Category 1 Disclosures (a) Conception and Design Hartmut Porst; Arthur Burnett; Ira Sharlip H. Porst: Investigator, speaker, and consultant for (b) Acquisition of Data Bayer Healthcare, Eli Lilly, VIVUS; investiga- Hartmut Porst; Arthur Burnett; Ira Sharlip tor and advisor for Auxilium. (c) Analysis and Interpretation of Data A.L. Burnett: Consultant/medical advisor or Hartmut Porst; Arthur Burnett; Gerald Brock; research support for Endo Pharmaceuticals, Hussein Ghanem; Francois Giuliano; Sidney Glina; Abbott, Auxilium Inc., Pfizer Inc., VIVUS, Wayne Hellstrom; Antonio Martin-Morales;

J Sex Med 2013;10:130–171 Conservative Treatment of Erectile Dysfunction 165

Figure 19 Therapeutic algorithm of ED based on history and diagnostic findings and considering cardiac health status according to Princeton II. ED = erectile dysfunction; PDE5 = phosphodiesterase type 5

Andrea Salonia; Ira Sharlip; the ISSM Standards Andrea Salonia; Ira Sharlip; the ISSM Standards Committee for Sexual Medicine Committee for Sexual Medicine

Category 2 Category 3 (a) Drafting the Article (a) Final Approval of the Completed Article Hartmut Porst; Arthur Burnett; Ira Sharlip Hartmut Porst; Arthur Burnett; Gerald Brock; (b) Revising It for Intellectual Content Hussein Ghanem; Francois Giuliano; Sidney Glina; Hartmut Porst; Arthur Burnett; Gerald Brock; Wayne Hellstrom; Antonio Martin-Morales; Hussein Ghanem; Francois Giuliano; Sidney Glina; Andrea Salonia; Ira Sharlip; the ISSM Standards Wayne Hellstrom; Antonio Martin-Morales; Committee for Sexual Medicine

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