Long-Term Safety and Tolerability of Tadalafil in the Treatment of Erectile Dysfunction

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1 European Urology European Urology 45 (2004) Long-Term Safety and Tolerability of Tadalafil in the Treatment of Erectile Dysfunction F. Montorsi a,*, B. Verheyden b, E. Meuleman c, K.-P. Jünemann d, I. Moncada e, L. Valiquette f, A. Casabé g, C. Pacheco h, J. Denne i, J. Knight i, S. Segal j, V.S. Watkins i a Department of Urology, Università Vita e Salute San Raffaele, Via Olgettina 60, Milan, Italy b Department of Urology, University Hospital of Antwerp, University of Antwerp, Edegem, Belgium c Department of Urology, University Hospital Nijmegen, Nijmegen, The Netherlands d Department of Urology, Christian-Albrechts University, Kiel, Germany e Urology Department, Hospital General Universitario Gregorio Maranon, Madrid, Spain f Department of Urology, Centre Hospitalier de l Université de Montréal, Montreal, Canada g Instituto Médico Especializado, Buenos Aires, Argentina h Clinica Londres, Mexico City, Mexico i Eli Lilly and Company, Indianapolis, IN, USA j Lilly ICOS LLC, Bothell, WA, and Indianapolis, IN, USA Accepted 12 November 2003 Published online 2 December 2003 Abstract Objective: To assess the long-term safety and tolerability of tadalafil for patients with erectile dysfunction (ED). Patients and Methods: This was a multicentre, open-label, 24-month extension trial involving 1173 men with ED. The mean age was 57 (range 23 83) years and 74.8% of patients were taking concomitant medications for comorbid conditions, including diabetes mellitus in 30.5% of men and hypertension in 29.5%. These patients had participated in 1 of 5 previous 8-week or 12-week randomised, double-blind, placebo-controlled tadalafil studies. In the present trial, the starting 10 mg dose of tadalafil could be increased to 20 mg if the patient could not achieve satisfactory intercourse or reduced to 5 mg for an adverse event that was persistent, intolerable and judged by the investigator to be related to tadalafil. Results: Four hundred ninety-three (42.0%) men completed 24 months of treatment. In addition, a further 234 (19.9%) completed 18 months of treatment due to a sponsor decision to reduce the study duration. The total tadalafil exposure was patient-years. Tadalafil was safe and well tolerated. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%), and back pain (8.2%) were the most common treatment-emergent adverse events. The rate of discontinuations due to adverse events for this month study was 6.3% and the rate for any individual event was <1%. Serious adverse events occurred in 8.6% of patients. No consistent pattern of serious adverse events assessed as causally associated with tadalafil administration was observed. None of the four deaths that occurred during the study was assessed as tadalafil related. There were no clinically significant laboratory or electrocardiographic findings or changes in vital signs in mean baseline-to-endpoint analysis attributable to tadalafil. Tadalafil administration was not causally associated with drug-induced hepatotoxicity, neutropenia, thrombocytopenia, or renal dysfunction. Conclusion: Tadalafil at doses of 5, 10, or 20 mg taken as needed up to once daily for 18 to 24 months was safe and well tolerated. These findings support the long-term use of tadalafil in the clinical management of erectile dysfunction. # 2003 Elsevier B.V. All rights reserved. Keywords: Drug therapy; Impotence; Phosphodiesterase inhibitors; Safety; Tolerability * Corresponding author. Tel. þ ; Fax: þ address: montorsi.francesco@hsr.it (F. Montorsi) /$ see front matter # 2003 Elsevier B.V. All rights reserved. doi: /j.eururo

2 340 F. Montorsi et al. / European Urology 45 (2004) Introduction Erectile dysfunction (ED) affects approximately 150 million men worldwide and the prevalence is projected to more than double by the year 2025 [1,2]. The anticipated increase in the population of patients seeking treatment for ED and the consequent requirement for safe and effective therapy have prompted development of novel therapies for ED, with oral dosing being the preferred route [3 5]. Tadalafil is a selective, reversible phosphodiesterase type 5 (PDE5) inhibitor with demonstrated efficacy as an oral ED treatment [6]. PDE5 inhibitors potentiate the male erectile response to sexual arousal by amplifying the nitric oxide cyclic guanosine monophosphate signalling pathway, with consequent penile vasodilation resulting in engorgement of the corpus cavernosum. Tadalafil possesses a favourable pharmacokinetic profile, with a rapid onset and prolonged duration of proerectile effects [7]. In integrated analyses of 12- week randomised, double-blind, placebo-controlled trials, more than 70% of sexual-intercourse attempts were successfully completed from >30 minutes to 36 hours after tadalafil dosing [6]. The pharmacokinetics of tadalafil are not affected by food intake [8]. Because most patients with ED require treatment on a chronic basis, therapeutic agents for ED treatment must have satisfactory long-term safety profiles. To assess the long-term safety and tolerability of tadalafil, we conducted a multicentre, long-term, open-label extension study in men with ED who had participated in prior tadalafil placebo-controlled clinical trials. 2. Methods 2.1. Patients Men who had participated in prior placebo-controlled tadalafil studies, did not discontinue prematurely, and wished to continue ED treatment were eligible. The starting dose of tadalafil was 10 mg taken as needed before sexual intercourse at a maximum frequency of once daily. No other ED therapies were permitted for 7 days before the initial study dose and for 96 hours after the final visit. The 5 parent studies contributing patients into this open-label study enrolled men aged 18 years who experienced a 3-month history of ED of various severities (i.e. mild, moderate, severe) and aetiologies (i.e. organic, psychogenic, mixed), and who were in a stable heterosexual relationship. Erectile dysfunction was defined as a consistent alteration in the quality of erections that adversely affected the patient s satisfaction with sexual intercourse. None of the 5 parent studies excluded patients who had used sildenafil prior to entry, although 2 of the 5 did exclude patients with prior unsuccessful sildenafil treatment. Exclusion criteria included any of the following 6 months before screening: myocardial infarction, cardiac intervention (e.g. coronary artery bypass surgery, percutaneous coronary intervention), unstable angina pectoris, angina pectoris during intercourse, or congestive heart failure. Also excluded were patients with (1) any supraventricular arrhythmia with an uncontrolled ventricular response (mean heart rate >100 beats per minute) at rest despite medical or device therapy, (2) any history of spontaneous or induced sustained ventricular tachycardia (heart rate >100 beats per minute for 30 seconds) despite medical or device therapy, or (3) an automatic internal cardioverter-defibrillator. Patients with poorly controlled blood pressure (systolic >170 or <90 mmhg; diastolic >100 or <50 mmhg) or malignant hypertension at screening were also excluded. These cardiovascular exclusions are consistent with consensus guidelines for risk-stratifying patients with sexual dysfunction and cardiovascular disease [9]. Other exclusion criteria were clinically significant hepatobiliary disease (e.g. alanine aminotransferase [ALT] or aspartate aminotransferase [AST] elevations >3 times the upper limit of normal at screening); a recent (6-month) history of clinically significant renal insufficiency; stroke or other significant central nervous system injury; or drug, alcohol, or substance abuse. Treatment with nitrates, cancer chemotherapy, or antiandrogens during the study period was prohibited Study design This was a multicentre, open-label, 24-month extension trial for ED patients who had participated in any 1 of 5 prior 8-week or 12-week randomised, double-blind, placebo-controlled tadalafil studies. In the 5 parent studies, patients received tadalafil, sildenafil, or placebo. In this open-label trial, 1173 patents were enrolled at 69 centres in Canada (n ¼ 563), Europe (Belgium, Germany, Italy, Spain, The Netherlands) (n ¼ 520), Argentina (n ¼ 68), and Mexico (n ¼ 22). An additional 5 patients (2 in Canada and 3 in Italy) were entered (consented) but discontinued before taking any study drug. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Local ethical review boards approved the protocol and informed consent document before study onset. Patients and their sexual partners provided written informed consent. Patients who met eligibility criteria and signed informed consents were seen at months 1, 3, 6, 9, 12, 15, 18, 21, and 24. Individuals who had completed a placebo-controlled active-comparator trial underwent a 7-day washout period prior to screening laboratory tests. For patients completing a tadalafil study 28 days before entry into this extension study, the physical examination and electrocardiograms (ECGs) of the prior study s termination visit were allowed to serve as baseline. Haematology, chemistry, and urinalysis data from the prior trial s termination visit could serve as baseline if obtained 14 days of entry into the extension. The initial tadalafil dose was 10 mg taken as needed before intercourse at a maximum frequency of once daily. Increases or decreases in doses according to prespecified rules were allowed at subsequent visits. At subsequent visits, of which some could be unscheduled visits, doses could be increased by 1 dose level (e.g. from 10 to 20 mg or 5 to 10 mg) or decreased by 1 dose level (e.g. from 10 to 5 mg or 20 to 10 mg). A decrease in dose of 1 level was permitted if the patient experienced an adverse event that was persistent or disrupted daily activities and was deemed by the investigator to be related to treatment. A dose increase of 1 level was allowed if the patient could not attain sufficient hardness or successfully complete intercourse after an adequate number of sexual attempts. At each of these visits, blood pressure and pulse, adverse events, concomitant medications and the reason for dose modification were recorded.

3 F. Montorsi et al. / European Urology 45 (2004) Safety analysis The primary objective of this trial was to evaluate the safety and tolerability of tadalafil (5 20 mg) taken as needed prior to intercourse at a maximum frequency of once daily for up to 24 months. Patients were seen 1 month after study entry and at 3-month intervals beginning with month 3. Safety analyses included the evaluation of adverse events, vital signs, serum chemistry, haematology, ECGs, and urinalysis. Treatment-emergent adverse events were defined as any untoward medical occurrences that either first appeared or worsened in a patient receiving tadalafil. Serious adverse events were defined according to regulatory requirements as adverse events that resulted in 1 of the following outcomes (or was significant for any other reason): death; initial or prolonged inpatient hospitalisation; a lifethreatening experience (i.e. immediate risk of dying); severe or permanent disability; cancer; or congenital anomaly Statistical analysis Safety and tolerability were evaluated for all patients enrolled in the open-label extension study (n ¼ 1173). Data were summarised according to treatment received in the previous study. Continuous variables were summarised by mean, standard deviation, median and minimum/maximum values, and categorical variables by numbers and frequencies. Treatment-emergent adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 5.0. Proportions of patients experiencing an adverse event were calculated and summarised by MedDRA body system and preferred term and by severity. If a patient reported an event more than once, the most closely related event and the most severe event were included. Reasons for premature study discontinuation, including adverse events, were also recorded and summarised by numbers and frequencies. Analyses of the proportions of patients with treatment-emergent adverse events, abnormal ECGs, or laboratory analytes outside reference ranges at the final visit (or at the maximum or minimum value) were based on pooled data from all sites. 3. Results 3.1. Patient characteristics Of 1173 patients enrolled, most had been treated in the prior parent double-blind trials with tadalafil (n ¼ 727, 62.0%). Others had received either placebo (n ¼ 335, 28.6%) or sildenafil (n ¼ 111, 9.5%). A total of 493 (42.0%) patients completed 24 months of openlabel treatment. An additional 234 (19.9%) patients discontinued after 18 months of treatment due to a sponsor decision to reduce the duration of the study to 18 months. Of the remaining 446 patients, there were 4 deaths, 40 lost to follow-up, and 402 study discontinuations. For the 402 discontinuations, 173 were due to patient-perceived lack of efficacy, 94 personal conflict or other patient decision, 74 adverse events, 42 protocol and entry criteria violations, and 19 investigator or sponsor decisions. Most patients increased the starting dose of tadalafil to a dose of 20 mg within the first 3 months. At 3 months, 72% of patients received 20 mg. The mean duration of treatment with tadalafil was days (range: ), during which patients received a mean of total doses of tadalafil (1.9 doses/week). Total exposure to tadalafil was patient-years, including patient-years with tadalafil 20 mg and patient-years with tadalafil 10 mg. Nine hundred ninety-one (84.5%) men received treatment with tadalafil at an as-needed dose of 10 mg for a continuous interval of 6 months, including 870 (74.2% of all enrolled patients) for 12 months and 670 (57.1%) for 18 months. An as-needed tadalafil dose of 20 mg was taken continuously for 6 months by 746 patients (63.6% of all enrolled patients), including 624 (53.2%) for 12 months and 374 (31.9%) for 18 months. Baseline characteristics are presented in Table 1. The mean patient age was 57 years; 94.6% of patients were Caucasian; 25.5% of patients reported smoking; and 74.8% of patients were taking medications for concomitant conditions, including hypertension, diabetes mellitus, and hypercholesterolaemia. The mean body mass index was 28.0 kg/m 2. A total of 438 (37.3%) patients were taking concomitant antihypertensive medication; 75 (6.4%) were on alpha-blockers Safety and tolerability Tadalafil was safe and well tolerated during long-term treatment. The most frequently reported treatmentemergent adverse events included headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%), and back Table 1 Baseline characteristics Tadalafil (n ¼ 1173) Age, yrs (mean, range) 57.0 ( ) Body mass index a, kg/m 2 (mean S:D:) Systolic/diastolic blood pressure b, 132.4/ /8.4 mmhg (mean S:D:) Smokers (n (%)) 299 (25.5) Race/ethnicity (n (%)) Caucasian 1110 (94.6) African 20 (1.7) Hispanic 24 (2.0) Asian 16 (1.4) Other 3 (0.3) Comorbidity (n (%)) Hypertension 346 (29.5) Diabetes mellitus 358 (30.5) Hypercholesterolaemia 143 (12.2) Hyperlipidaemia 45 (3.8) Depression 44 (3.8) >1 concomitant medication 877 (74.8) a No baseline weight available for 6 patients. b No baseline blood pressure available for 5 patients.

4 342 F. Montorsi et al. / European Urology 45 (2004) Table 2 Treatment-emergent adverse events reported by 2% of patients a Tadalafil (n ¼ 1173) Patients with 1 adverse event 840 (71.6) Headache 185 (15.8) Dyspepsia 139 (11.8) Nasopharyngitis 134 (11.4) Back pain 96 (8.2) Influenza 52 (4.4) Hypertension 48 (4.1) Flushing 42 (3.6) Nasal congestion 42 (3.6) Arthralgia 41 (3.5) Cough 38 (3.2) Influenza-like illness 37 (3.2) Myalgia 34 (2.9) Bronchitis 32 (2.7) Diarrhoea 30 (2.6) Dizziness 28 (2.4) Upper-abdominal pain 27 (2.3) Nausea 25 (2.1) Limb pain 23 (2.0) a Values are numbers (%). pain (8.2%) (Table 2). Most adverse events were mild or moderate. The percentage of events reported as mild or moderate was 88% and the percentage of events reported as severe was 12%. Four deaths (3 cardiac deaths and 1 suicide) occurred during the 24-month open-label study, none of which was assessed as related to study drug. Two additional deaths were reported after the patients had discontinued from the study: 1 patient with bile-duct cancer and 1 patient with metastatic prostate cancer (both assessed as unrelated to study drug). There were no clinically significant laboratory or ECG findings or changes in vital signs in mean baseline-to-endpoint analysis attributable to tadalafil. Tadalafil administration was not causally associated with drug-induced hepatotoxicity, neutropenia, thrombocytopenia, or renal dysfunction. Serious adverse events were experienced by 101 (8.6%) patients. Of these, 35 withdrew from treatment (3.0% of total enrolled). Serious adverse events included myocardial infarction in 9 (0.8%) patients and cerebrovascular accident in 5 (0.4%) patients. No consistent pattern of serious adverse events causally related to tadalafil emerged from this long-term study. Seventy-four (6.3%) patients discontinued the trial prior to completion of the months of therapy because of adverse events. Thirty-six (3.1%) patients discontinued due to adverse events that were assessed by the investigator as possibly related to tadalafil. For any single adverse event, the discontinuation rate was less than 1%. Adverse events leading to discontinuation in 0.3% were headache in 9 (0.8%), dyspepsia in 7 (0.6%), myocardial infarction in 7 (0.6%), back pain in 5 (0.4%), cerebrovascular accident in 5 (0.4%), and angina pectoris in 4 (0.3%). Ocular events that may have been related to PDE inhibition including eyelid oedema, conjunctival hyperaemia, and sensations described as pressure were uncommon and generally mild or moderate. One patient discontinued due to eyelid oedema. With regard to visual symptoms known to be associated with PDE6 inhibition, 1 patient complained of a single episode of mild blue vision, but the patient did not report this event after subsequent doses. No cases of priapism were reported. 4. Discussion In this open-label, long-term extension study, tadalafil was safe and well tolerated. Most patients received a tadalafil dose of 20 mg, and most of the remainder received a dose of 10 mg. Tadalafil treatment was not associated with any major safety concerns. Demographics of this study reflected those of the parent studies and ED populations in general [6,10], including various degrees of ED severities and aetiologies. Compared with the Massachusetts Male Aging Study (MMAS) [10], the present study population had similar proportions of patients with vascular diseases or other factors that increase the risk of developing ED [11 13], including hypertension in 29.5% of patients, diabetes mellitus in 30.5% (vs. 6.8% in MMAS [10]) and smoking in 25.5% (vs. 22%). The incidence of diabetes mellitus was increased because patients who enrolled in this study also included patients from 1 randomised clinical trial that investigated the effects of tadalafil in patients with diabetes mellitus who had ED. Treatment-emergent adverse events, including headache, dyspepsia, flushing, back pain, myalgia, and nasal congestion, that occurred in this study are consistent with the pharmacodynamic effects of PDE5 inhibition. All these adverse events have been reported previously in association with this and the other PDE5 inhibitors, sildenafil and vardenafil [14,15]. There is no obvious pharmacological explanation for myalgias associated with PDE5 inhibitor therapy [16]. Of the 1173 men in this long-term safety study, 34 (2.9%) reported myalgia and 96 (8.2%) back pain. However, of the 74 patients in this study who discontinued prior to completion of months of therapy because of adverse events, only 5 (0.4%) discontinued due to back pain. In all, treatment-emergent adverse events prompted discontinuation in 6.3% of patients prior to completion of the long-term (18 24 months) open-label therapy. A

5 F. Montorsi et al. / European Urology 45 (2004) total of 173 (14.7%) men discontinued because of patient-perceived lack of efficacy over months of treatment. Most discontinuations occurred within the first 6 months of this extension study. Sixty-eight percent of patients who discontinued due to perceived lack of efficacy did so within the first 6 months, and 90% did so within the first 12 months. Cardiovascular events occurred at low rates in the present patient population, given the presence at baseline of vascular disease or risk factors (e.g. hypertension, diabetes, hypercholesterolaemia). Nine patients experienced myocardial infarction. There were 3 deaths attributable to cardiac causes. In an analysis of prior studies in which 4399 patients were treated with tadalafil, the incidence rate of myocardial infarction was 0.43 per 100 patient-years [17]. The incidence rate for placebo controls in tadalafil and sildenafil studies was [17,18] per 100 patient-years. In the present long-term study, for patient-years of exposure to open-label tadalafil, the incidence rate of myocardial infarction was 0.54 per 100 patient-years. This rate is no higher than that expected for a similarly age-matched population [19]. The incidence rate of cardiac death in this long-term study was 0.18 per 100 patient-years. This rate was no higher than that observed in the general male population under 75 years of age in the United Kingdom (an incidence rate of 0.26 per 100 patient-years) [19]. Cyanopsia (usually described as blue vision), other colour-visual abnormalities, increased brightness/sensitivity to light, haziness, and other generally mild and transient visual effects have been reported with the PDE5 inhibitors sildenafil and vardenafil, and are attributed to PDE6 inhibition [15,18,20 25]. Focused studies of colour vision assessments and retinal examinations have been associated with demonstrable abnormalities in a temporal fashion with sildenafil administration [26,27]. Tadalafil is more selective for PDE5 over PDE6 (700 times more selective) than sildenafil (6.8 times more selective) or vardenafil (>15 times more selective) [15,28]. Only 1 patient complained of blue vision in this long-term tadalafil safety study. Furthermore, this was a single episode that was not reported with additional doses of tadalafil. This is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. No impairment of bluegreen colour discrimination was detected in a previous trial evaluating the effects of tadalafil on vision, and colour-vision alterations were rare (<0.1%) across tadalafil clinical trials [28]. In conclusion, this long-term open-label extension study demonstrated that the favourable safety and tolerability observed with tadalafil during earlier randomised, double-blind, placebo-controlled trials of up to 12 weeks duration were maintained over an additional months of open-label treatment. These findings support the long-term use of tadalafil in the clinical management of erectile dysfunction. Acknowledgements Funding by Lilly ICOS LLC (Bothell, Washington, and Indianapolis, Indiana, USA). References [1] Aytaç IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50 6. [2] McKinlay JB. The worldwide prevalence and epidemiology of erectile dysfunction. Int J Impot Res 2000;12(Suppl 4):S6 11. [3] Hatzichristou DG, Pescatori ES. Current treatments and emerging therapeutic approaches in male erectile dysfunction. BJU Int 2001; 88(Suppl 3):11 7. [4] Hatzichristou DG. Current treatment and future perspectives for erectile dysfunction. Int J Impot Res 1998;10(Suppl 10):S3 13. [5] Jardin A, Wagner G, Khoury S, Giuliano F, Goldstein I. editors, Recommendations of the First International Consultation on Erectile Dysfunction, cosponsored by the World Health Organization (WHO). Plymouth: Health Publications Ltd; [6] Brock GB, McMahon CG, Chen KK, Costigan T, Shen W, Watkins V, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002;168: [7] Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. Dose-normalized pharmacokinetics of single-dose tadalafil (IC351) in healthy volunteers. Int J Impot Res 2001;13(Suppl 5):S62 [Abstract 14]. [8] Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351). Int J Impot Res 2001;13(Suppl 5):S63 [Abstract 16]. [9] DeBusk R, Drory Y, Goldstein I, Jackson G, Kaul S, Kimmel SE, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol 2000;86: [10] Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151: [11] Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts Male Aging Study. J Urol 2000;163: [12] Sullivan ME, Thompson CS, Dashwood MR, Khan MA, Jeremy JY, Morgan RJ, et al. Nitric oxide and penile erection: is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999;43: [13] Shabsigh R, Fishman IJ, Schum C, Dunn JK. Cigarette smoking and other vascular risk factors in vasculogenic impotence. Urology 1991; 38:

6 344 F. Montorsi et al. / European Urology 45 (2004) [14] Padma-Nathan P, Giuliano F. Oral drug therapy for erectile dysfunction. Urol Clin North Am 2001;28: [15] Summary of Product Characteristics. Levitra European Public Assessment Report (EPAR). First published March 19, 2003 at Accessed May 20, [16] Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russell Jr RO, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol 1999;33: [17] Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol 2003;92(Suppl 8A):37M 46M. [18] Sadovsky R, Miller T, Moskowitz M, Hackett G. Three-year update of sildenafil citrate (Viagra 1 )efficacy and safety. Int J Clin Pract 2001;55: [19] Shakir S, Wilton I, Heeley E, Layton D. Sildenafil prescriptionevent monitoring study: no evidence of an increase in cardiovascular outcomes among 5,000 men prescribed sildenafil in general practice in England. J Am Coll Cardiol 2001;17(Suppl A): 299A. [20] Fink HA, Mac Donald R, Rutks IR, Nelson DB, Wilt TJ. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002;162: [21] Morales A, Gingell G, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (VIAGRA TM ) in the treatment of erectile dysfunction. Int J Impot Res 1998;10: [22] Hellstrom WJG, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T, the Vardenafil Study Group. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl 2002;23: [23] Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E, et al. the Vardenafil Study Group. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impot Res 2001;13: [24] Estrade M, Grondin P, Cluzel MJ, Bonhomme B, Doly M. Effect of a GMP-specific phosphodiesterase inhibitor on retinal function. Eur J Pharmacol 1998;352: [25] Gonzalez CM, Bervig T, Podlasek C, Huang CF, McKenna KE, McVary KT. Sildenafil causes a dose- and time-dependent downregulation of phosphodiesterase type 6 expression in the rat retina. Int J Impot Res 1999;11(Suppl 1):S9 14. [26] Luu JK, Chappelow AV, McCulley TJ, Marmor MF. Acute effects of sildenafil on electroretinogram and multifocal electroretinogram. Am J Ophthalmol 2001;132: [27] McCulley TJ, Lam BL, Marmor MF, Hoffman KB, Luu JK, Feuer WJ. Acute effects of sildenafil (Viagra) on blue-on-yellow and whiteon-white Humphrey perimetry. J Neuroophthalmol 2000;20: [28] Summary of Product Characteristics. Cialis European Public Assessment Report (EPAR). First published June 12, 2002 at Accessed May 21, Editorial Comment Jeremy P.W. Heaton, Kingston, Ontario, Canada In the world of erectile dysfunction (ED) long-term safety and tolerability studies are the less glamorous relatives of the beautiful acute efficacy studies. In practice they probably reveal more about the future as long as the efficacy side of the equation is solid. This is because studies like Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction document the modern benign reality of living with ED and ED therapy. Furthermore long-term safety issues are possibly the most likely to express the divergence in molecular design that places tadalafil as the least typical of the current generation of the class of selective, reversible phosphodiesterase type 5 (PDE5) inhibitors. This is not a comparative study but certainly there are particular issues that will interest clinicians that have been highlighted by personal experience, prior literature and rumour or urban legend. In fact comparisons should not be constructed from these data because of the individual nature of study design, patient inclusion and exclusion criteria and eventual patient demographics including severity. Staying in a long-term study is burdensome for the patient even if the drug is free more than 60% remained in evaluation until the end of their study period. Why the patients left the study is of some interest but whatever the data say these patients are still impotent needing drug to function sexually they have the same partner, the same image in the mirror and the same financial and domestic situations. In a few patients the effects of the drug itself will cause the patients to discontinue prematurely here only 3.1% of patients. Most patients will choose to migrate to the highest dose (72% at 3 months had chosen 20 mg tadalafil) following the well established trend of men wanting to be as good as they imagined themselves to be. With a different selectivity profile from other published PDE5 inhibitors visual disturbances were here limited to just 1 patient who complained of a single episode that did not recur. The patient population looked very like those reported in the Massachusetts Male Aging Study (MMAS) and other ED clinical trials. The present study population had similar proportions of patients with cardiovascular diseases and in the 1676 patient years represented here there were no deaths attributable to drug. There were just 9 myocardial infarctions (0.8% of patients) giving a rate that is similar to that reported in similar studies with an average rate of 1.9 tablets a week and a long half-life it would be difficult to make a case for complete absence of drug during all these events but neither did it alter the profile. There were 75 patients (6.4%) who were on alpha blockers and there is no specific mention of safety signals from them. Back pain (8.2%) joins the more familiar headache (15.8%), dyspepsia (11.8%) and nasopharyngitis (11.4%) that should be mentioned to patients as minor issues that may affect a proportion of them at one time or another. We are no further ahead from this paper in

7 F. Montorsi et al. / European Urology 45 (2004) understanding the various myalgias associated with PDE5 inhibitor therapy but neither was that an intent for the study. In summary therefore, the growing diversity in oral therapies for ED appears to be entirely in the patient s favour. The new clinical properties for tadalafil we have seen documented elsewhere are complemented by a solid long-term safety profile. Patients will tell their physicians how they want their PDE5 inhibitor served up.