Profile of Silodosin. Francesco Montorsi * Article info. Abstract

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1 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) available at journal homepage: Profile of Silodosin Francesco Montorsi * Department of Urology, University Vita-Salute San Raffaele, Scientific Institute H. San Raffaele, Milan, Italy Article info Keywords: a1a-adrenoceptor antagonist Silodosin Tamsulosin Pharmacology Efficacy Safety Abstract Silodosin is a highly selective a1a-adrenoceptor antagonist approved for the treatment of the signs and symptoms of benign prostatic hyperplasia. Its clinical pharmacology profile offers a number of advantages, including uroselectivity, once-daily (QD) dosing, a standard dose of 8 mg QD that does not need to be adjusted according to age, and the feasibility of concomitant treatment with phosphodiesterase type 5 (PDE5) inhibitors and antihypertensive agents. Three phase 3 double-blind, randomised trials using the dosage regimen of 8 mg QD in >800 patients have shown that silodosin is significantly more effective than placebo ( p < 0.001) and at least as effective as tamsulosin (0.4 mg QD) in improving International Prostate Symptom Score (IPSS) total score, storage subscore, and voiding subscore. It is significantly more effective than tamsulosin in inducing simultaneous improvement of bothersome lower urinary tract symptoms such as incomplete emptying, frequency, and nocturia ( p = 0.03). Safety data collected in 1581 patients exposed to chronic treatment with silodosin 8 mg QD have shown that the drug is safe and well tolerated. As was to be expected with a uroselective compound, cardiovascular effects have been minimal. The most common adverse reaction is retrograde ejaculation (anejaculation), which led to treatment discontinuation in only 3.9% of patients. The rare, drug class related safety issue of intraocular floppy iris syndrome can be satisfactorily managed by warning patients simply to inform their ophthalmologist that they are or were on treatment with an a1-adrenoceptor blocker. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel.: ; fax: address: montorsi.francesco@hsr.it. 1. Introduction Silodosin is an a1-adrenoceptor antagonist with unequalled selectivity for the a1a-adrenoceptor subtype (a1a-to-a1b binding ratio: 162:1) (unpubl data, Recordati [1]). Silodosin is approved for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) in Europe, the United States, and Japan. As with many other medicinal products, the recommended dose is different in Europe and the United States as compared to Japan: one 8-mg capsule daily (with a starting dose of one 4-mg capsule daily in patients with moderate renal function impairment) in both Europe and the United States versus either one 2-mg or 4-mg capsule twice daily in Japan. 2. Clinical pharmacology 2.1. The importance of a1a-adrenoceptor selectivity The function of the three a1-adrenoceptor subtypes differs considerably: The a1a receptors predominate in mediating prostate contraction and the human urethra contains only a1a receptors [2,3], whereas a1a, a1b, and a1d all mediate blood vessel dilation [4]. Consequently, the high selectivity /$ see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 492 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) of silodosin for the a1a subtype should result in better cardiovascular tolerability without any loss of efficacy on urinary tract symptoms, as compared to less selective a-adrenoceptor blockers. Indeed, negligible effects on the cardiovascular system have been documented in the animal model as well as in studies in healthy volunteers. Moderate effects on blood pressure and no effects on cardiac repolarisation were recorded in dogs given oral doses of silodosin up to 200 times the standard therapeutic dose proposed for humans [5]. No meaningful effects on heart rate, pulse rate, and QRS interval duration were observed in healthy volunteers receiving silodosin at a dose three times higher than that proposed as the standard therapeutic dose (24 mg) [6] Pharmacokinetics The pharmacokinetic profile of silodosin enables once-daily (QD) dosing and a standard dosage regimen that does not have to be tailored to the patient, with the only exception being patients with moderate impairment of renal function. Silodosin is readily absorbed from the gut, and peak plasma concentration (C max ) and area under the curve (AUC) for plasma concentration versus time increase linearly with dose [7]. Absolute bioavailability amounts to approximately 32% [8]. Food blunts C max and delays time to C max by about 1 h without affecting the AUC. This feature has been exploited by recommending the administration of silodosin with food, ideally during breakfast in the morning, to avoid plasma concentration peaks that could potentially be associated with adverse effects [7 9]. Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and oxidative pathways involving CYP3A4. The main metabolite in plasma is the glucuronide conjugate, which is active and reaches concentrations that are three to four times higher than those of the parent compound. Both silodosin and its glucuronide conjugate have a long terminal half-life that makes QD dosing feasible (approximately 11 and 18 h, respectively) [8 10]. Studies in special populations of patients have established that the pharmacokinetic profile of silodosin does not change significantly with age and that body clearance does not diminish, even with advanced age (>85 yr) [11]. Thus, the standard dose of one 8-mg capsule daily can be administered even to elderly patients a very important factor, as the prevalence of BPH increases steeply with age. Dosage adjustment is also not an issue for patients with mild renal function impairment or with mild to moderate liver function impairment. A starting dose is required in patients with moderate renal function impairment (one 4- mg capsule daily), with uptitration after 1 wk. Administration of silodosin is not recommended in patients with severe renal or liver function impairment [8] Pharmacologic interactions Silodosin can be prescribed together with other drugs that are commonly used by patients with symptomatic BPH for example, phosphodiesterase type 5 inhibitors (PDE5-I) and antihypertensive agents provided that the patients are monitored for adverse events [8]. In a placebo-controlled, open-label crossover study in 22 healthy subjects aged yr given 8 mg silodosin for 21 d, orthostatic tests showed minimal reductions in systolic and/or diastolic blood pressure after coadministration of silodosin with a PDE5-I (sildenafil 100 mg or tadalafil 20 mg) [12]. Very few of the 500 hypertensive patients included in the phase 3 clinical trial program reported episodes of orthostatic hypotension (n = 7; 1.4%). They were taking a broad range of antihypertensive agents, including drugs acting on the renin angiotensin system (24%), beta blockers (13%), calcium antagonists (8.7%), and diuretics (7.5%). The rate of orthostatic hypotension was similar amongst the 1081 patients included in the clinical trial program who were not on antihypertensive treatment (n = 13; 1.2%). The use of silodosin is not recommended in patients who are on treatment with strong inhibitors of CYP3A4, such as ketoconazole and anti-hiv protease compounds because its metabolism involves this pathway [8]. This precaution does not extend to moderate CYP3A4 inhibitors, such as diltiazem, which has proved not to interact significantly with silodosin (unpubl data, Recordati [1]). 3. Efficacy After a placebo-controlled, dose-finding, 6-wk treatment study in which the improvement in the American Urological Association (AUA) symptom score versus baseline was clearly better with 8 mg QD ( ; n = 90) than with both 4 mg QD ( ; n = 88) or placebo ( ; n = 86) (unpubl data, Recordati [1]), three large double-blind, randomised, pivotal phase 3 clinical trials were carried out with the selected dose regimen (8 mg QD) in >800 patients [8]. Two were placebo-controlled, double-blind trials in the United States designed to demonstrate superiority over placebo and one was a placebo-controlled, double-blind, three-armed clinical trial in Europe designed to demonstrate superiority over placebo and noninferiority to an active comparator (tamsulosin 0.4 mg QD). Patients were randomised to placebo or active treatment for 12 wk after a 4-wk placebo run-in. The randomisation ratio was 1:1 in the US studies and 2:2:1 (1 being the placebo arm) in the European study. The main inclusion criteria for patient recruitment were the same in the three trials and consisted of International Prostate Symptom Score (IPSS) or AUA total symptom score 13 and a maximum urine flow rate (Q max ) of 4 15 ml/s with a minimum voided volume 125 ml. The three clinical trials also had the same primary end point: change in IPSS total score versus baseline. IPSS subscores related to storage and voiding symptoms were taken as secondary end points in addition to the responder rate (only in the European study, defined as the rate of patients who experienced a decrease in IPSS total score 25% compared with baseline) and the Q max. Silodosin was consistently superior to placebo in terms of change in IPSS total score versus baseline in all the three trials (all p < 0.001). The mean difference in IPSS total score

3 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Table 1 Total International Prostate Symptom Score (IPSS): superior efficacy versus placebo in two pivotal phase 3 clinical trials Study Treatment arm No. patients IPSS total score Baseline value Change from baseline p value SI04009 Silodosin 8 mg QD <0.001 Placebo SI04010 Silodosin 8 mg QD <0.001 Placebo QD = once daily. versus placebo was always clinically significant, ranging from 2.3 to 2.9 [8] (Table 1). The results were similar when the storage and voiding subscores were taken into consideration, with a trend towards greater efficacy on voiding symptoms. The improvement versus placebo in storage symptom score amounted to 0.9 (95% confidence interval [CI]; 1.4, 0.4) and 1.0 (95% CI; 1.5, 0.6) in the two US trials (both p < 0.001) [13] and to 0.7 (95% CI; 1.1, 0.2) in the European trial ( p = 0.002) [14]; the improvement versus placebo in the voiding symptom score was 1.9 (95% CI; 2.6, 1.2) and 1.8 (95% CI; 2.5, 1.1) in the two US trials and 1.7 (95% CI; 2.2, 1.1) in the European trial (all p < 0.001). The responder rate was also consistently higher with silodosin than with placebo: 52.8% and 53.6% of patients responded to silodosin versus 31.6% and 32.8% to placebo, respectively, in the two US studies (both differences p < ). In the European trial, the responder rate was 68% in the silodosin group and 53% in the placebo group ( p < 0.001) [14]. In the European trial, silodosin was also superior, albeit not significantly so, as compared with tamsulosin in reducing the total IPSS score as well as the storage subscore ( 0.7 vs 0.6) and voiding subscore ( 1.7 vs 1.4) [14]. Itshouldbe borne in mind that the study was designed to demonstrate noninferiority to tamsulosin and superiority over placebo; in the absence of preliminary direct comparisons, the superiority over tamsulosin was not the objective of the study. The same was true for the responder rates: 68% in the silodosin group and 65% in the tamsulosin group, both significantly higher than 53% in the placebo group ( p < for silodosin and p = for tamsulosin) [14]. Nevertheless, all the data were consistently numerically higher with silodosin than with tamsulosin. The measurement of Q max after the first dose in the US studies showed an onset of action within 2 6 h after administration, and the measurement of IPSS during the first week after the introduction of treatment showed that the change in total IPSS versus baseline became clinically meaningful after 3 4 days [13]. A total of 661 patients in the United States and 500 patients in Europe entered an openlabel, long-term phase for up to 12 months. Patients who had previously received placebo experienced larger decreases in total score ( ) than patients who had previously received silodosin, who continued to experience the same degree of improvement in the long term ( ) [15]. Explorative post hoc analyses were carried out to assess the efficacy of silodosin according to the severity of symptoms ( moderate or severe defined as IPSS total score < 20 or 20, respectively) and on nocturia (in view of the potential complications caused by this symptom, such as falls). In addition, the percentage of patients showing a contemporary improvement in three bothersome symptoms (ie, incomplete emptying, frequency, and nocturia) has been evaluated. In fact, these symptoms could be seen as linked. The sensation of incomplete emptying indicates that a lower percent of urinary volume is voided; consequently, the patient is obliged to void more often to empty his bladder during the day (frequency) and during the night (nocturia). The results did not differ according to severity of symptoms. Silodosin was significantly more effective than placebo in reducing both moderate and severe symptoms as compared to placebo in all the three studies ( p < 0.001). Also tamsulosin was significantly more effective than placebo ( p < 0.01), and a slight superiority of silodosin over tamsulosin was recorded in both subgroups (mean difference in total IPSS score change vs placebo: moderate symptoms, 0.4; severe symptoms, 0.3). In the pooled dataset of the three studies, the mean number of nocturia episodes diminished significantly by 0.2 episodes per night (95% CI; 0.3, 0.1; p < 0.001); also the percentage of patients reporting an improvement was significantly higher in the silodosin group (53.4% vs 42.8%; p < 0.001). The findings were similar in the subgroup of patients who reported 2 episodes at baseline: The mean difference in score between treatments was 0.2 (95% CI; 0.3, 0.1; p < 0.001), and the improvement rate was 60.6% in the silodosin group versus 48.7% in the placebo group ( p < ). In the European study, the percentage of the intention-to-treat (ITT) population that reported a reduction in mean nocturia versus baseline by at least one episode was significantly higher in the silodosin group than in the placebo group (59% vs 45%; p = 0.01), whereas the difference between the tamsulosin group and the placebo group was not significant (54% vs 45%). The same was true in the subgroup of patients who reported at least two episodes of nocturia at baseline (silodosin 67%, tamsulosin 63%, placebo 55%; p < 0.05 only silodosin vs placebo; Fig. 1). In the pooled dataset, the percentage of patients with simultaneous improvement in the three bothersome symptoms (incomplete emptying, frequency, and nocturia) was significantly higher in the silodosin group than in the placebo group, both in the ITT population (30.5% vs 20.2%; p < ) and in the subgroup of patients who reported two or more episodes of nocturia at baseline (34.9% vs 23.2%; p < ). In the European study, the improvement

4 494 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) Fig. 1 Percentage of patients with reduction of at least one episode of nocturia (placebo = 148; silodosin = 308; tamsulosin = 308). * p < 0.05 versus placebo. Fig. 2 Percentage of patients with simultaneous improvement in incomplete emptying, frequency, and nocturia (patient population and subgroup with two or more episodes of nocturia). p = 0.02 versus placebo; p = 0.03 versus tamsulosin. # p = 0.04 versus placebo; p = 0.03 versus tamsulosin. in the percentage of these patients was significantly higher with silodosin than with both tamsulosin ( p = 0.03) and placebo ( p = 0.02; Fig. 2) (unpubl data, Recordati [1]). 4. Safety A total of 1581 patients were exposed to chronic treatment with silodosin 8 mg QD. Of these, 961 patients (62.4%) were exposed for 6 months and 384 patients (24.9%) for 12 months [8]. In the placebo-controlled studies, 28.8% of patients given silodosin (n = 931) experienced one drugrelated adverse event or more compared with 9% of patients in the placebo group (n = 733). Out of the 1581 patients exposed to silodosin, 31.8% reported one drug-related adverse event or more (Table 2). In the placebo-controlled trials, 4.3% of patients discontinued treatment because of an adverse event in the silodosin groups versus 1.9% in the placebo groups; thus, the difference between active treatment and placebo amounted to only 2.4%. The main adverse events that caused discontinuation were retrograde ejaculation (3.9%), dizziness (0.5%), and orthostatic hypotension in 0.2% of patients. The most common adverse reactions reported were the same reactions that caused the discontinuations: retrograde ejaculation (21.5% of patients in placebo-controlled trials vs 0.8% with placebo; 23.6% overall), followed by dizziness (1.8% in placebo-controlled trials vs 0.8% with placebo; 2.1% overall). Other adverse reactions reported by 1% of patients overall were orthostatic hypotension, nasal congestion, and headache (all 1.3%) as well as diarrhoea (1.0%). It is interesting to note that, considering the US and European studies overall, 32% of patients concomitantly took antihypertensive medications. Nevertheless, no statistically significant differences in orthostatic hypotension have been shown versus placebo (1.4% vs 1% respectively). Retrograde ejaculation does not appear to be particularly bothersome. Whereas >20% of patients reported this adverse effect, only 3.9% discontinued treatment because of it. Furthermore, this effect is fully and promptly reversible within a few days after discontinuation of treatment [8]. The most likely explanation for the difference between the occurrence rate and discontinuation rate is that patients with lower urinary tract symptoms (LUTS) often suffer from initial sexual dysfunction, including diminished ejaculation, independent of any subsequent treatment [16]. This effect was historically called retrograde ejaculation, because it was believed that failure to ejaculate was the result of smooth muscle relaxation in the prostate, urethra, and bladder neck leading to abnormal urethral flow, as is the case after transurethral resection of the prostate. However, recent studies have shown that the mechanism is rather a loss of seminal emission resulting Table 2 Safety profile of silodosin in placebo-controlled trials * Preferred term Placebo-controlled studies All studies Silodosin 8 mg (n = 931) Placebo (n = 733) Silodosin (n = 1581) Patients with drug-related adverse events, n (%) 268 (28.8) 66 (9.0) 502 (31.8) Retrograde ejaculation, n (%) 200 (21.5) 6 (0.8) 373 (23.6) Dizziness, n (%) 17 (1.8) 6 (0.8) 33 (2.1) Orthostatic hypotension, n (%) 11 (1.2) 7 (1.0) 20 (1.3) Nasal congestion, n (%) 9 (1.0) 1 (0.1) 20 (1.3) Headache, n (%) 10 (1.1) 9 (1.2) 20 (1.3) Diarrhoea, n (%) 6 (0.6) 2 (0.3) 16 (1.0) * Source: Silodosin Integrated Summary of Safety (September 2008).

5 EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) from relaxation of the vas deferens [17,18]. Thus, the correct term for the observed effect is anejaculation. An unresolved issue is whether anejaculation has an impact on the quality of orgasm. According to a preliminary randomised, double-blind crossover study in 15 healthy volunteers, orgasm is preserved regardless of ejaculatory dysfunction [19]. Isolated reports of intraoperative floppy iris syndrome (IFIS) manifesting with the triad of pupil constriction, fluttering, and billowing of the iris stroma together with the tendency of the iris to prolapse during cataract surgery have been received with a1 blockers, mainly tamsulosin. However, reports have also been received with other a1 blockers. The event is believed to be a drug class effect resulting from inhibition of the iris dilator muscle [20]. A few cases of IFIS occurred with silodosin in Japan, and one case occurred with silodosin in the US open-label study before investigators were warned about the risk of this event. No cases have been reported in Europe after patients were warned about the risk. 5. Conclusions Silodosin is a novel a1-adrenoceptor blocker that is highly selective for the a1a receptor subset responsible for prostatic and urethral contractility. At the dosage regimen of 8 mg QD, it has proved to be significantly more effective than placebo in controlling LUTS and at least as effective as tamsulosin. Moreover, it is significantly more effective than tamsulosin in inducing simultaneous improvement of some of the most bothersome LUTS (ie, incomplete emptying, frequency, and nocturia). Extensive long-term exposure for up to 1 yr has shown that silodosin is safe and well tolerated. As was to be expected with a highly uroselective compound, the cardiovascular effects of silodosin are minimal. The most common adverse reaction is anejaculation, which was not bothersome in most patients. The rare, drug class related safety issue of IFIS can be satisfactorily managed by warning patients simply to inform their ophthalmologist that they are or were on treatment with an a1-adrenoceptor blocker. Conflicts of interest In recent years, the author has received research support, consultancy, and/or lecturer honoraria in the field of a1- adrenoceptors from Recordati. References [1] Unpubl. data, Recordati SpA, Milano, Italy. Summary of Safety (September 2008), Common Technical Documents on file, Recordati, Milano, Italy. [2] Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006;147: S [3] Roehrborn CG. Efficacy of a-adrenergic receptor blockers in the treatment of male lower urinary tract symptoms. Rev Urol 2009; 11(Suppl 1):S1 8. [4] Guimaraes S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev 2001;53: [5] Tatemichi S, Kiguchi S, Kobayashi M, Yamazaki Y, Shibata N, Uruno T. Cardiovascular effects of the selective alpha1a-adrenoceptor antagonist silodosin (KMD-3213), a drug for the treatment of voiding dysfunction. Arzneimittelforschung 2006;56: [6] Morganroth J, Lepor H, Hill LA, Volinn W, Hoel G. Effects of the selective alpha(1a)-adrenoceptor antagonist silodosin on ECGs of healthy men in a randomized, double-blind, placebo- and moxifloxacin-controlled study. Clin Pharmacol Ther 2010;87: [7] Yoshida M, Homma Y, Kawabe K, Silodosin. a novel selective a1a adrenoceptor selective antagonist for the treatment of benign prostatic hyperplasia. Exp Opin Invest Drugs 2007;16: [8] EPARs for authorised medicinal products for human use: Urorec. European Medicines Agency Web site. humandocs/humans/epar/urorec/urorec.htm. [9] Guay DRP. Silodosin: an orally active selective a1-adrenoceptor antagonist for benign prostatic hyperplasia. 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