ࡱ> [_VWXYZy Hbjbj 0T{{q 8.dDz$:$($$$% & &$q#&%%&&$$7H;;;&r$$;&;; $?9bHDzRs;"8@&&;&&&&&;&&&Dz&&&&&&&&&&&&&  : National Drug Monograph Silodosin (Rapaflo) March 2012 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary1-14 Silodosin is a selective alpha-1 adrenergic receptor antagonist, which results in smooth muscle relaxation in the tissues of the prostate, bladder base and neck, and prostatic urethra Smooth muscle relaxation in these tissues leads to improved urine flow, relief of symptoms associated with benign prostatic hyperplasia (BPH), and increased quality of life Silodosin is indicated for treatment of signs/symptoms associated with BPH The recommended dose of silodosin is 8 mg by mouth once daily with a meal The efficacy of silodosin has been established in three clinical trials, two of which were reported together as pooled data The pooled data demonstrated that, compared to placebo, silodosin produced a significant decrease in total International Prostate Symptom Score (IPSS) at week 12 (decrease of -6.4 6.63 for silodosin vs. -3.5 5.84 for placebo, P < 0.0001) A third trial showed that silodosin was significantly superior to placebo and noninferior to tamsulosin (P < 0.001 for both) at decreasing total IPSS score over 12 weeks All trials showed silodosin significantly improved peak urine flow rate (Qmax) vs. placebo All trials showed increased quality of life in patients taking silodosin vs. placebo The most common treatment-related adverse events occurring in e" 2% of patients taking silodosin included retrograde ejaculation (28.1%), dizziness (3.2%), diarrhea (2.6%), orthostatic hypotension (2.6%), headache (2.4%), nasopharyngitis (2.4%), and nasal congestion (2.1%) Patients with planned cataract surgery should not start silodosin until after surgery due to risk of intraoperative floppy iris syndrome with alpha-1 antagonists The rate of discontinuation of silodosin secondary to retrograde ejaculation was 2.8% in the two pooled trials and 2.9% in the third trial None of the studies found a clinically significant difference in the rate of orthostatic hypotension between silodosin vs. placebo or silodosin vs. tamsulosin Silodosin is extensively metabolized via glucuronidation, alcohol and aldehyde dehydrogenase, and CYP3A4 enzymes in the liver In vitro data demonstrate that silodosin does not inhibit or induce CYP450 enzymes Silodosin is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min), severe hepatic impairment (Child-Pugh score e" 10), or concomitant use of strong CYP3A4 inhibitors such as clarithromycin, ritonavir, ketoconazle, or itraconazole The cost of silodosin is approximately twelve times greater than the formulary alpha-1 adrenergic receptors Introduction The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost and other pharmaceutical issues that would be relevant to evaluating silodosin for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics1 Pharmacokinetic properties were found to be linear across a dosage range from 0.1 mg to 24 mg daily in adult males. Mechanism of action Silodosin selectively antagonizes post-synaptic alpha-1 adrenoreceptors found in prostate, bladder base and neck, prostatic capsule and prostatic urethra. This alpha-1 adrenoreceptor antagonism leads to smooth muscle relaxation, which improves urine flow and reduces benign prostatic hyperplasia (BPH) symptoms. Absorption A multi-dose, open-label, 7-day study conducted in 19 healthy males e" 45 years old yielded the following data: Table 1: Absorption Data for SilodosinCmax (ng/mL)Tmax (hours)T1/2 (hours)AUCss (ng" hr/mL)61.6 27.542.6 0.9013.3 8.07373.4 164.94 The absolute bioavailability of silodosin is approximately 32%. While the maximum effect of a high fat, high calorie meal was not studied, a moderate fat, moderate calorie meal decreased Cmax by 18-43% and AUC by 4-49%. Distribution The apparent volume of distribution of silodosin is 49.5 L. The drug is approximately 97% protein bound. Metabolism Silodosin is extensively metabolized via glucuronidation, alcohol and aldehyde dehydrogenase, and CYP3A4 enzymes in the liver. Direct conjugation by UGT2B7 produces the main metabolite, KMD-3213G. UGT2B7 inhibitors (e.g., probenecid, valproic acid, fluconazole) may increase plasma silodosin concentrations. KMD-3213G is active in vitro, with a t1/2 of ~24 hours and an AUC ~4 times that of silodosin. Alcohol and aldehyde dehydrogenases produce another major metabolite, KMD3293. Plasma concentrations of this metabolite are similar to silodosin, but it is unlikely to contribute to silodosin pharmacological activity. Excretion Ten days after administration of 14C-labeled silodosin, approximately 33.5% was recovered in urine and approximately 54.9% was recovered in feces. Plasma clearance following IV administration was approximately 10 L/hr. Special Populations Race The effect of race was not evaluated. Geriatric With respect to age, geriatric males (mean age 69 years, n = 12) were compared to young males (mean age 24, n = 9). The geriatric AUC was approximately 15% greater, and the geriatric t1/2 was approximately 20% greater than those of the young males. Cmax was unchanged. Pediatric Use in patients < 18 years was not evaluated. Impaired renal function When comparing moderate renal impairment to normal renal function (N=6), total AUC was 3.2 times higher, total Cmax was 3.1 times higher, total t1/2 was 2 times higher, unbound AUC was 2.0 times higher, and unbound Cmax was 1.5 times higher. Additionally, patients with moderate renal dysfunction experienced a greater incidence of orthostatic hypotension and dizziness. Impaired hepatic function Moderate hepatic impairment (Child-Pugh scores 7-9) does not significantly alter pharmacokinetics. Severe hepatic impairment was not evaluated. Table 2: Pharmacokinetics of Selected Alpha-1 AntagonistsParameterSilodosinTerazosin2Tamsulosin3MetabolismHepaticHepaticHepaticElimination~54.9% feces ~33.5% urine~60% feces ~40% urine21% feces 76% urineHalf-life (hrs)13.3 8.07~1214-15Protein Binding~97%90-95%94-99% FDA Approved Indication(s) and Off-label Uses1 Silodosin is indicated for treatment of BPH signs and symptoms. It is not indicated for hypertension, and no off-label uses are described. Potential Off-label Uses Brachytherapy-induced lower urinary tract symptoms in patients with prostate cancer Expulsion of ureteral stones4 Current VA National Formulary Alternatives The current formulary alpha-1 adrenergic receptor antagonists are terazosin, tamsulosin, doxazosin and prazosin. Dosage and Administration1 The recommended dose is 8 mg by mouth once daily with a meal. Renal Impairment Severe (CrCl < 30 mL/min): Contraindicated Moderate (CrCl 30-49 mL/min): 4 mg by mouth once daily with meal Mild (CrCl 50-80 mL/min): No adjustment necessary Hepatic Impairment Severe (Child-Pugh score e" 10): Contraindicated Mild-Moderate (Child-Pugh score 7-9): No adjustment necessary Efficacy U.S. Data Marks, et al5 pooled data from two phase-three trials to evaluate efficacy and safety of silodosin for treating symptoms of benign prostatic hyperplasia. Study Design Pooled data from two identically designed parallel group, multicenter, randomized, double-blind, placebo controlled phase three studies (N = 923) was evaluated. Patients were randomized 1:1 and received either placebo or silodosin 8 mg daily with breakfast. Both studies were 12 weeks long, preceded by a placebo run-in period of 4 weeks. Primary efficacy endpoint was mean change in total International Prostate Symptom Score (IPSS) from baseline to week 12. This measure incorporated total IPSS, irritative and obstructive IPSS subscores, and quality of life (QoL) scores. Secondary efficacy measure was change in peak urine flow rate (Qmax) from baseline to week 12. Safety measures included adverse event reporting, 12-lead electrocardiograms, clinical laboratory tests, vital signs, evaluation of postural hypotension and physical examination. Data Analysis Sample size for each study was chosen to meet regulatory requirement of exposing at least 100 patients for one year and 300 patients for six months. A pilot phase II study of silodosin led to an observed standard deviation of 5.2 in change from IPSS baseline total score. From this, the authors calculated that a sample size of 240 patients per group with 90% power and  = 0.05 would enable detection of a 1.54 difference in mean IPSS change from baseline between the two groups. Therefore, the sample size in this study enabled detection of a significant difference in mean IPSS of 2 to 2.5. Analysis of covariance (ANCOVA) was used to evaluate differences between treatment groups. The baseline measure served as the covariate, and treatment effect for each efficacy measure was included in the model. The results were calculated as adjusted means with 95% CI, and a 2-sided 5% significance level was employed for all tests. Inclusion Criteria Men e" 50 years of age IPSS e" 13 Qmax 4-15 mL/second Post-void residual < 250 mL Table 3: Exclusion Criteria from Marks, et al5Intravesical obstruction unrelated to BPHBladder calculiHistory of or current condition affecting bladder functionPrior surgical intervention to relieve BPH or bladder neck obstructionActive UTI or history of recurrent UTI within past 2 yearsProstatitis within past 3 monthsBPH unrelated urinary retention within past 3 monthsHistory of recurring prostatitis (>3 times in past year)Prior or current prostate cancer or PSA > 10 ng/mLPrior invasive bladder cancerBladder catheterization or bladder/prostate instrumentation within past 30 daysHistory of or current significant postural hypotension Table 4: Efficacy Results from Marks, et al5Mean (SD) Change from BaselineDifference Silodosin vs. PlaceboVariableSilodosinPlaceboAdjusted Mean (95% CI)p-valueIPSSTotal Wk 0.5-4.2 (5.26)-2.3 (4.37)-1.9 (-2.5, -1.3)<0.0001 Wk 12*-6.4 (6.63)-3.5 (5.84)-2.8 (-3.6, -2.0)<0.0001Irritative Wk 0.5-1.4 (2.35)-0.8 (2.16)-0.5 (-0.8, -0.3) 0.0002 Wk 12*-2.3 (2.93)-1.4 (2.66)-1.0 (-1.3, -0.6)<0.0001Obstructive  Wk 0.5-2.8 (3.55)-1.4 (2.99)-1.4 (-1.8, -1.0)<0.0001 Wk 12*-4.0 (4.31)-2.1 (3.76)-1.9 (-2.4, -1.4)<0.0001Qmax (mL/sec) Hours 2-62.8 (3.44)1.5 (3.76)1.3 (0.9, 1.8)<0.0001 Wk 12*2.6 (4.43)1.5 (4.36)1.0 (0.4, 1.5) 0.0007*Data from week 12 included last observation carried forward for some patients Table 5: Quality of Life Outcomes from Marks, et al5Silodosin n/466 (%)Placebo n/457 (%)BaselineDelighted / pleased / mostly satisfied32 (6.9)33 (7.2)Equally satisfied / dissatisfied126 (27.0)124 (27.1)Mostly dissatisfied / unhappy / terrible308 (66.1)300 (65.6)Wk 12*Delighted / pleased / mostly satisfied149 (32.0)103 (22.5)Equally satisfied / dissatisfied141 (30.3)110 (24.1)Mostly dissatisfied / unhappy / terrible176 (37.8)244 (53.4)*Data from week 12 included last observation carried forward for some patients Conclusions Silodosin therapy rapidly and sustainably improves the urinary symptoms associated with BPH. Patients tolerate therapy well, and the incidence of orthostatic hypotension is low. Silodosin provides a useful therapeutic option for patients suffering with symptoms of BPH. Strengths This study enrolled a large number of patients. The treatment groups were well-matched with respect to demographic characteristics. Limitations A limitation is that the trial was only 12 weeks long, and some week 12 results are actually last observation carried forward. The results may not accurately reflect long term efficacy and safety of silodosin. Additionally, no direct comparison to other 1 antagonists was performed. While silodosin was shown to be superior to placebo, its place among other agents is yet to be determined. Finally, the extensive exclusion criteria limit external validity to the VA patient population. Extension Trial Marks, et al6 went on to perform an open-label extension study to evaluate the safety of long-term silodosin use. Study Design Multicenter, 9-month, open-label extension study which enrolled patients completing one of the two 12-week studies detailed in Marks, et al4 above. Previously, 347 patients received placebo in the 12 week studies (the de novo group) and 314 received silodosin (the continuing group). All patients received silodosin 8 mg daily with breakfast for a duration of 40 weeks. Seven follow-up visits occurred at weeks 0 (on the last visit of the initial double-blind study), 2, 8, 16, 24, 32, and 40 (or at discharge). Primary endpoint was safety evaluation of silodosin over 9 months (40 weeks), as determined by adverse event reports, vital sign assessments, electrocardiogram (ECG), laboratory tests, and physical exam. Additionally, changes from baseline IPSS and QoL were evaluated in patients who had received placebo and in patients who had received treatment during the initial double-blind study. Total treatment duration for those who received treatment during the initial study was no more than one year. Data Analysis All patients receiving at least one dose of study drug were included in all analyses. Adverse event reports were obtained at each visit after initiation of treatment. Baseline safety data (except adverse events) and assessments of efficacy were identical to data gathered at the final visit of the initial double-blind study. Subsequent safety data (except adverse events) was gathered at visits 3 and 7; vital signs and laboratory tests were obtained during the fourth visit. Adverse event classification was based upon terminology in the Medical Dictionary for Regulatory Acitivities (MedDRA). Postbaseline IPSS was assessed at visit 7 (week 40) or upon discharge. Evaluation of QoL was achieved using patient responses to IPSS question 8: If you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that? A 7-point scale was used, with 0 being delighted and 6 being terrible. Changes in IPSS throughout the study were analyzed without data imputation from observed cases as well as with last observations carried forward in order to ascribe any values that were lacking at week 40. Paired t tests assessed the statistical significance of changes from baseline. Inclusion Criteria Inclusion criteria for the initial double-blind trials were detailed above in Marks, et al4. For the open-label extension study, patients had to be at least 50 years of age and in good health as determined by medical history, physical exam, and laboratory tests. Table 6: Exclusion Criteria from Marks, et al6Participation in any other drug study within past 30 days or 5 half-lives of other study drugIntravesical obstruction not due to BPHBladder calculiNeurogenic bladder/other conditions potentially affecting bladder functionPrior surgery to relieve BPH or bladder neck obstructionActive UTI, current prostatitis, or chronic prostatitis/urinary retention not related to BPHSuspected prostate cancer or PSA > 10.0 ng/mLInvasive bladder cancerPrior radiation to pelvisBladder catheterization or bladder/prostate instrumentationCurrent medical condition/device precluding safe inclusionDrug/alcohol abuse within past 12 monthsAllergy to inactive ingredients of silodosinUncontrolled hypo- or hyperthyroidism Table 7: Excluded Medications from Marks, et al6-Blockers (other than silodosin) and -agonistsKetoconazole and other potent CYP450 3A4 inhibitorsNatural/herbal products for prostateAndrogens/antiandrogensExcluded unless dose was considered low and stable by investigator:DiureticsAntispasmodicsCholinomimeticsAnticholinergicTricyclic antidepressantsPsychiatric drugs with anticholinergic side effects (potential effect on bladder function) Table 8: Adverse Events Affecting e" 2% of Patients from Marks, et al6Silodosin TreatmentMedDRA Term, n (%)De Novo (n = 347)Continuing (n = 314)Total (n = 661)Retrograde ejaculation108 (31.1)30 (9.6)138 (20.9) Orgasm, no semen86 (24.8)23 (7.3)109 (16.5) Orgasm, semen quantity reduced17 (4.9)6 (1.9)23 (3.5)Diarrhea16 (4.6)11 (3.5)27 (4.1)Nasopharyngitis12 (3.5)12 (3.8)24 (3.6)Dizziness12 (3.5)7 (2.2)19 (2.9)Upper respiratory tract infection9 (2.6)9 (2.9)18 (2.7)Arthralgia11 (3.2)6 (1.9)17 (2.6)Orthostatic hypotension10 (2.9)7 (2.2)17 (2.6)Increased PSA8 (2.3)6 (1.9)14 (2.1)Nasal congestion8 (2.3)5 (1.6)13 (2.0) Table 9: Changes in IPSS from Marks, et al6Silodosin TreatmentMean (SD)De Novo (n = 347)Continuing (n = 314)IPSS total score Baseline17.8 (6.9)14.5 (7.1) CFB to wk 40 (OC)-4.5 (6.7)-1.6 (6.0) CFB to wk 40 (LOCF)-3.0 (6.2)-1.0 (5.5)IPSS irritative subscore Baseline7.9 (3.2)6.9 (3.3) CFB to wk 40 (OC)-1.7 (3.2)-0.6 (2.8) CFB to wk 40 (LOCF)-1.2 (2.9)-0.5 (2.6)IPSS obstructive subscore Baseline9.9 (4.5)7.6 (4.5) CFB to wk 40 (OC)-2.8 (4.2)-1.0 (3.9) CFB to wk 40 (LOCF)-1.8 (3.9)-0.5 (3.6)CFB: Change from baseline; OC: Observed cases; LOCF: Last observation carried forward P values for all changes from baseline: <0.001 (de novo group); <0.01 (continuing group) Conclusions Silodosin was safely tolerated over a 9-month period by patients with signs and symptoms of BPH. Low incidences of dizziness and orthostatic hypotension occurred with its use. The most common adverse event, retrograde ejaculation, led to discontinuation in the de novo group more often than in the continuation group. The investigators did not consider any cardiac events to be drug-related, and no QTc prolongation was observed. Strengths This study evaluated the safety of silodosin therapy over a longer period of time than previous double-blind trials. Limitations No placebo control was utilized in this study. Additionally, some results are actually last observation carried forward, which may not accurately reflect long term safety of silodosin. Finally, the extensive exclusion criteria limit external validity to the VA patient population. Japanese Data Kawabe, et al7 performed a multi-site study in Japan to compare efficacy and safety of silodosin to tamsulosin and placebo in patients with lower urinary tract symptoms due to BPH. Study Design A randomized, double-blind, placebo-controlled clinical trial (N=457) was performed at 88 sites in Japan. Patients were randomized to receive either silodosin 4 mg twice daily, tamsulosin 0.2 mg/day, or placebo twice daily for 12 weeks following a 7-day washout period and a 7-day observation period. Primary efficacy endpoint was change in total IPSS from baseline. Secondary endpoints included change in Qmax, urodynamics, and evaluation of subjective symptoms (IPSS voiding and storage scores and QoL score). Safety assessment included evaluation of adverse events, physical examination, vital signs and laboratory tests. Data Analysis Power calculations were not detailed, but target sample size was 170 men in the silodosin group, 170 in the tamsulosin group, and 85 in the placebo group. A two-sided t-test was used to verify superiority over placebo, and proof of noninferiority to tamsulosin was obtained using a noninferiority test with a delta of 1.0. Safety parameters were assessed using Fishers exact method. Inclusion Criteria e" 50 years of age Lower urinary tract symptoms (LUTS) due to BPH BPH diagnosed by digital rectal examination or ultrasound Total IPSS e" 8 QoL score e" 3 Prostate volume e" 20 mL Qmax < 15 mL/s with void volume e" 100 mL and residual volume < 100 mL Table 10: Exclusion Criteria from Kawabe, et al7Use of antiandrogen preparations or within past yearHistory of prostatectomy, intrapelvic radiation therapy, or prostatic hyperthermia Confirmed or suspected prostate cancerNeurogenic bladderBladder neck constrictionUrethral strictureBladder calculusSevere bladder diverticulumActive UTI requiring medical treatmentRenal impairment (SCr e" 2.0 mg/dL)Other complications likely to impact micturitionSevere hepatic disordersSevere CV diseaseHistory of orthostatic hypotension Table 11: Efficacy Data from Kawabe, et al7 Silodosin N=175Tamsulosin N=192Placebo N=89P*P Mean (SD):Change in total IPSS, wk 1-3.4 (4.2)-2.7 (4.1)-1.2 (3.4)<0.0010.110Change in total IPSS, wk 2-4.9 (4.9)-3.7 (4.4)-2.2 (4.1)<0.0010.011IPSS voiding symptoms Baseline10.8 (4.1)10.8 (4.2)10.9 (4.4) Change-5.8 (4.6)-4.8 (4.1)-3.8 (4.8)<0.0010.023IPSS storage symptoms Baseline6.4 (3.0)6.2 (2.9)6.3 (2.8) Change-2.5 (2.9)-2.1 (2.6)-1.5 (2.6)<0.0060.106n/N (%) patients with e" 25% improvement in IPSS133/174 (76.4)126/192 (65.6)45/89 (50.6)<0.0010.028Mean (SD):IPSS in severe (IPSS e" 20) patients Baseline23.9 (3.6)23.9 (3.3)24.9 (3.8) Change-12.4 (7.3)-10.1 (6.1)-8.7 (8.4)0.0440.063IPSS in moderate (IPSS 8-19) patients Baseline13.9 (3.2)13.8 (3.1)13.7 (3.0) Change-6.3 (4.9)-5.3 (4.9)-3.8 (5.3)0.0010.105QoL score Baseline4.9 (0.8)4.7 (0.8)4.7 (0.9) Change-1.7 (1.4)-1.4 (1.3)-1.1 (1.2)0.0020.052Qmax Baseline9.88 (2.75)9.41 (2.81)10.18 (2.72) Change1.70 (3.31)2.60 (3.98)0.26 (2.21)0.0050.063*Silodosin vs. placebo Silodosin vs. tamsulosin Values from post hoc subgroup analysis of patient with change of voided volume from baseline of < 50% The change in total IPSS from baseline in silodosin, tamsulosin and placebo groups was -8.3, -6.8, and -5.3, respectively. Silodosin resulted in a significant decrease in IPSS vs. placebo at week 1 (P < 0.001), and a significant decrease in IPSS vs. placebo and tamsulosin at week 2 (P < 0.001). Mean (95% CI) differences in total IPSS between silodosin and placebo, and between silodosin and tamsulosin, were -3.0 (-4.6,-1.3) and -1.4 (-2.7,-0.2), respectively. Silodosin was significantly superior to placebo and noninferior to tamsulosin (P<0.001). It improved QoL scores significantly better than placebo (p=0.002). It also improved Qmax significantly better than placebo (P=0.005). A post hoc analysis of this trial was performed8. Subjects randomized in the trial to receive silodosin were stratified by whether or not an ejaculation disorder was present. Efficacy was evaluated by the looking at total IPSS, IPSS subscores, 25% decrease in total IPSS, and QOL scores. Safety was analyzed by evaluating frequency of ADRs as well as silodosin discontinuation. The subgroup with ejaculation disorder had a greater change in total IPSS when compared to those without ejaculation disorder or those in the placebo group. Using a 25% reduction in IPSS as a marker of success, the success rate in those with ejaculation disorder was higher than in the other groups, without a significant difference in the rate of ADRs other than ejactulation disorder. The rates of silodosin discontinuation were similar between the group with ejaculation disorder and the group without. This post hoc analysis demonstrated that, while ejaculation disorder is an undesirable adverse event associated with silodosin therapy, patients with ejaculation disorder may actually experience greater improvements in BPH symptoms without increased risk of other ADRs. Conclusions Silodosin provides a therapeutic alternative for treating BPH-associated lower urinary tract symptoms. It is superior to placebo and noninferior to tamsulosin, and is not associated with obtrusive adverse events. Strengths This trial compared silodosin not only to placebo, but also to tamsulosin. It was a large, multi-center trial. The treatment groups were well-matched with respect to demographic characteristics. None of the authors disclosed a relationship with Watson, nor did Watson fund this study. Limitations The trial was only 12 weeks long, which may not accurately reflect long term efficacy and safety of silodosin. The power calculations used to determine sample size were not clearly outlined. Additionally, the study only demonstrates noninferiority to tamsulosin, rather than superiority. Finally, the extensive exclusion criteria limit external validity to the VA patient population. European Data Chapple, et al9 performed an international, randomized, double-blind clinical trial which compared the efficacy of silodosin to both placebo and tamsulosin. Study Design This multicenter double-blind, placebo- and active-controlled parallel group clinical study took place in 72 sites throughout 11 countries in Europe. A 14-day washout period was followed by a 4-week single-blind placebo run-in. Subjects meeting selection criteria were randomized 2:2:1 to receive silodosin 8 mg daily, tamsulosin 0.4 mg daily, or placebo, respectively. Treatment duration was 12 weeks. Study visits occurred at day -42 (beginning of washout period), day -28 (beginning of placebo run-in), and after days 7,14,28, 56, and 84 of treatment (or at the time of early study discontinuation). Prior to randomization, medical history was collected on each patient, as well as a check of concurrent medications, a physical exam including digital rectal exam, and postvoid residual evaluation by ultrasound. The IPSS questionnaire was given to patients at screening, baseline, and after days 7,14, 28, 56, and 84 of treatment (or at the time of early study discontinuation). Qmax was measured 2-6 hours after a dose during the same time period as IPSS administration. At each visit BP and HR were measured and postural hypotension was assessed at screening and baseline (pre- and postdose). Laboratory testing and ECG were obtained at screening, baseline, and study end (or at the time of early study discontinuation). Adverse events were recorded at each visit. Primary endpoint was change in IPSS from baseline, with the goal of demonstrating silodosin superiority to placebo and noninferiority to tamsulosin. Secondary efficacy endpoints included improvement in storage/voiding symptom subscores, QoL, Qmax, and percentage of responders by IPSS (decrease from baseline of 25% or more) and by Qmax (increase from baseline of 30% or more). Safety analysis included an assessment of treatment-related adverse events as well as change from baseline in BP, HR, orthostatic hypotension, laboratory tests, ECG results, and physical exam. Data Analysis Superiority of silodosin and tamsulosin over placebo was evaluated in the intent-to-treat (ITT) population, which included all patients having a baseline and at least one postbaseline IPSS measurement. Noninferiority of silodosin as compared to tamsulosin was evaluated in all patients who finished the study without a major protocol violation (per protocol, or PP population). Because these predetermined tests were satisfied, superiority of silodosin was assessed in the ITT population. Overall treatment group comparisons of IPSS change from baseline, by visit and at the end of the study (PP and ITT populations) were estimated using adjusted means from the main analysis of the covariance model. This included terms for treatment, pooled center, and baseline value. Percentage of responders by IPSS and Qmax was summarized at each visit as well as at the end of the study. Comparisons of the silodosin and tamsulosin groups vs. placebo were done with the Cochran Mantel Haenszel test and were stratified by pooled center for both patient populations. Safety population included all patients who were randomized and received at least one dose of study medication. Safety was evaluated base on the occurrence of adverse events in each group postrandomization. Change from baseline was also assessed for BP, HR, orthostatic hypotension, laboratory tests, ECG results, and physical exam. Total number to be randomized was 820 (328 silodosin 8 mg, 328 tamsulosin 0.4 mg, 164 placebo) in order to reject the null hypothesis that the active treatments were not equivalent with the assumptions of: SD = 5.2, one-sided, 90% power, noninferiority margin of a mean change of -1.5 IPSS points, and 20% of patients not eligible for inclusion in PP population. The sample size also allowed for two-sided testing at 0.05 significance level with 90% power to detect a mean change in IPSS of -2 from baseline between each active treatement group and the placebo group. Inclusion Criteria Men e" 50 years of age with the following: LUTS (stable IPSS e" 13 points) Bladder outlet obstruction (Qmax of 4-15 mL/s with minimum void volume of e" 125 mL) Compliance with study medication (80-100% during run-in) Table 12: Exclusion Criteria from Chapple, et al9 Improvement in IPSS e" 25% during run-inPostvoid residual volume e" 250 mLIntravesical obstruction not due to BPHHistory of any interventional procedure for BPHActive UTI or history of recurrent UTIsCurrent or chronic prostatitisHistory of prostate or invasive bladder cancerSignificant postural hypotension5-ARI use within past 6 months-blocker or phytotherapy use within past 2 wks Table 13: Change in IPSS Total Score from Chapple, et al9SilodosinTamsulosinPlaceboITT Populationn = 371n = 376n = 185Baseline, mean SD19 419 419 4Change from baseline to end point, adjusted means-7.0-6.7-4.7Difference active vs. placebo (95% CI)-2.3 (-3.2, -1.4)*-2.0 (-2.9, -1.1)*-Difference tamsulosin vs. silodosin (95% CI)0.3 (-0.4, 1.0)--PP Populationn = 346n = 347n = 168Baseline, mean SD19 419 419 4Change from baseline to wk 12, adjusted means-7.0-6.7-4.8Difference active vs. placebo (95% CI)-2.2 (-3.2, -1.3)*-1.9 (-2.8, -0.9)*-Difference tamsulosin vs. silodosin (95% CI)0.4 (-0.4, 1.1)--* p < 0.001 vs. placebo Noninferiority Table 14: Change in IPSS Storage and Voiding Symptoms Subscores from Chapple, et al9IPSS Storage Symptoms SubscoreIPSS Voiding Symptoms SubscoreChange from BaselineDifference (95% CI) vs. PlaceboChange from BaselineDifference (95% CI) vs. PlaceboSilodosin-2.5-0.7* (-1.1, -0.2)-4.5-1.7 (-2.2, -1.1)Tamsulosin-2.4-0.6* (-1.1, -0.2)-4.2-1.4 (-2.0, -0.8)Placebo-1.8--2.9- * p = 0.002 vs. placebo p < 0.001 vs. placebo Table 15: Change in QoL Related to Urinary Symptoms from Chapple, et al9Silodosin No. (%)Tamsulosin No. (%)Placebo No. (%)BaselineDelighted, pleased, or mostly satisfied29 (7.8)32 (8.5)12 (6.5)Mixed: about equally satisfied and dissatisfied94 (25.3)103 (27.4)43 (23.2)Mostly dissatisfied, unhappy, or terrible248 (66.9)241 (64.1)129 (69.7)Week 12*Delighted, pleased, or mostly satisfied163 (44.0)168 (44.7)63 (34.0)Mixed: about equally satisfied and dissatisfied82 (22.1)99 (26.3)38 (20.5)Mostly dissatisfied, unhappy, or terrible126 (34.0)109 (29.0)84 (45.4) Responder Rates All treatment groups showed an increase from baseline to week 12 in the percentage of responders. Upon conclusion of the study, 66.8% of patients receiving silodosin and 65.4% of patients receiving tamsulosin were responders, as compared to 50.8% in the placebo group. Both active treatments demonstrated a statistically significant difference (p < 0.001) when compared to placebo, but no statistically significant difference was found between silodosin and tamsulosin. Qmax Both active treatment groups demonstrated a larger increase from baseline Qmax when compared to placebo, but the difference was not statistically significant. Mean change from baseline (adjusted) was as follows: silodosin 3.77 mL/s (p = 0.089 vs. placebo), tamsulosin 3.53 mL/s (p = 0.221 vs. placebo), and 2.93 mL/s for placebo. Percentage of responders by Qmax was greater for the silodosin and tamsulosin groups vs. placebo. However, due to a high placebo effect, this difference was only statistically significant at sporadic times during various follow-up visits. Upon conclusion of the study, 46.6% of patients in the silodosin group (p = 0.155 vs. placebo) were responders, compared to 46.5% (p = 0.141 vs. placebo) in the tamsulosin group and 40.5% in the placebo group. These differences were not statistically significant. Safety Overall, patients reporting at least one adverse event included 133/381 (34.9%) in the silodosin group, 111/384 (28.9%) in the tamsulosin group, and 46/190 (24.2%) in the placebo group. The most common adverse events, occurring in > 2% of patients, were retrograde ejaculation and headache. Retrograde ejaculation occurred more often in the silodosin group (54/381; 14.2%) vs. the tamsulosin group (8/384; 2.1%) or placebo group (2/190; 1.1%). Headache was reported more frequently in the tamsulosin group (21/384; 5.5%) compared to the silodosin group (11/381; 2.9%); however, this rate was not significantly different than the placebo group (9/190; 4.7%). The percentage of patients discontinuing the study due to adverse events did not differ significantly between all three treatment groups (silodosin 2.1%, tamsulosin 1.0%, placebo 1.6%). Nine patients out of the 955 included in the safety analysis (0.9%) had a serious adverse event, and three of these were considered by investigators to be due to the study drug: prostate cancer and supraventricular arrhythmia attributed to silodosin, and anxiety attributed to tamsulosin. Two patients died during the study but neither death was related to study drugs. No clinically meaningful changes occurred with respect to laboratory tests or ECGs in any of the treatment groups. Silodosin did not cause a statistically significant change from baseline in BP or HR when compared to placebo; however, tamsulosin caused a small but statistically significant difference vs. placebo. No patients in either treatment group experienced significant orthostasis following first dose administration. Conclusions This study confirms the results of prior trials, which have shown silodosin to be efficacious and safe for the treatment of BPH signs and symptoms. Silodosin is superior to placebo and noninferior to tamsulosin. Strengths This study was a large, prospective, multi-center, international, randomized, placebo- and active-controlled clinical trial. It was designed to be well-powered, with power calculations clearly detailed. Silodosin was compared not only to placebo, but also to tamsulosin. Limitations The study only demonstrates noninferiority to tamsulosin, rather than superiority. The trial was only 12 weeks long, which may not accurately reflect long term efficacy and safety of silodosin. Finally, the exclusion criteria limit external validity to the VA patient population. Crossover Data Miyakita, et al10 compared safety and efficacy of silodosin and tamsulosin by utilizing a random crossover method. In this study, patients who had BPH and complained of LUTS were randomized to the silodosin-preceding group (4 weeks of silodosin 4 mg twice daily followed by 4 weeks of tamsulosin 0.2 mg daily) or the tamsulosin-preceding group (4 weeks of tamsulosin 0.2 mg daily followed by 4 weeks of silodosin 4 mg twice daily). Patients did not undergo a withdrawal period prior to making the crossover. During the first 4 week treatment phase, silodosin showed a significantly superior improvement in symptoms as compared to tamsulosin; however, both drugs significantly improved IPSS total scores. After the crossover, significant improvement was found only in the silodosin treatment group. An intergroup comparison demonstrated significant improvement in straining and nocturia with silodosin versus tamsulosin, both in the first and crossover treatments. Silodosin also showed significant improvement in WOL scores throughout both treatment periods; tamsulosin only significantly improved QOL during the initial treatment period. It should be noted that the dosing of tamsulosin utilized in this trial (0.2 mg daily) is below the recommended dose of 0.4 mg daily, which potentially biases the results toward silodosin. The incidence of ejaculation disorder with both silodosin and tamsulosin was similar. The authors of this trial concluded that silodosin provides great efficacy in symptom improvement in both initial and crossover phases, in addition to improving patients QOL. A published comment in response to this crossover trial advises caution when interpreting its results11. The crossover study enrolled only 97 patients; of these, only 65 were ultimately evaluated. Also, the follow-up period was only 8 weeks. This short trial evaluating a small number of patients may not adequately assess the role of silodosin therapy, especially for patients who have failed to respond to other alpha-blockers. Adverse Events (Safety Data)1 Table 16: Adverse Events Occurring in e" 2 % of Patients during 12-week, Placebo-Controlled Randomized Clinical TrialsAdverse ReactionSilodosin (N = 466) n (%)Placebo (N = 457) n (%)Retrograde ejaculation131 (28.1)4 (0.9)Dizziness15 (3.2)5 (1.1)Diarrhea12 (2.6)6 (1.3)Orthostatic Hypotension12 (2.6)7 (1.5)Headache11 (2.4)4 (0.9)Nasopharyngitis11 (2.4)10 (2.2)Nasal Congestion10 (2.1)1 (0.2) Other Adverse Events The following adverse events occurred in 1-2% of the silodosin patients (and more frequently than in the placebo group): Insomnia Elevated PSA Sinusitis Abdominal pain Asthenia Rhinorrhea The following rare adverse events occurred in the silodosin group: One case of syncope; patient was concomitantly taking prazosin One case of priapism One case of Intraoperative Floppy Iris Syndrome (IFIS); occurred during a 9-month open-label safety trial Postmarketing adverse events: Toxic skin eruption Purpura Jaundice Increased transaminase values/impaired hepatic function Deaths and Other Serious Adverse Events (Sentinel Events) No data available. Tolerability Silodosin was discontinued by 6.4% of patients in the treatment group; of these, 2.8% were due to retrograde ejaculation. Retrograde ejaculation is reversible upon discontinuation of the drug. Precautions/Contraindications1 Precautions Orthostatic Hypotension Orthostatic hypotension may develop, with or without symptoms such as dizziness, upon initiation of silodosin treatment. The potential for syncope exists; therefore, upon initiation, patients should exercise caution with respect to driving, operating machinery, or performing other hazardous chores. Moderate Renal Impairment The plasma concentration of silodosin is approximately 3 times higher and half-life is approximately doubled in moderate renal impairment. Dose should be reduced to 4 mg, and patients should be monitored for adverse events. Severe Hepatic Impairment No data exists for this patient population; therefore, silodosin is contraindicated. Prostate Cancer BPH frequently coexists with prostate cancer, and symptoms of both conditions are similar. Prescribers should rule out prostate cancer before initiation of silodosin therapy. Intraoperative Floppy Iris Syndrome Intraoperative floppy iris syndrome has been observed during cataract surgery in some patients currently or previously taking alpha antagonists. It is comprised of a combination of symptoms, including a flaccid iris which billows when exposed to intraoperative irrigation currents, progressive miosis intraoperatively despite use of mydriatic drugs before surgery, and possible iris prolapsed toward phacoemulsification incisions. Patients should inform ophthalmologists of silodosin therapy when planning cataract surgery. The latest BPH management guideline from the American Urological Association recommends that patients who are candidates for alpha-blocker therapies be asked about potential cataract surgery12. Patients with planned cataract surgery should not start alpha-blockers until they have had surgery. Contraindications Severe renal impairment (CrCl < 30 mL/min) Severe hepatic impairment (Child-Pugh score e" 10) Concomitant use with strong CYP3A4 inhibitors such as clarithromycin, ritonavir, ketoconazole or itraconazole Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name silodosin: sildenafil LA/SA for trade name Rapaflo: Rapamune, Raptiva Drug Interactions1 Drug-Drug Interactions Strong CYP3A4 Inhibitors Concomitant administration of silodosin 8 mg with ketoconazole 400 mg led to 3.8-fold and 3.2-fold increases in silodosin Cmax and AUC, respectively. Concomitant use of strong CYP3A4 inhibitors such as ketoconazole is contraindicated. Moderate CYP3A4 Inhibitors The effects of moderate CYP3A4 inhibitors has not been evaluated. Concomitant administration may increase silodosin concentration; exercise caution and monitor patients for adverse events. Strong P-glycoprotein (P-gp) Inhibitors In vitro studies show silodosin to be a P-gp substrate; therefore, P-gp inhibition may lead to increased silodosin concentration. Silodosin is not recommended for patients taking strong P-gp inhibitors. Alpha Antagonists Interactions between silodosin and other alpha antagonists have not been studied. Silodosin should not be combined with other alpha antagonists as interactions are possible. Digoxin Concomitant administration did not significantly alter digoxin steady state pharmacokinetics. No dose adjustment is necessary. PDE5 Inhibitors13 A placebo-controlled clinical trial evaluated co-administration of silodosin with single dose of sildenafil (100 mg ) or tadalafil (20 mg ) in 24 healthy males between 45 and 78 years of age. Vital signs were monitored for 12 hours after dosing to evaluate orthostatic events. The silodosin + PDE5 group demonstrated a higher incidence of orthostatic test results than silodosin alone; however, no symptomatic orthostasis or dizziness were reported. Exercise caution with concomitant administration. Antihypertensives Interactions between silodosin and antihypertensives have not been rigorously studied. Of patients enrolled in clinical trials, approximately one-third also took antihypertensive medications. These patients experienced a higher incidence of orthostatic hypotension (3.4% vs. 3.2%) and dizziness (4.6% vs. 3.8%) than patients not taking antihypertensives. Use silodosin cautiously with concomitant antihypertensives and monitor patients for adverse events. Metabolic Interactions In vitro data demonstrate that silodosin does not inhibit or induce CYP450 enzymes. Drug-Food Interactions Moderate fat, moderate calorie meals decrease Cmax by approximately 18-43% and AUC by approximately 4-49%. Clinical trials of safety and efficacy were performed with food intake. Patients should take silodosin with food to reduce the risk of adverse events. Drug-Lab Interactions No interactions were found between silodosin and laboratory tests, including PSA. Special Populations1 Pregnancy Silodosin is pregnancy category B, and is not indicated for use in women. A rabbit embryo/fetal study demonstrated decreased maternal body weight at a dose of 200 mg/kg/day (~13-25 times maximum recommended human exposure [MRHE]). No significant teratogenicity was observed with this dose. Administration of 1000 mg/kg/day (~20 times MRHE) to pregnant rats did not result in maternal or fetal effects. Treatment of rats during pregnancy and lactation with doses up to 300 mg/kg/day did not cause physical or behavioral development effects in offspring. Rabbits and rats are not able to produce glucuronidated silodosin, which exists in human serum at approximately 4 times the concentration of circulating silodosin. Glucuronidated silodosin has similar pharmacological activity compared to silodosin. Pediatric Safety and efficacy in pediatric patients has not established. Silodosin is not indicated for use in this patient population. Geriatric Two double-blind, placebo-controlled, 12-week clinical trials demonstrated increased risk of orthostatic hypotension with increasing age. No other significant differences in safety or efficacy were seen with respect to age. Table 17: Percent of Patients Experiencing Orthostatic Hypotension by AgeAgeSilodosin (%)Placebo (%)<65 N=259 (55.6%)2.31.2e" 65 N=207 (44.4%)2.91.9e"75 N=60 (12.9%)5.00 Renal Impairment Plasma concentration of silodosin is approximately 3 times higher and half-life is approximately doubled in moderate renal impairment (CrCl 30-50 mL/min). 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No studies have evaluated use in severe renal impairment (CrCl < 30 mL/min); therefore, use is contraindicated in this patient population. Hepatic Impairment Single dose pharmacokinetics were not significantly altered in patients with moderate hepatic impairment (Child-Pugh score 7-9). No dose adjustment necessary with mild to moderate hepatic impairment. No studies have been done in patients with severe hepatic impairment (Child-Pugh score e" 10); therefore, use is contraindicated in this patient population. QTc14 No statistically or clinically significant relationship has been demonstrated between silodosin plasma concentration and QTc. Additionally, silodosin has not been shown to induce clinically relevant changes in HR, PR segment, QRS complex, or ECG data. Acquisition Costs Table 18: Acquisition Costs (12/2011) DrugDose (mg)Cost/Day/Patient ($)Cost/Year/Patient ($)Terazosin10.02167.88420.02167.8842 (unit dose)0.112541.062550.0257 9.38055 (unit dose)0.154756.4655100.1010 36.865Tamsulosin0.40.094334.41950.4 (unit dose)0.3050 111.325Silodosin4 (30-pack)1.9840 724.168 (30-pack)1.9887 725.87558 (90-pack)1.9506 711.969Doxazosin10.039314.34451 (unit dose)0.02569.3442 (90-pack)0.044216.1334 (90-pack)0.056720.69558 (90-pack)0.088732.0105Prazosin1 (90-pack)0.109640.0042 (90-pack)0.033612.2645 (90-pack)0.058421.316Pharmacoeconomic Analysis Currently, no pharmacoeconomic analysis of silodosin has been published. Conclusions Silodosin improved signs and symptoms associated with BPH, as well as peak urine flow rate and quality of life. Studies have shown it is significantly more efficacious than placebo, yet only noninferior to tamsulosin, another selective alpha-1 adrenergic receptor antagonist. While silodosin offers another treatment alternative for the management of BPH, no clear benefit of this drug over others in its class has been clearly delineated. The available clinical evidence demonstrates short-term efficacy of silodosin. However, long-term data about its ability to prevent progression of BPHalone or in combination with a 5-alpha-reductase inhibitoris lacking. Orthostatic hypotension, an adverse event of concern for the VA patient population, was not proven to occur at a significantly different rate with use of silodosin. Additionally, abnormal ejaculation occurred in 22.3% of patients in the silodosin treatment group compared to only 1.6% in the tamsulosin group, and this adverse event is the most common reason patients discontinue the drug. As with any alpha-1 antagonist, silodosin should be avoided in patients with planned cataract surgery due to the risk of intraoperative floppy iris syndrome. The cost of silodosin is approximately $720 per patient per year, in contrast to $21-37 per patient per year for the current formulary agents. While silodosin presents a reasonable alternative for the management of BPH signs and symptoms, the lack of clear benefit to VA patients in combination with its higher price will likely limit its usefulness at this time. References: Rapaflo [package insert]. Corona, CA: Watson Pharmaceuticals, Inc; 2009. Terazosin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at:  HYPERLINK "http://online.lexi.com/crlonline" http://online.lexi.com/crlonline Accessed September 9, 2011. Tamsulosin. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp, Inc. Hudson, OH. Available at:  HYPERLINK "http://online.lexi.com/crlonline" http://online.lexi.com/crlonline Accessed September 9, 2011. Itoh Y, Okada A, Yasui T, et al. Efficacy of selective 1A adrenoceptor antagonist silodosin in the medical expulsive therapy for ureteral stones. Int J Urol 2011;18(9):672-4. Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective 1A-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol 2009;181:2634-40. Marks LS, Gittelman MC, Hill LA, et al. Silodosin in the treatment of the signs and symptoms of benign prostatic hyperplasia: a 9-month, open-label extension study. J Urol 2009;74(6):1318-22. Kawabe K, Yoshida M, Homma Y. Silodosin, a new 1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III, randomized, placebo-controlled, double-blind study in Japanese men. BJU Int 2006;98(5):1019-24. Homma Y, Kawae K, Takeda M, et al. Ejaculation disorder is associated with increased efficacy of silodosin for benign prostatic hyperplasia. J Urol 2010;76:1446-50. Chapple CR, Montorsi F, Tammela TLJ, et al. Silodosin therapy for lower urinary tract symptoms in men with suspected benign prostatic hyperplasia: results of an international, randomized, double-blind, placebo- and active-controlled clinical trial performed in Europe. Eur Urol 2011;59:342-52. Miyakita H, Yokoyama E, Onodera Y, et al. Short-term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia. Int J Urol 2010;17:869-75. Gravas S. Short-term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia [comment]. Int J Urol 2010;17:875. McVary KT, Roehrborn CG, Avins AL, e!lz?Bb~tu̿袘xk_SDhJhJCJOJQJ^JhJCJOJQJ^JhwGkCJOJQJ^Jhn9CJH*OJQJ^JhJhJCJH*OJQJ^JhJhwGk6CJOJQJ^Jh~SOJQJ^JhkkhkOJQJ^JhJvhJv6CJOJQJ^JhJv6CJOJQJ^Jh96CJOJQJ^Jh9hkCJOJQJ^Jh!U.CJOJQJ^JhkCJOJQJ^J`uexkdxn$$IfTl  0644 lap yt,T$$$Ifa$gd{m$gdm$gdm$gd!U.m$ u56IJhi$%JKUVκrhh_^CJ^JaJh_^h_^CJ^JaJ h}th'\h}th'\CJ^JaJ h}th~Sh}th'\5CJ\^JaJh}th~S5CJ\^JaJ h}th{h9]5CJ\^JaJh}th{5CJ\^JaJh}th}t5CJ\^JaJhkkh~S^Jh{h~S^J'Nkd o$$IfTl\\ 0644 layt,T$$$Ifa$gd'\m$ J> $$Ifgdm$kdo$$IfTl4\\ `0644 layt,T$$$Ifa$gd'\m$&-5[O@@@$$$Ifa$gd'\m$ $$Ifgdm$kd p$$IfTl4\\  0644 layt,T5679@I[PBBB $$Ifa$gd'\m$ $Ifgdm$kdp$$IfTl4\\  0644 layt,TIJKY`h[PBBB $$Ifa$gd'\m$ $Ifgdm$kd:q$$IfTl4\\  0644 layt,Thijmt[PBB7 $Ifgd'\m$ $$Ifa$gd'\m$ $Ifgdm$kdq$$IfTl4\\  0644 layt,T[MMMM $$Ifa$gd'\m$kdTr$$IfTl4\\  0644 layt,T[PBB7 $Ifgd'\m$ $$Ifa$gd'\m$ $Ifgdm$kdr$$IfTl4\\ `0644 layt,T[MMMB $Ifgd'\m$ $$Ifa$gd'\m$kdns$$IfTl4\\  0644 layt,T $[PBB7 $Ifgd'\m$ $$Ifa$gd'\m$ $Ifgdm$kds$$IfTl4\\ `0644 layt,T$%&29J[PBB7 $Ifgd'\m$ $$Ifa$gd'\m$ $Ifgdm$kdt$$IfTl4\\  0644 layt,TJKUW^f[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdu$$IfTl4\\  0644 layt,TVW]^efghuv|}  &'-.45ؽ߰߰߰߰߰߰߰߰߰ *h}th9]CJ^JaJ h}th9]h}th9]CJ^JaJh9]h9]CJ^JaJ *h}th_^CJ^JaJ h}th_^h9]CJ^JaJh_^CJ^JaJh}th_^CJ^JaJ=fghv}[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdu$$IfTl4\\ `0644 layt,T[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kd/v$$IfTl4\\  0644 layt,T[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdv$$IfTl4\\  0644 layt,T[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdIw$$IfTl4\\  0644 layt,T[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdw$$IfTl4\\  0644 layt,T [PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdcx$$IfTl4\\ `0644 layt,T'.5[PBB4 $$Ifa$gd9]m$ $$Ifa$gd'\m$ $Ifgdm$kdx$$IfTl4\\  0644 layt,T56P[UOUOOOgdm$gdm$kd}y$$IfTl4\\  0644 layt,T56Pa?Afh¸ϫϗϗyσoeUhkh~S5>*CJ^JaJhkB*^Jphh@cB*^JphhHB*^JphhJ B*^JphhgB*^Jphh{B*^JphhG7cB*^JphhMK'hG7cB*^Jphh>B*^JphhMK'h>B*^Jphh<:B*^Jphhkkh~SB*^JphhDaB*^Jphhkkh~S^J h}th9]!-.^_\wdwWIWhOhOH*OJQJ^JhOhOOJQJ^J$hMK'hn96B*OJQJ^Jph!hMK'hn9B*OJQJ^Jphjh0JOJQJU^Jh-3Mh0JOJQJ^JhjhUh~SB*OJQJ^JphhB*OJQJ^Jphh$B*OJQJ^JphhD6VB*OJQJ^Jph'hkh~S5>*B*CJ^JaJph.u@p@rCEEEFFFFFFFFgdm$$d&dNPgdm$gdm$  & Fgdm$\ctu%,67>?@VpvƼƼƝ~mcXcG<h.6OJQJ^J!h.hmOB*OJQJ^JphhmO6OJQJ^JhmOOJQJ^J!hmOhyB*OJQJ^Jphhu6OJQJ^JhyOJQJ^JhuOJQJ^J!hyh.B*OJQJ^JphhOh.6OJQJ^Jh.OJQJ^JhOh.OJQJ^J!h.hB*OJQJ^JphhOhOOJQJ^JhOhO6OJQJ^J,NUXbop@u@v@@@@@@DCRCpCrCۿ۵۵~z~k[MhD6VB*OJQJ^Jphjh0JOJQJU^JhMK'h"0JOJQJ^JhjhUU!hMK'h"B*OJQJ^Jph!h"hQB*OJQJ^Jphh%.6OJQJ^Jh%.OJQJ^J!hQhQB*OJQJ^JphhQ6OJQJ^JhQOJQJ^J!hQh.B*OJQJ^Jphh.OJQJ^Jt al. American Urological Association guideline: management of benign prostatic hyperplasia (BPH). Available at:  HYPERLINK "http://www.auanet.org" www.auanet.org Accessed March 16, 2012. MacDiarmid SA, Hill LA, Volinn W, et al. Lack of pharmacodynamic interaction of silodosin, a highly selective 1a-adrenoceptor antagonist, with the phosphodiesterase-5 inhibitors sildenafil and tadalafil in healthy men. J Urol 2009;75:520-25. Morganroth J, Lepor H, Hill, LA, et al. Effects of the selective 1A-adrenoceptor antagonist silodosin on ECGs of healthy men in a randomized, double-blind, placebo- and moxifloxacin-controlled study. Clin Pharmacol Ther 2010;87:609-13. Prepared 03/2012. Contact person: Stacey R. Bailey, PharmD, PGY1 Pharmacy Resident/Mark C. 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J K {X x 3+ 4&aO\$ 2U'>/o5dW 8y ">"i""#R$%Z%h%N~%%&6'MK'+Z'9))+[+,J,m4-+b-./C.!U.7R01p122=2 03.b3R56a7v78=93Q9<:U:3C<==9>L>^?YBO%B'BCB7E ;G4IG7R%.b6Fn> &/(A YD| LUWxutg#Iew<,2bGS:,i,n9t\*DGm)~a{GOli>iG2HJ=kK#pPVvqs@ """"s"s#3%3&#0#1>?@nNnOPQSTqrstRRXXXXGG@$@0@<@*X@2h@6p@B@RT@d@h@l@$@d@@@@@@@BDUnknown The Baileys VHAPBHGeracMG*Ax Times New Roman5Symbol3. *Cx Arial5" Tahoma?= *Cx Courier New;WingdingsACambria Math"1h'7:go7:goI$0 BHX  ?L2%2$!xx Silodosin Drug Monograph F. Goodman Carl DeMoss.                           ! " # $ % & ' ( ) * + , - Oh+'0 $ D P \ ht|Silodosin Drug Monograph F. 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