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Scott Martin Vouri, PharmD, BCPS, CGP Assistant Professor St. Louis College of Pharmacy April 12, 2013 Objectives 1. Describe the use of PDE-5 inhibitors in men with BPH 2. Identify potential areas of therapy where PDE-5 inhibitors may be beneficial and Benign Prostatic Hyperplasia (BPH) • Benign prostatic hyperplasia (BPH) is nearly universal in aging men with a prevalence exceeding 80% in those over the age of 80 • Lower urinary tract symptoms (LUTS) occur as a result of bladder outlet obstruction o Urinary hesitancy, weak urinary stream, Sensation of incomplete bladder o Urinary frequency, nocturia, urinary urgency, rge incontinence • The American Urological Association Symptom Index (AUA-SI) and International o Self-administered questionnaires o Mild = 0-7, Moderate 8-19 and Severe 20-35 indicate moderate and severe o Of note, a reduction of three or more points on the AUA-SI is considered Page 1 of 7
• In patients with moderate to severe BPH, standard pharmacologic treatment includes two classes: alpha-1 (α1) adrenergic receptor antagonists (ARA) and 5-α reductase inhibitors • All currently available α1-ARA are effective in reducing LUTS by relaxing muscle tissue ƒ Selective: tamsulosin (Flomax®), silodosin (Rapaflo®), alfuzosin’s ƒ Non-selective: doxazosin (Cardura®), terazosin (Hytrin®) o Equally efficacious – takes one week to have therapeutic benefit • The enzyme 5-α reductase is an important regulator of prostate growth by controlling conversion of testosterone to dihydrotestosterone (DHT). Inhibition of 5-α reductase reduces volume of the prostate ƒ Finasteride (Proscar®), Dutasteride (Avodart®) o Equally efficacious – takes 6 – 12 months to have therapeutic benefits • Can be taken together for a more enhanced effect Phosphodiesterase (PDE) – 5 inhibitors • First approved in 1998 for erectile dysfunction • Four FDA approved medications for prostate o Sildenafil (Viagra®), vardenafil (Levitra®), tadalafil (Cialis®), avanafil • Discovered 2001 may be beneficial in BPH associated LUTS • PDE-5 inhibitors may improve LUTS via several biological mechanisms; including alterations in nitric oxide (NO), rho-kinase deactivation, and reductions in pelvic atherosclerosis. • All currently available PDE-5 inhibitors reverse the tension induced by norepinephrine in prostate tissue with effects ranging from 17% with sildenafil, 35% with vardenafil and 52% with tadalafil. • 5 studies evaluated use of PDE-5 inhibitors vs. placebo in evaluating BPH associated Page 2 of 7
Stief et al (2008)15 VAR 10mg PO BID vs. Porst et al (2011)16 TAD 5mg/day vs. PBO TAD 2.5mg/day (198); IPSS: Placebo (-3.8; 5mg/day; PBO (1:1:1) x TAD 5mg/day (208); 2.5mg/day (-4.6; p=0.18); TAD 5mg/day (-6.1; p<0.01) IIEF-EF: PBO (+1.8; p=N/A); TAD 2.5mg/day (+5.2; p<0.001); TAD 5mg/day (+6.5; p<0.001) Page 3 of 7
• Oelke and colleagues compared tamsulosin 0.4 mg (n = 168), tadalafil 5 mg (n = 171), or placebo (n = 172) daily in a 12 week randomized, double-blind analysis. Compared to placebo, both tadalafil and tamsulosin improved IPSS, BII, and Qmax. Tadalafil—but not tamsulosin—improved quality of life measurements compared to placebo. There were no significant differences in TEAEs. Superiority of one treatment option over the other (tadalafil or tamsulosin) could not be assessed as the study was not adequately powered.18 • In the second double-blind, crossover-trial, 30 patients received tamsulosin 0.4 mg/day for 6 weeks followed by tadalafil 5 mg/day or placebo for an additional 6 weeks. Both tamsulosin plus placebo (-6.7, p < 0.001) and tamsulosin plus tadalafil (-9.2, p < 0.001) reduced IPSS compared to baseline. Tamsulosin plus tadalafil compared to tamsulosin plus placebo significantly improved scores (-2.5, p < 0.05). There were more adverse events with the combination compared to tamsulosin and placebo, specifically headaches (n = 12), dyspepsia (n = 3), and hypotension (n = 2).19 Adverse Drug Reactions / Drug Interactions • In a similar randomized, double-blind, crossover study, subjects received either doxazosin titrated to 4 mg/day plus tadalafil 5 mg/day or doxazosin plus placebo or tamsulosin 0.4 mg/day plus tadalafil or tamsulosin plus placebo. Clinically important hypotension was reported in a higher frequency in doxazosin arms. Standing SBP decreased to <85 mmHg in 7.7% and 2.6% of subjects receiving doxazosin plus tadalafil and doxazosin plus placebo, respectively. Despite blood pressure changes all patients remained asymptomatic. For the tamsulosin arms, mean change in standing SBP, DBP, and heart rate were not considered clinically important. Myalgia occurred in 17% and 7% of subjects receiving doxazosin plus tadalafil and doxazosin plus placebo, respectively; while back pain occurred in 17% and 2% of subjects, respectively. In the tamsulosin plus tadalafil arm, commonly reported adverse events included myalgia (43%), headache (32%), back pain (27%), and dizziness (8%).21 • Tadalafil is a substrate of the hepatic enzyme CYP3A4 and is affected by several medications that induce or inhibit this enzyme.21 • Tadalafil exacerbated the hypotensive effect of sublingual nitroglycerin for up to 24 hours after concomitant administration; these findings support the well-established contraindication of PDE-5 inhibitors use with organic nitrates.22 • Tadalafil (Cialis®) was approved for BPH by the Food and Drug Administration (FDA) in October 2011. The dose is 5 mg by mouth approximately the same time every day with or without food. Use of once daily tadalafil is not recommended in patients with a creatinine clearance (CrCl) < 30 ml/min. Tadalafil should be initiated at 2.5 mg daily in patients with a CrCl of 30 – 50 ml/min and titrated to 5 mg based on response. Tadalafil for daily use has not been evaluated extensively in patients with hepatic impairment. Caution is recommended for patients with mild to moderate impairment and should not be used in patients with severe impairment. Tadalafil is predominantly metabolized by Page 4 of 7
cytochrome P450 (CYP) 3A4. With the concomitant use of a CYP 3A4 inhibitor, the maximum recommended dose is 2.5 mg daily.23 • The most recent AUA guidelines does not include where tadalafil would be used. • There are limited well-designed clinical trials comparing PDE-5 inhibitor use to α1-ARA • Additional studies are needed to determine if PDE-5 inhibitors should be considered as an alternative to α1-ARA or as adjunctive therapy. • Likely best used as monotherapy in men with BPH associated LUTS and ED • Tadalafil daily has an FDA approved indication for BPH • Appears to be safe an effective; however, more studies are likely needed to determine its Page 5 of 7
1. Guess, HA, Arrighi, HM, Metter, EJ, Fozard, JL. Cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia. The Prostate. 1990;17(3):241-246. 2. Thorpe, A. Benign prostatic hyperplasia. Lancet. 2003;361(9366):1359-1367. 3. Barry MJ, Fowler FJ, Jr, O'Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol. 1992;148:1549-1557. 4. Barry MJ, Fowler FJ, Jr, O'Leary MP, et al. Measuring disease-specific health status in men with benign prostatic hyperplasia. Measurement Committee of the American Urological Association. Med Care. 1995;33:AS145-AS155. 5. American Urological Association. AUA guideline on management of benign prostatic hyperplasia (2003/2006). Chapter 1: Diagnosis and treatment recommendations. 170:530-47; 2003; updated 2006. Available at: 5/2013. meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36:1-13. . Long-term effects of finasteride in patients with benign prostatic hyperplasia: a double-blind, placebo-controlled, multicenter study. PROWESS Study Group. Urology. 1998;51:677-686. et al: . The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008;179:616-621. 9. Drugs@FDA. FDA approved products. Accessed on 1/26/2013. 10. Roumeguere T, Boujeltia KZ, Hauzer C, et al. Is there a rationale for chronic use of phospho-diesterase inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia? BJUI. 2009;104:511-517. 11. Kohler TS, McVary KT. The Relationship between erectile dysfunction and lower urinary tract symptoms and the role of phosphodiesterase type 5 inhibitors. European Urology. 2009. 55(1):38-48. 12. Uckert S, Sormes M, Kedia G, et al. Effects of phosphodiesterase inhibitors on tension induced by norepinephrine and accumulation of cyclic nucleotides in isolated human prostatic tissue. Urology. 2008;71(3):526-530. 13. McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007;177(4):1401-1407. Page 6 of 7
14. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234. 15. Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E . A Randomised, Placebo-Controlled Study to Assess the Efficacy of Twice-Daily Vardenafil in the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Eur Urol. 2008;53(6):1236-1244. 16. Porst H, Kim ED, Casabe AR, et al. Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International Randomized, Double-Blind, Placebo-Controlled Trial. Eur Urol. 2011;60(6):1105-1113. 17. Egerdie RB, Auerbach S, Roehrborn CG, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med. 2012;9(1):271-281. 18. Oelke M, Guiliano F, Mirone V, et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012;(print ahead):1-9. 19. Bechara A, Romano S, Casabe A, Haime S, et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot Study. J Sex Med. 2008;5:2170-2178. 20. Guillaume M, Lonsdale F, Darstein C, Jimenez MC, Mitchell MI. Hemodynamic interaction between a daily dosed phosphodiesterase 5 inhibitor, tadalafil, and the alpha-adrenergic blockers, doxazosin and tamsulosin, in middle-aged healthy male subjects. J Clin Pharmacol. 2007;47(10):1303-1310. 21. Ring BJ, Patterson BE, Mitchell MI, et al. Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo. Clin Pharmacol Ther. 2005;77(1):63-75. 22. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol. 2003 ;42(10):1855-1860. 23. Cialis (tadalafil) [prescribing information]. Eli Lilly and Company: Indianapolis, IN: October 2011. Page 7 of 7
Tadalafil in BPH: An Old Dog with New Tricks Scott Martin Vouri, PharmD, BCPS, CGP 0121-9999-13-034-L01-P Annotated Bibliography
Roumeguere T, Boujeltia KZ, Hauzer C, et al. Is there a rationale for chronic use of phospho-diesterase inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia? BJUI. 2009;104:511-517. This review article discusses the available literature regarding the potential impact of PDE-5 inhibitors on BPH associated LUTS. Here, article with secondary outcomes purporting improvements in LUTS is described in detail. The potential pathophysiology relationship between ED and BPH associated is addressed. The proposed mechanisms of action of PDE-5 inhibitors on a molecular level are also discussed based on available literature. Roehrborn CG, McVary KT, Elion-Mboussa A, Viktrup L. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a dose finding study. J Urol. 2008;180(4):1228-1234. This trial compares the use of tadalafil 2.5mg, 5mg, 10mg, 20mg by mouth daily to placebo for 12 weeks to evaluate the reduction in subjective IPSS (International Prostate Symptom Score) to determine an appropriate dose for BPH associated LUTS. Additionally, these doses were evaluated for peak urine flow and quality of life. There was a statistically significant improvement in IPSS for 2.5mg (3.88), 5mg (4.87), 10mg (5.17), and 20mg (5.21) compared to placebo. There was no improvement across any of the doses compared to placebo in regards to peak urine flow. Finally, there was improvement in quality of life, based on a questionnaire, for 5mg, 10mg, and 20mg doses; however, there was no difference in 2.5mg and placebo (p>0.05). Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E . A Randomised, Placebo-Controlled Study to Assess the Efficacy of Twice-Daily Vardenafil in the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia. Eur Urol. 2008;53(6):1236-1244. This trial compared the use of vardenafil 10mg by mouth twice daily to placebo for eight weeks to evaluate the reduction in subjective IPSS. Additionally, this trial assessed the peak urine flow and post-void residual (PVR) volume. There was a statistically significant improvement in IPSS of 2.3 points compared to placebo (p=0.0013). However, there was no improvement in peak urine flow (p=0.5613) or PVR volume (p=0.6994). Oelke M, Guiliano F, Mirone V, et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol. 2012;(print ahead):1-9. This trial compared the use of tamsulosin 0.4mg by mouth daily, tadalafil 5mg by mouth daily, and placebo for 12 weeks to evaluate the reduction in subjective IPSS. Additionally, this trial evaluated BPH Impact Index (BII) and nocturia. There was a significant reduction in IPSS compared to placebo for both tamsulosin (1.5 points; p=0.023) and tadalafil (2.1 points; p=0.001). This study was not powered to assess superiority between the two agents in BPH. There was also a significant reduction on the BII for both tamsulosin (0.6 points; p=0.026) and tadalafil (0.8 points; p=0.003). There was no significant improvement in either treatment group in regards to nocturia. Page 1 of 2
Bechara A, Romano S, Casabe A, Haime S, et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot Study. J Sex Med. 2008;5:2170-2178. In this pilot study, tamsulosin 0.4mg by mouth daily plus placebo was compared to tamsulosin 0.4mg by mouth daily plus tadalafil 5mg by mouth daily for 45 days each in a cross-over designed trial to evaluate subjective IPSS. The use of tamsulosin (6.7 points; p<0.001) and tamsulosin plus tadalafil (9.2 points; p<0.001) both significantly improved IPSS compared to baseline. Additionally, there was a significant improvement in IPSS in the combination tamsulosin plus tadalafil compared to tamsulosin plus placebo (2.5 points; p<0.05). In evaluating adverse drug events, only headache (12 vs. 0), hypotension (2 vs. 1), and dyspepsia (3 vs 1) occurred more often in the tamsulosin plus tadalafil group compared to tamsulosin plus placebo. Page 2 of 2
Tadalafil in BPH: An Old Dog with New Tricks Scott Martin Vouri, PharmD, BCPS, CGP 0121-9999-13-034-L01-P 1. Which of these PDE- 5 inhibitors is approved for use in BPH? a. 2. With which additional BPH medication can a PDE-5 inhibitor be administered with for treatment of LUTS? a. 3. What mechanism of tadalafil may make tadalafil superior to other PDE-5 inhibitors? b. Avoids interactions with selective alpha-antagonists 4. FR is a 59 year old male who currently complains of difficulty maintaining an erection. His physical exam is significant for DRE 30, IPSS of 7, BP 112/68, HR 55. His PMH include BPH and atrial fibrillation. He is currently taking diltiazem 240mg PO daily, ASA 325mg PO daily, terazosin 10mg PO QHS, and vitamin 1000 int units PO daily. Which of the following would be the preferred recommendations? a. Initiate tadalafil 5mg PO daily b. Discontinue terazosin and initiate tadalafil 5mg PO daily c. Change terazosin to silodosin 8mg PO daily and initiate tadalafil 5mg PO daily d. Change terazosin to silodosin 8mg PO daily, initiate finasteride 5mg PO daily, and initiate tadalafil 5mg PO daily. 5. UH is a 56 year old male who presents to the urologist for issues with urination (post-urine dribbling, incomplete voiding, and weak stream) and difficulty achieving an erection. On exam, DRE 25g and AUA-SI score 17. UH has PMH significant for diabetes type 2, erectile dysfunction, and post-MI (2 years prior). His medication list includes: metformin 1000mg PO BID, pioglitazone 30mg PO daily, ASA 81mg PO daily, enalapril 20mg PO BID, isosorbide mononite ER 60mg PO daily, atenolol 50mg PO daily, and rosuvastatin 10mg PO daily. Which of the following medications is the best option for UH?

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