Therapeutic Class ReviewSM Urology Medication Update Benign Prostatic Hyperplasia February 2012 Confidential Executive Summary Conclusion (Product Value) • Tadalafil (Cialis) improves BPH symptoms; however the clinical significance is uncertain. It is unknown how it compares to generically available alpha-1 adrenergic blockers (“alphablockers”) and 5-alpha-reductase inhibitors (“5ARIs”). • Generic alpha-1-adrenergic blockers (alpha-blockers) and generic 5ARIs remain the best value in the treatment of BPH, with no evidence of superiority of branded options. Evidence of Efficacy Key Evidence Question Assessment Does tadalafil (Cialis) improve BPH symptoms? Does the evidence allow for comparisons between tadalafil (Cialis) and other medications in the treatment of BPH? Evidence Quality Modest improvement Moderate Certainty Insufficient Evidence Low Certainty Considerations of BPH medications in Subpopulations: • Pediatrics: The safety and effectiveness in pediatrics have not been established. • Geriatrics: BPH is prevalent in aging men. There is dose adjustment warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered such as postural hypotension and risk of falls with alpha-blockers. • Race, ethnicity: There is no apparent treatment difference due to race, or ethnicity. Page 1 of 6 © 2012 RegenceRx. All rights reserved. Formulary Considerations for tadalafil (Cialis) Consideration Efficacy Practical Considerations Other Treatment Options Safety Cost Description - There is moderate certainty that tadalafil (Cialis) provides a modest reduction in BPH symptoms. However, the improvement might not be clinically meaningful. - There is insufficient information as to how tadalafil (Cialis) compares with other BPH medications, as it has not been studied in head-to-head trials. - Alpha-blockers, 5ARIs, and their combinations have been mainstay of therapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS). Most are available generically. - Alpha-blockers have a relatively rapid onset with regard to improving BPH symptoms - 5-alpha-reductase inhibitors reduce prostate size, to relieve BPH symptoms over time. - Alpha-blockers and 5ARIs have a long track record for safety. Common adverse events include postural hypotension and impotence, respectively. - While tadalafil (Cialis) has a long track record for safety for on-demand use in erectile dysfunction, long-term safety for daily use in BPH is unknown. - Safety of tadalafil (Cialis) in combination with alpha-blockers or 5ARIs has not been established. Tadalafil (Cialis) for BPH is significantly more costly than generic alternatives. Disease Treatment Aspects Benign prostatic hyperplasia is a very common chronic and progressive disease in aging men. Symptoms include increased frequency of urination, nocturia, hesitancy urgency and weak urinary stream. [1] Treatments are aimed at short-term symptom relief and long-term avoidance of urinary retention and the need for surgery. Standard of Care The American Urological Association (AUA) recommends alpha-blockers and 5ARIs in moderate to severe BPH symptoms. The AUA does not differentiate between the clinical efficacy among medications within each drug class.[2] Clinical Burden All existing BPH medications are dosed once daily. Tadalafil (Cialis) does not reduce clinical barriers to treatment. Commercial Formulary Decision Recommendation Maintain tadalafil (Cialis) nonpreferred/ non-formulary Rationale: See Appendix H, Table 1, “Scenario 3” When there is not high certainty in the evidence of effectiveness (U/P or I evidence) and there are other established treatment options available, the medication must be non-preferred / non-formulary unless there is uncertain confidence (or lacking confidence) in the other available treatment options AND: □ There are profound, proven safety advantages over established treatment options. OR □ Multiple treatment options are needed because established treatments are clearly insufficient for most affected patients AND there are no significant safety concerns AND overall costs are not raised. Medicare Part D Formulary Decision Do not add tadalafil (Cialis) to the formulary. Page 2 of 6 © 2012 RegenceRx. All rights reserved. Product Information and Cost A. Current products for benign prostatic hyperplasia (BPH) Drug Products FDA approval a Patent Expiration(s)b Phosphodiesterase 5 (PDE5) Inhibitor tadalafil (Cialis®)[3] 11/21/03 11/21/2017 [Eli Lilly and Company] Alpha-1 Adrenergic Blockers (Alpha-Blockers) alfuzosin HCl XL[4] 06/2003 Expired [generic] doxazosin mesylate[5] [generic] BPH: 5 mg PO once daily $135c for BPH None listed. Treatment of the signs and symptoms of BPH 10 mg PO once daily after a meal $98d -Treatment of the signs and symptoms of BPH -Hypertension Treatment of the signs and symptoms of BPH 2 mg to 8 mg PO once daily $9d 4 mg to 8 mg PO once daily $58d - Bladder neck obstruction, Primary - LUTS - Chronic prostatitis chronic pelvic pain syndrome - ED - LUTS - Hypertension - Spinal cord injury - Cardiac syndrome X - Congestive heart failure - Disorder of the urinary system - ED; Diagnosis - Pheochromocytoma - Ureteric stone Expired 10/2008 12/2013 Treatment of the signs and symptoms of BPH 8 mg PO once daily with a meal $121d None listed. 04/1997 Expired Treatment of the signs and symptoms of BPH 0.4 mg to 0.8 mg PO once daily $20d 08/1987 Expired - Treatment of the signs and symptoms of BPH - Hypertension 2 mg to 10 mg PO once daily at bedtime $9d - Chronic prostatitis - Pelvic pain syndrome - Disorder of the urinary system - Spinal cord injury - LUTS - Neurogenic bladder - Radiation-induced disorder - Urethritis - Ureteric stone - Carcinoma of prostate - Chronic prostatitis chronic pelvic pain syndrome - Congestive heart failure - Hyperlipidemia - Nocturia - Oligozoospermia - Radiation-induced urethritis - Spinal cord injury [generic] terazosin HCl[9] - Treatment of the signs and symptoms of BPH - ED Potential Off-label Uses 02/2005 [Watson] tamsulosin HCl[8] Cost Expired [Pfizer] silodosin (Rapaflo®)[7] Usual Dose/Route 11/1990 [generic] doxazosin mesylate XL (Cardura XL®)[6] FDA approved indications Page 3 of 6 © 2012 RegenceRx. All rights reserved. 5-Alpha Reductase Inhibitors (5ARIs) dutasteride 11/2001 11/2015 (Avodart®)[10] [GlaxoSmithKline] finasteride[11] 06/1992 Expired [generic] Combination Products dutasteride/tamsulosin (Jalyn®)[12] 06/2010 11/2015 - Symptomatic BPH, alone or with tamsulosin - To reduce the risk of AUR and BPH-related surgery - Symptomatic BPH, alone or with doxazosin - To reduce the risk of AUR and BPH-related surgery - Alopecia 0.5 mg PO once daily $112d Male pattern alopecia 5 mg PO once daily $19d Treatment of symptomatic BPH One capsule (dutasteride 0.5 mg/tamsulosin 0.4 mg) PO once daily $117d [GlaxoSmithKline] - Carcinoma of prostate - Carcinoma of prostate; prophylaxis - Hidradenitis suppurativa - Hirsutism - Male pattern alopecia None listed. ED: erectile dysfunction; LUTS: lower urinary tract symptoms; AUR: acute urinary retention. a b c d e Date applies to approval date for the original brand name medication where there are now generics available. Based on patents listed in Orange Book as of 10/24/2011. Estimated cost per prescription for 30-day supply from AWP as of 10/24/2011, considering a dosing range, based on the prescribing information. Average cost per prescription based on RegenceRx claims data as listed on RegenceRx PriceGuide for 30 day supply as of 10/24/2011. As listed in © 1974 – 2011 Thomson MICROMEDEX database or as referenced. B. Pipeline products No pipeline products were identified. Page 4 of 6 © 2012 RegenceRx. All rights reserved. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. American Urological Association Guideline: Management of Benign Prostatic Hyperplasia (BPH). Revised, 2010. [cited 11/9/2011]; Available from: http://www.auanet.org/content/clinical-practiceguidelines/clinical-guidelines.cfm?sub=bph McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011 May;185(5):1793-803. PMID: 21420124 Cialis® [prescribing information]. Indianapolis, IN: Lilly USA, LLC; October 2011 sanofi-aventis U.S. LLC. Uroxatral (alfuzosin HCl) prescribing information. [cited 10/25/2011]; Available from: http://products.sanofi.us/uroxatral/uroxatral.html Cardura® [product information]. New York, NY: Pfizer; July 2009 Cardura® XL [product information]. New York, NY: Pfizer; July 2011 Watson Pharma, Inc. Rapaflo® (silodosin) prescribing information. [cited 10/24/2011]; Available from: http://pi.watson.com/data_stream.asp?product_group=1630&p=pi&language=E Flomax® [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2011 Hytrin® [presccribing information]. North Chicago, IL: Abbott Laboratories; July 2009 Avodart® [prescribing information]. Research Triangle Park, NC GlaxoSmithKline; June 2011 Proscar® [prescribing information] Whitehouse Station, NJ: Merck & CO., INC.; June 2011 Jalyn™ [prescribing information]. Research Triangle Park, NC GlaxoSmithKline June 2011 McNicholas T, Kirby R. Benign prostatic hyperplasia and male lower urinary tract symptoms (LUTS). Clin Evid (Online). 2011;2011. PMID: 21871136 Tacklind J, Fink HA, Macdonald R, Rutks I, Wilt TJ. Finasteride for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2010(10):CD006015. PMID: 20927745 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 Nov;60(5):1105-13. PMID: 21871706 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. 2011 Oct 7. PMID: 21981682 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 Oct;180(4):1228-34. PMID: 18722631 Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2year results from the CombAT study. J Urol. 2008 Feb;179(2):616-21; discussion 21. PMID: 18082216 Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010 Jan;57(1):123-31. PMID: 19825505 FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer. 6-9-2011. [cited 11/28/2011]; Available from: http://www.fda.gov/drugs/%20drugsafety/ucm258314.htm Centers for Medicare & Medicaid Services (CMS). Part D Patient Safety Measures-Updated NDC lists (July 16, 2010). [cited 11/21/2011]; Available from: https://www.cms.gov/PrescriptionDrugCovContra/Downloads/MemoPatientSafetyMeasures_07.16.10.p df FDA: Postmarket Drug Safety Information for Patients and Providers. Cialis (tadalafil) Information [11/2007]. [cited 11/29/2011]; Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1 18686.htm Page 5 of 6 © 2012 RegenceRx. All rights reserved. 23. 24. 25. 26. 27. 28. 29. 30. Donatucci CF, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. BJU Int. 2011 Apr;107(7):1110-6. PMID: 21244606 Kramer BS, Hagerty KL, Justman S, et al. Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Clin Oncol. 2009 Mar 20;27(9):1502-16. PMID: 19252137 Siami P, Roehrborn CG, Barkin J, et al. Combination therapy with dutasteride and tamsulosin in men with moderate-to-severe benign prostatic hyperplasia and prostate enlargement: the CombAT (Combination of Avodart and Tamsulosin) trial rationale and study design. Contemp Clin Trials. 2007 Nov;28(6):770-9. PMID: 17761460 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 Nov;148(5):1549-57; discussion 64. PMID: 1279218 Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997 Jun;49(6):822-30. PMID: 9187685 Rosen RC, Cappelleri JC, Gendrano N, 3rd. The International Index of Erectile Function (IIEF): a stateof-the-science review. Int J Impot Res. 2002 Aug;14(4):226-44. PMID: 12152111 Barry MJ, Fowler FJ, Jr., O'Leary MP, Bruskewitz RC, Holtgrewe HL, Mebust WK. Measuring diseasespecific health status in men with benign prostatic hyperplasia. Measurement Committee of The American Urological Association. Med Care. 1995 Apr;33(4 Suppl):AS145-55. PMID: 7536866 National Cancer Institute (NCI), U.S. National Institutes of Health [webpage]. Prostate-Specific Antigen (PSA) Test. [cited 12/13/2011]; Available from: http://www.cancer.gov/cancertopics/factsheet/Detection/PSA Disclaimer: The information contained within this document best reflects the current state of medication information at the date of publication. Conclusions may be subject to change over time because of many factors, including but not limited to: emerging scientific evidence for safety and efficacy, evolving best-practices for critical appraisal of scientific evidence, market availability of medications, medication cost information, and evolving medical practice standards. Page 6 of 6 © 2012 RegenceRx. All rights reserved.