Clinical BPH and Its Management A Comprehensive Slide Kit

Clinical BPH and Its Management A Comprehensive Slide Kit
Professor Kurt Dreikorn Director, Department of Urology Zentralkrankenhaus Teaching Hospital of the University of Gottingen Bremen, Germany Mark Speakman, MD Consultant Urologist Musgrove Park Hospital Taunton, UK Title Slide PSC 2001-W SS PSC 2001-W SS

This presentation is provided as a professional service by Merck & Co
This presentation is provided as a professional service by Merck & Co., Inc. The views expressed herein represent the independent opinions and experience of the speakers and not necessarily those of Merck & Co., Inc., or its related affiliates. Any product mentioned in this presentation should be used in accordance with the prescribing information issued by the manufacturer. Disclaimer PSC 2001-W SS

Definition, Pathophysiology, and Epidemiology of Clinical BPH Section I
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Definition of Terms LUTS Lower-urinary-tract symptoms
BPE Benign prostatic enlargement (macroscopic) BOO Bladder-outlet obstruction BPH Benign prostatic hyperplasia (microscopic/histologic) BPO Benign prostatic obstruction (BOO caused by BPE) Clinical BPH LUTS + BPE + BOO Slide I.1 Several terms are useful in describing features of clinical benign prostatic hyperplasia (BPH) and related disorders. These include lower-urinary-tract symptoms (LUTS), which may be independent of prostatic enlargement; benign prostatic enlargement (BPE), which indicates objectively demonstrable enlargement of the gland or an enlarged transition zone; bladder-outlet obstruction (BOO), benign prostatic hyperplasia (microscopic/histologic evidence of stromal and epithelial cell hyperplasia of the prostate; and benign prostatic obstruction (BPO), which indicates BOO caused by BPE. Finally, the term “clinical BPH” indicates BPE in the presence of bothersome LUTS and BOO.1-3 Slide I.1 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. Nordling J, Artibani W, Hald T et al. Pathophysiology of the urinary bladder in obstruction and ageing. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 3. Lee C, Cockett A, Cussenot O et al. Regulation of prostate growth. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: PSC 2001-W SS

Pathophysiology of Clinical BPH: Overlapping but Independent Features
LUTS Enlarged prostate BOO Slide I.2 BPH describes a condition comprising objectively demonstrable enlargement of the prostate or an enlarged transition zone, bothersome LUTS, and suspected or urodynamically proven BOO.1 Adapted from Nordling J et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Slide I.2 Reference 1. Nordling J, Artibani W, Hald T et al. Pathophysiology of the urinary bladder in obstruction and ageing. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: PSC 2001-W SS

Pathophysiology of Clinical BPH: Conditions Potentially Leading to LUTS
Anoxia High nocturnal diuresis Aging Slide I.3 Several conditions can lead to LUTS in men. Aging can cause changes in the function of smooth muscles and nerves of the bladder that cannot be reversed by outflow revision.1 Obstruction, which may affect bladder and urethral function by causing structural and metabolic changes, can lead to voiding symptoms including hesitancy, straining, weak stream, intermittency, terminal dribbling, prolonged voiding, retention, and overflow incontinence. Local disease, i.e., BPE, may be the primary cause of BOO. Neurologic diseases, such as cerebrovascular and Parkinson’s diseases, may cause bladder dysfunction and/or irritative urinary symptoms owing to detrusor hyperreflexia. Age-related disorders such as Alzheimer’s disease may lead to overactivity and/or low compliance of the bladder. Men with severe nocturnal diuresis are much likelier to have bothersome LUTS than are men without this complaint. Anoxia (ischemia) also may play a major role in progressive bladder dysfunction in the aging man. Bladder Age- related diseases Obstruc- tion Neuro- logic diseases Local disease LUTS Adapted from Nordling J et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Slide I.3 Reference 1. Nordling J, Artibani W, Hald T et al. Pathophysiology of the urinary bladder in obstruction and ageing. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: PSC 2001-W SS

Pathophysiology of Clinical BPH: Predictive Risk Factors
Increasing age Prostatic enlargement Elevated prostate-specific antigen (PSA) Lower-urinary-tract symptoms (LUTS) Decreased urinary flow rate Slide I.4 Several risk factors have been established for clinical BPH: age, prostatic enlargement, elevated prostate-specific antigen (PSA) levels, LUTS, and decreased urinary flow rates. Clinical BPH is primarily a disease of middle-aged and older men. Extremely rare in men younger than 40 years of age, BPH progressively increases in prevalence thereafter, affecting about 50% of men 51 to 60 years of age, more than 70% of men in their 60s, and approximately 90% of men in their 80s. The prostate begins to grow at puberty, reaching adult weight between the ages of 21 and 30 years. Thereafter, BPH-related growth occurs in three phases. An early phase of exponential growth takes place between the ages of 31 and 50 years, during which the doubling time of prostate size is 4.5 years. In the middle phase, between the ages of 51 and 70 years, the prostate size doubling time is 10 years. Thereafter, prostate growth levels off, with a doubling time of 100 years in men older than 70 years.1 The size of the prostate gland also correlates with the incidence of progressive BPH symptoms.2 Specifically, men with prostatic enlargement (i.e., >40 ml) are more than three times more likely to have moderate to severe urinary symptoms than men with smaller prostates.2 Elevated PSA levels are powerful predictors of clinical BPH and subsequent outcomes. In one community-based study, elevated free or total PSA concentrations conferred a highly significant increase (p<0.0001) in the risk of clinical BPH.3,* Another community-based study showed that men with PSA levels greater than 1.4 ng/ml were four times more likely to receive any treatment for BPH and nine times more likely to undergo BPH-related surgery than men with PSA values of 1.4 or lower.4,** Several clinical trials have established that the risk of acute urinary retention (AUR) increases in men with elevated PSA.5 Elevated PSA values should always be investigated as a potential marker for prostate cancer. LUTS are an integral component of BPH, and symptom severity correlates with both the need for treatment and the risk of complications (i.e., AUR and/or BPH-related surgery). 4,5 Alternatively, however, LUTS may signify non–BPH-related disorders, such as prostate cancer.6 Decreased urinary flow rates have been positively correlated with LUTS. In a community-based study, men with peak flow rates lower than 10 ml/sec were shown to be two times more likely to have moderate to severe LUTS than men with higher flow rates after adjusting for age.2,*** Slide I.4 *Determination of risk factors for clinical BPH in 1709 men aged 40 to 70 years followed for nine years (mean) in a population-based survey **Study of BPH treatments in a cohort of 2115 men 40 to 79 years of age randomly selected from participants in a community-based study ***Study of relationships among prostate volume, urinary symptoms, and flow rates in 2115 men 40 to 79 years of age participating in a community-based study References 1. Berry SJ, Coffey DS, Walsh PC et al. The development of human benign prostatic hyperplasia with age. J Urol 1984;132: 2. Girman CJ, Jacobsen SJ, Guess HA et al. Natural history of prostatism: Relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: 3. Meigs JB, Mohr B, Barry MJ et al. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54(9): 4. Jacobsen SJ, Jacobson DJ, Girman CJ et al. Treatment for benign prostatic hyperplasia among community-dwelling men: The Olmsted County Study of Urinary Symptoms and Health Status Among Men. J Urol 1999;162: 5. Roehrborn CG, Malice M-P, Cooke TJ et al. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: A comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58(2): 6. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tracts symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: PSC 2001-W SS

% of men with prostate volume >50 ml
Natural History of BPH: Relationship Between Symptoms and Prostate Volume 30 20 10 (N=2115) Mild symptoms Moderate/ severe symptoms Slide I.5 Epidemiologic data have shown that BPH symptoms are more severe in patients with enlarged prostates. In a population-based study of 2115 men 40 to 79 years of age, the risk of having moderate to severe BPH symptoms was five times higher in men with larger prostates (>50 ml) compared to men with smaller prostates. The slide depicts the results of this study according to patient age, also demonstrating the impact of age on the prevalence of BPH.1,* *Study of relationships among prostate volume, urinary symptoms, and flow rates in 2115 men 40 to 79 years of age participating in a community-based study % of men with prostate volume >50 ml 40–49 50–59 60–69 70–79 Age (years) Adapted from Girman CJ et al J Urol 1995;153: Slide I.5 Reference 1. Girman CJ, Jacobsen SJ, Guess HA et al. Natural history of prostatism: Relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: PSC 2001-W SS

% of men with peak flow rate <10 ml/sec
Natural History of BPH: Relationship Between Symptoms and Peak Urinary Flow 30 20 10 (N=2115) Mild symptoms Moderate/ severe symptoms Slide I.6 Epidemiologic data have shown that BPH symptoms are more severe in patients with reduced urinary flow. In a population-based study of 2115 men 40 to 79 years of age, the risk of having moderate to severe BPH symptoms was three times higher in men with decreased peak urinary flow rates (<10 ml/sec) compared to men with normal urinary flow. The slide depicts the results of this study according to patient age.1,* *Study of relationships among prostate volume, urinary symptoms, and flow rates in 2115 men 40 to 79 years of age participating in a community-based study % of men with peak flow rate <10 ml/sec 40–49 50–59 60–69 70–79 Age (years) Adapted from Girman CJ et al J Urol 1995;153: Slide I.6 Reference 1. Girman CJ, Jacobsen SJ, Guess HA et al. Natural history of prostatism: Relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: PSC 2001-W SS

Natural History of BPH: PSA Is a Powerful Risk Factor for Clinical BPH
5 4 3 2 1 (N=1709) 4.4 Slide I.7 PSA values are a powerful predictor of clinical BPH. In a population-based, random sample survey of 1709 middle-aged and older men, the odds of subsequent clinical BPH were fivefold higher in men in the top quartile of PSA levels adjusted for age and total PSA. There was a significant positive trend (p< ) across quartiles for odds ratios.1,* *Determination of risk factors for clinical BPH in 1709 men aged 40 to 70 years followed for nine years (mean) in a population-based survey Odds ratio 1.9 1.8 1 0.0–0.07 0.08–0.10 0.11–0.17 0.18–2.43 Free PSA value p< for trend across odds ratios Free PSA values adjusted for age and total PSA Adapted from Meigs JB et al J Clin Epidemiol 2001;54(9): Slide I.7 Reference 1. Meigs JB, Mohr B, Barry MJ et al. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54(9): PSC 2001-W SS

Baseline prostate volume (ml)
Pathophysiology of Clinical BPH: The Risk of AUR Increases with Increasing Prostate Volume (community-based data) 3.5 3 2.5 2 1.5 1 0.5 3 Slide I.8 Results from the Proscar™ (finasteride) Long-term Efficacy and Safety Study (PLESS)1* on the risk of AUR according to baseline prostate volume confirmed the findings of an earlier community-based study. The older community-based trial showed a threefold higher risk of AUR in men with larger (>30 ml) versus smaller (30 ml) prostates.2,* * Relative risk of AUR 1 30 >30 Baseline prostate volume (ml) Adapted from Jacobsen SJ et al J Urol 1997;158: Slide I.8 *Long-term study of the effects of finasteride on symptoms and development of AUR and/or need for surgery in 3040 men with BPH followed for four years **Evaluation of occurrence of AUR during 50 months of follow-up in 2115 randomly selected men aged 40 to 79 years in a community-based study References 1. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): 2. Jacobsen SJ, Jacobson DJ, Girman CJ et al. Natural history of prostatism: Risk factors for acute urinary retention. J Urol 1997; 158: PROSCAR (finasteride) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. PSC 2001-W SS

Baseline prostate volume (ml)
Pathophysiology of Clinical BPH: The Risk of TURP Increases with Increasing Prostate Volume (community-based data) 10 8 6 4 2 (N=2115) 9.2 Slide I.9 The results from PLESS on the risk of BPH-related surgery according to baseline prostate volume confirmed earlier findings that showed a ninefold higher risk of transurethral resection of the prostate (TURP) in men with larger (>30 ml) versus smaller (30 ml) prostates.1,* Relative risk of TURP 1 30 >30 Baseline prostate volume (ml) Adapted from Jacobsen SJ et al J Urol 1999;162: Slide I.9 *Study of BPH treatments in a cohort of 2115 men 40 to 79 years of age randomly selected from participants in a community-based study Reference 1. Jacobsen SJ, Jacobson DJ, Girman CJ et al. Treatment for benign prostatic hyperplasia among community-dwelling men: The Olmsted County Study of Urinary Symptoms and Health Status Among Men. J Urol 1999;162: PSC 2001-W SS

Definition, Pathophysiology, and Epidemiology of Clinical BPH: Summary
Clinical BPH is a multifactorial disease composed mainly of prostatic enlargement, LUTS, and BOO Age, prostatic enlargement, elevated PSA, LUTS, and decreased urinary flow rate are major independent predictive risk factors Elevated PSA levels powerfully predict clinical BPH and subsequent outcomes Prostate volume correlates with BOO, severity of symptoms, and risk of serious outcomes Slide I.10 Clinical BPH is a multifactorial disorder composed predominantly of prostatic enlargement, LUTS, and BOO.1 Major predictive risk factors are age, prostatic enlargement, elevated PSA levels, LUTS, and decreased urinary flow rate.2-4 The degree of prostatic enlargement correlates with the degree of BOO,5 severity of BPH symptoms,3 and risk of serious complications (AUR and BPH-related surgery).6 Slide I.10 References 1. Nordling J, Artibani W, Hald T et al. Pathophysiology of the urinary bladder in obstruction and ageing. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. Berry SJ, Coffey DS, Walsh PC et al. The development of human benign prostatic hyperplasia with age. J Urol 1984;132: 3. Girman CJ, Jacobsen SJ, Guess HA et al. Natural history of prostatism: Relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: 4. Meigs JB, Mohr B, Barry MJ et al. Risk factors for clinical benign prostatic hyperplasia in a community-based population of healthy aging men. J Clin Epidemiol 2001;54(9): 5. Ockrim JL, Laniado ME, Pate A et al. A probability based system for combining simple office parameters as a predictor of bladder outflow obstruction. J Urol 2001;166: 6. Roehrborn CG, McConnell JD, Lieber M et al for the PLESS Study Group. Serum prostate specific antigen is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53: PSC 2001-W SS

Consequences of BPH Section II
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Complications of Untreated Clinical BPH
Acute urinary retention Urinary tract infection Bladder calculi Bladder damage Renal impairment Hematuria Slide II.1 Untreated clinical BPH can lead to several complications and negative outcomes.1 One of the most serious is AUR, a painful condition characterized by the inability to initiate voiding and empty the bladder.2 Besides pain, incomplete voiding can cause stasis and thus predispose to urinary tract infection and the formation of bladder calculi.3 Progressive BOO may be accompanied by bladder damage including detrusor hypertrophy, trabeculation, and diverticula.3 Eventually, prolonged obstruction can lead to hydronephrosis and renal impairment.3 BPH-associated hematuria causes considerable morbidity. Slide II.1 References 1. Lieber MM, Jacobsen SJ, Roberts RO et al. Prostate volume and prostate-specific antigen in the absence of prostate cancer: A review of the relationship and prediction of long-term outcomes. Prostate 2001;49(2): 2. Roehrborn CG, Malice M-P, Cooke TJ et al. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: A comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58(2): 3. Beers MH, Berkow R, eds. Prostate disease. In Merck Manual of Diagnosis and Therapy. 17th ed. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1999: PSC 2001-W SS

Incidence of Serious Clinical Outcomes in Untreated Patients with BPH vs. Other Diseases
Condition Clinical Outcome Incidence (%)* Osteoporosis Vertebral fracture Hip fracture 18 Atherosclerosis Fatal/nonfatal MI 2.1 Superficial bladder cancer Recurrence 30–88 Kidney stones Recurrence 2–47 BPH AUR 7 Surgery 10 Slide II.2 Prevention of long-term negative outcomes is a major goal of clinical medicine.1 According to data from the placebo group in PLESS, men with BPH had a 7% incidence of AUR and a 10% incidence of BPH-related surgery.2,* These rates are comparable to the incidence of serious outcomes in several other diseases—fracture incidence in osteoporosis, myocardial infarction in atherosclerosis, seizures in epilepsy, and recurrences in patients with superficial bladder cancer and kidney stones.1 *Annual incidence or rate per person-years Adapted from Roehrborn CG et al Urology 2000;56:9-18. McConnell JD et al N Engl J Med 1998; 338(9): Slide II.2 *Long-term study of the effects of finasteride on symptoms and development of AUR and/or need for surgery in 3040 men with BPH followed for four years References 1. Roehrborn CG, Dolte KS, Ross KS et al. Incidence and risk reduction of long-term outcomes: A comparison of benign prostatic hyperplasia with several other disease areas. Urology 2000;56:9-18. 2. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

Impact of Clinical BPH on the Patient’s Quality of Life
10 8 6 4 2 (n=458) Prostate 40 ml Prostate >40 ml 9.0 6.1 Slide II.3 A community-based epidemiology study was conducted to clarify the impact of prostatic enlargement on health-related quality of life in a random sample of 2115 men, 40 to 79 years of age, with no history of prostate surgery, prostate cancer, or conditions known to interfere with normal voiding. Symptoms were evaluated on a scale of 0 to 35 with a questionnaire comparable to the American Urological Association Index; bother due to urinary symptoms was evaluated on a scale of 0 to 28 with an instrument comparable to the “bother” component of the International Prostate Symptom Score (IPSS); and interference with activities was evaluated on a scale of 0 to 28 with an instrument comparable to the IPSS. For all scales, higher scores reflected worse status.1 Both symptom severity and disease-specific health-related quality of life (as measured by scores for bother and activity interference due to urinary symptoms) worsened with increasing prostate size. After adjustment for age, least-square mean scores for symptoms, bother, and activity were approximately 50% higher (worse) for men with enlarged prostates (>40 ml) than for men with smaller prostates (40 ml). These differences were statistically significant for symptoms (p<0.0001) and bother (p<0.005).1 Logistic regression analysis corroborated the trends observed by least-square means analysis. After adjustment for age, men with larger prostates were nearly three times as likely to have severe symptoms and approximately twice as likely to be bothered by those symptoms and/or experience interference with daily activities than men with smaller prostates.1 5.6 Health-related quality-of-life score 3.6 3.1 2.3 Symptom score (p<0.0001) Bother score (p<0.005) Activity score (NS) Higher scores reflect worse status. Adapted from Girman CJ et al Eur Urol 1999;35(4): Slide II.3 Reference 1. Girman CJ, Jacobsen SJ, Rhodes T et al. Association of health-related quality of life and benign prostatic enlargement. Eur Urol 1999;35(4): PSC 2001-W SS

Impact of Clinical BPH on the Spouse’s Quality of Life
80 70 60 50 40 30 20 10 (n=90) 71 66 66 Slide II.4 A questionnaire was developed to evaluate quality of life in the spouses of men with BPH. Preliminary interviews were conducted with 15 couples to determine relevant health-related quality-of-life issues in this population, and 90 partners completed the questionnaire and were evaluated. Only one partner was not adversely affected at all by her spouse’s symptoms. Nearly half of spouses reported that the couple’s social life was affected by the husband’s symptoms; 66% reported worsening of their sex life; 71% were worried about the possibility of prostate cancer; and 66% were worried about the need for surgery. This study also showed that the spouses’ quality-of-life scores were correlated with the severity of the patient’s symptoms.1 47 % of spouses Adverse effects on social life Adverse impact on sex life Worry about prostate cancer Worry about partner’s need for surgery Adapted from Sells H et al Br J Urol Int 2000;85: Slide II.4 Reference 1. Sells H, Donovan J, Ewings P et al. The development and validation of a quality of life measure to assess partner morbidity in benign prostatic enlargement. Br J Urol Int 2000;85: PSC 2001-W SS

Consequences of Untreated Clinical BPH: Summary
Serious clinical outcomes AUR BPH-related surgery Adverse impact on quality of life For patients For spouses Slide II.5 Untreated BPH can give rise to several complications and negative outcomes, including AUR and other conditions requiring surgery.1 AUR and BPH-related surgery both occur at rates comparable to those of serious outcomes in other diseases.2,3 BPH symptoms can have a substantial negative impact on quality of life. For patients, the impact has been correlated positively with prostate size; i.e., men with larger prostates were more likely to experience bothersome symptoms and/or feel that symptoms interfered with their daily activities than were men with smaller prostates.4,* For spouses, the presence of LUTS was shown to have a substantial impact on quality of life.5 Slide II.5 *Prostate volumes considered “large” vary in different studies (>30, >40, >50 cc, etc.) in the absence of a standard definition. References 1. Lieber MM, Jacobsen SJ, Roberts RO et al. Prostate volume and prostate-specific antigen in the absence of prostate cancer: A review of the relationship and prediction of long-term outcomes. Prostate 2001;49(2): 2. Roehrborn CG, Dolte KS, Ross KS et al. Incidence and risk reduction of long-term outcomes: A comparison of benign prostatic hyperplasia with several other disease areas. Urology 2000;56:9-18. 3. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): 4. Girman CJ, Jacobsen SJ, Rhodes T et al. Association of health-related quality of life and benign prostatic enlargement. Eur Urol 1999;35(4): 5. Sells H, Donovan J, Ewings P et al. The development and validation of a quality of life measure to assess partner morbidity in benign prostatic enlargement. Br J Urol Int 2000;85: PSC 2001-W SS

Regulation of Prostate Growth Section III
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Regulation of Prostate Growth: Intrinsic and Extrinsic Factors
Testicular • Androgens • Estrogens • Nonandrogenic Intrinsic factors (prostate) Slide III.1 Multiple intrinsic and extrinsic factors play a continuing or episodic role in normal and/or pathologic prostate growth. Intrinsic factors include various cellular and noncellular components that mediate stromal-epithelial interactions and regulate prostatic growth through the actions of various growth factors or cytokines. By means of a constant dialogue of signals, intrinsic factors mediate extrinsic factors involved in prostate growth, including testicular factors, nontesticular systemic factors, and environmental and genetic factors.1 Epithelium • Luminal • Basal • Neuroendocrine Stroma • Fibroblast • Smooth muscle • Extracellular matrix Nontesticular • Endocrine organs • Neurotransmitters • Immunologic Genetic • Homeobox genes • Hereditary diseases Urethra • Urine • Testis-epididymal fluid Environmental • Dietary • Micro-organisms (immune response) Extrinsic factors Adapted from Lee C et al. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Slide III.1 Reference 1. Lee C, Cockett A, Cussenot O et al. Regulation of prostate growth. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: PSC 2001-W SS

Regulation of Prostate Growth: Role of Androgens
DHT is the principal androgen responsible for prostatic growth and BPH 5-reductase mediates the conversion of testosterone to DHT Slide III.2 Androgens are required to maintain the size and function of the prostate.1 While testosterone is the principal circulating androgen, maximal testosterone activity in the prostate (i.e., stimulation of prostatic growth and development of BPH) requires conversion of this hormone to dihydrotestosterone (DHT).1-4 The conversion of testosterone to the more potent androgen DHT is catalyzed by 5-reductase.2,4 OH OH 5-reductase O O H Testosterone Dihydrotestosterone Adapted from Bartsch G et al Eur Urol 2000;37(4): Slide III.2 References 1. Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327(17): 2. Rittmaster RS. 5-Alpha-reductase inhibitors. J Androl 1997;18(6): 3. Imperato-McGinley J. 5-Alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review. Eur Urol 1991;20(suppl 1):78-81. 4. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5-alpha-reductase inhibition in human benign prostate hyperplasia. Eur Urol 2000;37(4): PSC 2001-W SS

Regulation of Prostate Growth: Role of 5-Reductase
Inherited 5-reductase deficiency results in male pseudohermaphroditism, characterized by Markedly reduced DHT and normal testosterone levels Lack of prostatic development and/or enlargement (BPH) 5-reductase plays a key role in both normal and abnormal prostate growth Slide III.3 In the mid-1970s, inherited 5-reductase deficiency was found to result in male pseudohermaphroditism.1,2 These men demonstrated markedly reduced DHT levels and normal testosterone levels, and did not experience prostatic development and/or enlargement (BPH).1-3 The key role of 5-reductase in both normal and abnormal prostate growth was thus confirmed. In the 1980s, inhibitors that selectively blocked the action of 5-reductase were synthesized for the treatment of symptomatic BPH.4 In the 1980s, inhibitors that selectively blocked the action of 5-reductase were synthesized for the treatment of symptomatic BPH. Slide III.3 References 1. Imperato-McGinley J, Guerrero L, Gautier T et al. Steroid 5-alpha-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 1974;186(4170): 2. Walsh PC, Madden JD, Harrod MJ et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291(18): 3. Imperato-McGinley J. 5-Alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review. Eur Urol 1991;20(suppl 1):78-81. 4. Stoner E. Treatment of benign prostatic hyperplasia with 5a-reductase inhibitors. Endocrinologist 1995;5:1-7. PSC 2001-W SS

Relative Roles of Type I and Type II 5-reductase
Tissues in which type I and type II 5-reductase are predominant Type I Type II Slide III.4 Research during the early 1990s identified two isoenzymes of 5-reductase, type I and type II.1 In the prostate and other genital tissues, type II 5-reductase is dominant; the function of the type I enzyme is unclear.2-5 Type II 5-reductase also predominates in the hair follicles and is thus implicated in male-pattern baldness.3 The type I enzyme is prominent in skin because of its expression in sebaceous glands,5 and in vitro animal studies have demonstrated this enzyme in the adrenal cortex, although the functional significance of this finding is not clear.6 Both enzymes are present in the liver.7 Skin (sebaceous glands) Hair follicles Liver Seminal vesicles Liver Prostate gland Epididymis Adrenal glands Internal/external genital tissues Slide III.4 References 1. Russell DW, Wilson JD. Steroid 5-alpha-reductase: Two genes/two enzymes. Annu Rev Biochem 1994;63:25-61. 2. Norman RW, Coakes KE, Wright AS et al. Androgen metabolism in men receiving finasteride before prostatectomy. J Urol 1993;150(5, pt 2): 3. Rittmaster RS. 5-Alpha-reductase inhibitors. J Androl 1997;18(6): 4. Gnanapragasam VJ, Robson CN, Leung HY et al. Androgen receptor signaling in the prostate. BJU Int 2000;86: 5. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5-alpha-reductase inhibition in human benign prostate hyperplasia. Eur Urol 2000;37(4): 6. Yokoi H, Tsuruo Y, Miyamoto T et al. Steroid 5 alpha-reductase type 1 immunolocalized in the adrenal gland of normal, gonadectomized, and sex-hormone supplemented rats. Histochem Cell Biol 1998;109(2): 7. Thigpen AE, Silver RI, Guilyeyardo JM et al. Tissue distribution and ontogeny of steroid 5-alpha-reductase isozyme expression. J Clin Invest 1993;92(2): PSC 2001-W SS

Regulation of Prostate Growth: Summary
DHT is a key to the regulation of prostatic growth and BPH 5-reductase mediates the conversion of testosterone to DHT 5-reductase plays a key role in normal and abnormal prostate growth 5-reductase has two isoenzymes, type I and type II Type II predominates in the prostate and other genital tissues Agents that selectively block the action of 5-reductase have been synthesized for the treatment of symptomatic BPH Finasteride is a selective inhibitor of type II 5-reductase Slide III.5 Androgens—principally DHT—are key regulators of the size and function of the prostate. DHT is converted from testosterone by 5-reductase.1-4 Studies in the mid-1970s showed that men with inherited 5-reductase deficiency and consequent pseudohermaphroditism demonstrated markedly reduced DHT levels and normal testosterone levels, and did not experience prostatic development and/or enlargement (BPH).3,5,6 These findings confirmed the key role of 5-reductase in both normal and abnormal prostate growth. Subsequent studies identified two isoenzymes of 5-reductase, type I and type II.7 Type II predominates in the prostate and other genital tissues; the role of type I in these tissues is not clear.2,4,8,9 In the 1980s, agents that selectively block the action of 5-reductase were synthesized for the treatment of symptomatic BPH.10 Slide III.5 References 1. Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327(17): 2. Rittmaster RS. 5-Alpha-reductase inhibitors. J Androl 1997;18(6): 3. Imperato-McGinley J. 5-Alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review. Eur Urol 1991;20(suppl 1):78-81. 4. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5-alpha-reductase inhibition in human benign prostate hyperplasia. Eur Urol 2000;37(4): 5. Imperato-McGinley J, Guerrero L, Gautier T et al. Steroid 5-alpha-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 1974;186(4170): 6. Walsh PC, Madden JD, Harrod MJ et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291(18): 7. Russell DW, Wilson JD. Steroid 5-alpha-reductase: Two genes/two enzymes. Annu Rev Biochem 1994;63:25-61. 8. Norman RW, Coakes KE, Wright AS et al. Androgen metabolism in men receiving finasteride before prostatectomy. J Urol 1993;150(5, pt 2): 9. Gnanapragasam VJ, Robson CN, Leung HY et al. Androgen receptor signaling in the prostate. BJU Int 2000;86: 10. Stoner E. Treatment of benign prostatic hyperplasia with 5a-reductase inhibitors. Endocrinologist 1995;5:1-7. PSC 2001-W SS

Management of BPH Section IV
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Diagnosis of Clinical BPH: International Recommendations
Assessment ICBPH Guidelines Quantification of symptoms–IPSS Recommended Quantification of symptoms—bother score Recommended Digital rectal examination Recommended Urinalysis Recommended PSA measurement Recommended Voiding diary (frequency-volume charts) Recommended Urinary flow-rate recording Optional Postvoid residual urine volume studies Optional Pressure-flow studies Optional Prostate imaging (TRUS) Optional Upper-urinary-tract imaging (US or IVU) Optional Lower-urinary-tract endoscopy Optional Serum creatinine measurement Not recommended Slide IV.1 Guidelines for the management of BPH have been issued by the International Scientific Committee of the 5th International Consultation on BPH (ICBPH), under the auspices of the World Health Organization and the Union Internationale Contre le Cancer, and by the European Association of Urology (EAU). These guidelines largely agree with respect to recommended tests and other investigations in the initial workup of patients with LUTS and suspected BPH.1,2 The ICBPH guidelines emphasize the importance of a thorough medical history in the initial evaluation, which should focus on the nature and duration of urinary tract symptoms, previous surgical procedures, general health, current medications, and the patient’s fitness for possible surgery or other treatments.1 Quantification of symptoms by means of the IPSS is recommended in both guidelines to provide a baseline description of symptom frequency.1,2 Subsequently, this instrument can be used to document changes with or without treatment.1,2 In addition to the IPSS, the ICBPH guidelines recommend use of the bother score. This single question, which asks how the patient would feel about tolerating his current level of symptoms for the rest of his life, can open a discussion about the impact of symptoms.1 Both the EAU and the ICBPH recommend digital rectal examination (DRE) to evaluate the prostate (including abnormalities suggestive of prostate cancer) and surrounding organs.1,2 Urinalysis is recommended by the ICBPH for the detection of hematuria, proteinuria, pyuria, or other pathologic findings.1 Both sets of guidelines recommend PSA measurement in the initial evaluation of patients with an anticipated life expectancy of more than 10 years with LUTS, and in whom the diagnosis of prostate cancer once established would change the treatment plan. The physician and patient should discuss the benefits and risks of this test, including the possibility of false-positive and false-negative results, possible complications of subsequent transrectal ultrasound (TRUS)–guided biopsy, and the potential for false-positive biopsy findings.1,2 Both guidelines cite voiding diaries (frequency-volume charts) as a way to identify patients with nocturia or excessive fluid intake.1,2 Urinary flow-rate recording is a simple, noninvasive test that can reveal abnormal voiding. While the EAU recommends this assessment in the initial workup of men with LUTS, the ICBPH reserves its use for evaluation by the specialist (urologist). Both guidelines recommend urinary flow-rate recording before treatment begins, however. Two or more serial flows will provide a representative maximum urinary flow-rate value.1,2 Measurement of postvoid residual urine volume, performed during TRUS, is recommended for the initial workup by the EAU and as part of specialized evaluation by the ICBPH. Subsequent values may be useful to monitor progress.1,2 Pressure-flow studies, the only way to distinguish detrusor underactivity from BOO in men with low urinary flow rates, are an option before invasive therapies or when a precise diagnosis of BOO is important.1,2 TRUS-guided prostate imaging can assess prostatic size and shape in patients scheduled to undergo hormonal therapy, thermotherapy, stenting, transurethral incision of the prostate (TUIP), or any other treatment that depends on the anatomic characteristics of the prostate gland. TRUS is also the method of choice to guide prostate biopsies.1,2 Upper-urinary-tract imaging by means of ultrasonography (US) or intravenous urography (IVU) is recommended in patients with hematuria, renal insufficiency, or a history of upper-urinary-tract infections or urolithiasis.1,2 Lower-urinary-tract endoscopy is a recommended assessment of prostatic size and shape in patients scheduled to undergo hormonal therapy, thermotherapy, stenting, TUIP, or any other treatment that depends on the anatomic characteristics of the prostate gland.1,2 EAU guidelines advocate measurement of serum creatinine to rule out renal insufficiency in all patients with suspected BPH.2 Adapted from Fifth International Consultation 2001 on BPH. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Slide IV.1 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. De la Rosette JJMCH, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: PSC 2001-W SS

Treatment of Clinical BPH: International Recommendations
Findings Recommendation Minimal/not bothersome LUTS Watchful waiting No absolute indication for surgery* Bothersome LUTS Watchful waiting Enlarged prostate Medical treatment No absolute indication for surgery* • Finasteride • Alpha blocker Interventional treatment Bothersome LUTS Watchful waiting Normal prostate Medical treatment No absolute indication for surgery* • Alpha blocker Interventional treatment Bothersome LUTS Surgery Normal or enlarged prostate Absolute indication for surgery* Slide IV.2 Before treatment can be considered, the ICBPH guidelines specify referral to a urologist of some patients with LUTS, including those with any of the following: DRE suspicious for prostate cancer, hematuria, abnormal PSA values, pain, recurrent infection, palpable bladder, or neurologic disease. For all other patients, the guidelines provide a step-care approach based on the degree of bother due to symptoms.1 Both the ICBPH and the EAU guidelines suggest watchful waiting for patients with mild symptoms that do not interfere with daily life. Therapy with finasteride or alpha blockers is an option for patients with bothersome LUTS, an enlarged prostate (>40 ml), and no absolute indication for surgery; alpha blockers are the treatment of choice for men with normal prostate size, bothersome LUTS, and no absolute indication for surgical treatment.1,2 Neither these nor any other international guidelines recommend plant extracts (phytotherapy) for BPH, primarily because long-term efficacy data are lacking.3 TURP, TUIP, or open prostatectomy is recommended by both guidelines for the first-line treatment of patients who require or desire surgery. Second-line procedures include transurethral electrovaporization (TUVP), laser vaporization (LVAP), interstitial laser coagulation (ILC), transurethral microwave therapy (TUMT), or transurethral needle ablation (TUNA).1,2 *Absolute indications for surgery include urinary retention; significant gross hematuria refractory to finasteride treatment; renal failure, bladder stones, or recurrent urinary tract infections due to BOO; or large bladder diverticulum. Adapted from Fifth International Consultation 2001 on BPH. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: ; De la Rosette JJMCH et al Eur Urol 2001;40: Slide IV.2 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. De la Rosette JJMCH, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: 3. Roehrborn CG, Bartsch C, Kirby R et al. Guidelines for the diagnosis and treatment of benign prostatic hyperplasia: A comparative, international overview. Urology 2001;58(5): PSC 2001-W SS

Treatment of Clinical BPH: Objectives
ICBPH guidelines Short term Improve symptoms Long term Slow disease progression Minimize adverse effects of treatment Preserve quality of life Slide IV.3 Traditionally, physicians have focused on improving urinary flow, residual urine volume, and urodynamic parameters in patients with clinical BPH. More recently, recognition of the negative effects of clinical BPH on quality of life, the potential for serious adverse outcomes (AUR and prostate surgery), and the adverse effects of drug treatment has shifted the objectives of therapy to reducing symptoms, preventing long-term complications, and minimizing the adverse effects of treatment.1,2 Adapted from Fifth International Consultation 2001 on BPH. In Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Slide IV.3 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. Holtgrewe HL. The medical management of lower urinary tract symptoms and benign prostatic hyperplasia. Urol Clin North Am 1998;25(4): PSC 2001-W SS

Alpha Blockers: Mechanism of Action
Improve urinary flow and reduce BOO and LUTS Do not affect prostate enlargement Established mechanisms Blockade of sympathetic activity Relaxation of prostatic and bladder-neck smooth muscle No effect on disease progression Slide IV.4 Alpha1-adrenergic antagonists (alpha blockers) have been used for more than 20 years in the symptomatic treatment of BPH. These agents act by blocking sympathetic activity, which relaxes prostatic and bladder-neck smooth muscle to improve urinary flow, reduce BOO, and alleviate LUTS without affecting prostate size.1 Additionally, these agents may induce prostate apoptosis in epithelial and stromal cells, inhibit contraction of differentiated stromal smooth muscle, and/or inhibit noradrenaline-induced phenotypic modulation of stromal smooth-muscle-cell differentiation.2-5 Slide IV.4 References 1. De la Rosette JJMCH, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: 2. Jardin A, Andersson K-E, Chapple C et al. Alpha1-adrenoceptor antagonists in the treatment of BPH. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 3. Chon JK, Borkowski A, Partin AW et al. Alpha1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with BPH. J Urol 1999;161: 4. Boesch ST, Curvin S, Zhang J et al. Modulation of the differentiation status of cultured prostatic smooth muscle cells by an alpha1-adrenergic receptor antagonist. Prostate 1999;39: 5. Smith P, Rhodes NP, Ke Y et al. Influence of the alpha1-adrenergic antagonist, doxazosin, on noradrenaline-induced modulation of cytoskeletal proteins in culture hyperplastic prostatic stromal cells. Prostate 1999;38: PSC 2001-W SS

5-Reductase Enzyme Inhibitors: Mechanism of Action of PROSCAR™
Type II 5-reductase Testosterone DHT Conversion of Testosterone to Dihydrotestosterone Slide IV.5 PROSCAR™, a synthetic 4-azasteroid compound, is a specific inhibitor of type II 5-reductase. By blocking the conversion of testosterone to DHT by type II 5-reductase, PROSCAR causes regression of the enlarged prostate, thereby improving urinary flow (BOO) and BPH symptoms. By selectively inhibiting type II 5-reductase, PROSCAR reduces the amount of testosterone converted to DHT.1 In a clinical study of 69 men with BPH, PROSCAR decreased intraprostatic DHT by approximately 90%, with reciprocal increases in intraprostatic testosterone.2,* In other studies, PROSCAR decreased circulating (serum) concentrations of DHT by approximately 70% while increasing serum testosterone by 10 to 20% from baseline versus placebo.** Through these actions, PROSCAR decreases androgen-dependent prostate growth, the underlying cause of clinical BPH.3 PROSCAR Type II 5-reductase Testosterone DHT Enzyme Inhibition Significantly reduces serum and intraprostatic DHT Treats the underlying cause of BPH 8.9/10.3 = 86% 9.8/10.3 = 95% 3.6/0.7 = 5 PROSCAR (finasteride) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Slide IV.5 *Evaluation of the effects of seven days of treatment with finasteride on androgen levels in 69 men (47 to 77 years of age) scheduled to undergo TURP **In studies of finasteride 5 mg/day given for four years to men with BPH References 1. Span PN, Völler MCW, Smals AGH et al. Selectivity of finasteride as an in vivo inhibitor of 5-alpha-reductase isoenzyme activity in the human prostate. J Urol 1999;161: 2. McConnell JD, Wilson JD, George FW et al. Finasteride, an inhibitor of 5 -reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992;74(3): 3. Norman RW, Coakes KE, Wright AS et al. Androgen metabolism in men receiving finasteride before prostatectomy. J Urol 1993;150(5, pt 2): PSC 2001-W SS

Management of Clinical BPH: Summary
International guidelines for the management of clinical BPH recommend Diagnostic tests to characterize disease severity and rule out other disorders Treatment to relieve symptoms and prevent complications Alpha blockers relieve BPH symptoms primarily by relaxing smooth muscle PROSCAR™ relieves BPH symptoms primarily by reducing prostate volume PROSCAR slows the progression of BPH Slide IV.6 ICBPH and EAU guidelines recommend a variety of diagnostic tests to characterize disease severity and rule out other disorders in men with LUTS.1,2 For men with bothersome symptoms, treatment should provide symptomatic relief and prevent complications of BPH.1 Alpha blockers relieve BPH symptoms primarily by relaxing prostatic and bladder-neck smooth muscle, thereby reducing BOO and improving urinary flow;2 PROSCAR™ improves symptoms primarily by reducing prostatic enlargement, the underlying cause of BPH. Slide IV.6 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. De la Rosette JJMCH, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: PSC 2001-W SS

Time-Tested Clinical Benefits of PROSCAR™ Section V
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Evidence-Based Medicine: Proven Treatment for Clinical BPH
Evidence-based medicine is based on results of clinical research. Drugs in the same therapeutic class may exert different pharmacologic effects. Independent clinical studies must establish each drug’s efficacy, safety, and effect on outcomes. Outcome studies with drugs for clinical BPH should evaluate the effects of therapy on AUR and BPH-related surgery. Slide V.1 The consensus is growing that medical therapies should be “evidence-based,” that is, supported by clinical research showing benefits (and risks).1,2 Drugs in the same therapeutic class are generally assumed to produce similar pharmacologic effects and outcomes (“class effects”). 3 This is not always the case, however, as individual drugs within a class may act through mechanisms other than those that placed them in that class. 3 Hence, it may be unwise to extrapolate the clinical outcomes with one drug to another member of the same class.3 Regardless of any indirect evidence of benefit, therefore, any new drug should be rigorously tested in clinical studies with carefully chosen efficacy and outcomes measures.3,4 In the case of clinical BPH, appropriate outcomes measures are long-term complications (AUR and the need for surgery).4,5 Slide V.1 References 1. Laupacis A. The future of evidence-based medicine. Can J Clin Pharmacol 2001;8(suppl A):6A-9A. 2. Guyatt GH, Haynes RB, Jaeschke RZ et al. Users’ Guides to the Medical Literature: XXV. Evidence-based medicine: Principles for applying the Users’ Guides to patient care. JAMA 2000;284(24): 3. McAlister FA, Laupacis A, Wells GA et al. Users’ Guides to the Medical Literature: XIX. Applying clinical trials results B. Guidelines for determining whether a drug is exerting (more than) a class effect. JAMA 1999;282(14): 4. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 5. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

Acute Urinary Retention in Clinical BPH Treatment Trials
Trials with Trials with PROSCAR™ Alpha Blockers Patient population (no.) 3000– –2084 Study duration 2–4 years 6 months–1 year Average prostate size 41–55 ml 41 ml Follow-up of discontinued Yes No patients No. of AUR events during trial 72–81 4–24 Predicted no. of AUR events for 5–8 1– patients after discontinuation Total no. of AUR events 80–86 4– (actual and predicted) Slide V.2 Randomized clinical trials with PROSCAR™ and alpha blockers have evaluated the occurrence of AUR, although results are not comparable because of important differences in data collection. AUR data for PROSCAR were collected prospectively in large long-term trials in men with enlarged prostates that had low discontinuation rates (with follow-up of discontinued patients) and event rates sufficiently high to allow statistical analysis. AUR data for alpha blockers come from relatively small trials in men with smaller prostates that had shorter durations, high discontinuation rates (with no follow-up of discontinued patients), and low event rates. Case definitions also differed. Whereas trials with PROSCAR rigorously defined spontaneous events, the alpha-blocker trials included both spontaneous and precipitated events. A recent analysis of these trials concluded: “It remains speculative whether [alpha blockers] are of benefit in reducing the occurrence of spontaneous AUR in men with BPH….Although [PROSCAR] has been prospectively shown to reduce the incidence of AUR, definitive confirmation of the potential effects of alpha-blocker therapy awaits completion of long-term outcome studies in men with BPH with AUR as a predefined, prespecified endpoint.…”1 PLESS was the only study to provide spontaneous AUR data for the active treatment versus post-treatment follow-up. Adapted from Roehrborn CG Urology 2002;59: Slide V.2 Reference 1. Roehrborn CG. Reporting of acute urinary retention in BPH treatment trials: Importance of patient follow-up after discontinuation and case definitions. Urology 2002;59: PSC 2001-W SS

PROSCAR™: Treatment Goals
PROSCAR has been proved effective in the treatment of clinical BPH in men with an enlarged prostate. Improves symptoms Reduces risk of AUR Reduces risk of BPH-related surgery Slows disease progression Slide V.3 PROSCAR™ can be used in the treatment of clinical BPH in men with an enlarged prostate to improve symptoms and reduce the risks of AUR and of BPH-related surgery, including TURP and prostatectomy. PROSCAR has been shown to slow disease progression. Slide V.3 PSC 2001-W SS

PROSCAR™: Durable Efficacy in Long-Term Trials
Duration Long-Term Improvement Study (years) Symptoms Prostate Volume Urinary Flow North American 1 Ö Ö Ö SCARP 2 Ö Ö Ö PROSPECT 2 Ö Ö Ö PROWESS 2 Ö Ö Ö PLESS 4 Ö Ö Ö North American Extension* Maintained Maintained Maintained Scandinavian Open Extension* Maintained Maintained Maintained Slide V.4 In five multicenter, double-blind, placebo-controlled trials, PROSCAR™ significantly improved symptoms, reduced prostate volume, and increased maximum urinary flow (p0.05 vs. placebo) over one to four years of treatment.1-5,a-e Maximum effects became evident early1-5 and were maintained throughout five-year (North American Study extension) and six-year trials (Scandinavian Open-Extension Study).6,7 These results demonstrate that PROSCAR provides durable benefits. Initial improvements become apparent early and are maintained with continuous therapy. Ö = significant improvement from baseline vs. placebo (p0.05); SCARP = Scandinavian Study of Reduction of the Prostate; PROSPECT = Proscar Safety Plus Efficacy Canadian Two-Year Study; PROWESS = Proscar Worldwide Efficacy and Safety Study; PLESS = Proscar Long-term Efficacy and Safety Study *Benefits achieved during double-blind therapy were maintained in extensions. aOne-year study in 895 men with BPH (aged 40–83 years) bTwo-year study in 707 men with BPH (aged 46–80 years) cTwo-year study in 613 men with BPH (aged 45–80 years) dTwo-year study in 3270 men with BPH (aged 50–75 years) eFour-year study in 3040 men with BPH (mean age, 64 years) Slide V.4 References 1. Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327(17): 2. Andersen JT, Ekman P, Wolf H et al for the Scandinavian BPH Study Group. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 1995;46(5): 3. Nickel JC, Fradet Y, Boake RC et al for the PROSPECT Study Group. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: Results of a 2-year randomized controlled trial (the PROSPECT Study). Can Med Assoc J 1996;155(9): 4. Marberger MJ for the PROWESS Study Group. Long-term effects of finasteride in men with benign prostatic hyperplasia: A double-blind, placebo-controlled, multicenter study. Urology 1998;51: 5. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): 6. Hudson PB, Boake R, Trachtenberg J et al for the North American Finasteride Study Group. Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. Urology 1999;53: 7. Ekman P for the Scandinavian Finasteride Study Group. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years. Follow-up of the Scandinavian Open-Extension Study. Eur Urol 1998;33: PSC 2001-W SS

Effects of PROSCAR™ on the Natural History of Clinical BPH: Reduced Risk of AUR
15 10 5 57% risk reduction p<0.001 Probability of AUR Slide V.5 In the PLESS trial, AUR occurred in 42 of 1513 men (3%) who received PROSCAR™ 5 mg per day and in 99 of 1503 men (7%) who received placebo daily for four years. This difference represents a significant 57% reduction (p<0.001) in the risk of AUR with PROSCAR. No other medical therapies have been shown to reduce the risk of AUR in long-term clinical studies.1 Placebo PROSCAR 1 2 3 4 Years Placebo PROSCAR No. of AURs No. at risk No. of AURs No. at risk p<0.001 at 4 years PROSCAR vs. placebo Adapted from McConnell JD et al N Engl J Med 1998;338(9): Slide V.5 Reference 1. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

Probability of surgery
Effects of PROSCAR™ on the Natural History of Clinical BPH: Reduced Risk of Surgery 15 Placebo 55% risk reduction p<0.001 10 Probability of surgery Slide V.6 Over the four years of PLESS, 69 of 1513 men (5%) receiving PROSCAR™ required BPH-related surgery, compared with 152 of 1503 men (10%) receiving placebo, representing a significant risk reduction of 55% (p<0.001).1 The placebo group in PLESS represents the natural progression of BPH without treatment. Reductions in the risk of BPH-related surgery (shown on this slide) and in AUR (shown on slide V.5) demonstrate that treatment with PROSCAR can change the natural history of this disease. 5 PROSCAR 1 2 3 4 Years Placebo PROSCAR No. of surgeries No. at risk No. of surgeries No. at risk p<0.001 at 4 years, PROSCAR vs. placebo Adapted from McConnell JD et al N Engl J Med 1998;338(9): Slide V.6 Reference 1. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

Effect of PROSCAR™ on the Natural History of BPH: Relative Risk Reductions vs. Interventions in Other Diseases Risk Condition Outcome Intervention Reduction (%) Osteoporosis Vertebral fracture Alendronate 44–47 Hip fracture Alendronate 21–51 Atherosclerosis PTCA or CABG Statins 17–37 Fatal/nonfatal MI Statins 25–40 Epilepsy Seizures Anticonvulsants 38–87 Superficial bladder cancer Recurrence BCG + surgery 31–80 Kidney stones Recurrence Pharmacotherapy 63–80 BPH AUR PROSCAR 57 Surgery PROSCAR 55 Slide V.7 This slide compares reductions in long-term negative BPH outcomes after treatment with PROSCAR™ with risk reductions from interventions in other diseases.1 In clinical trials of patients with osteoporosis, alendronate sodium reduced the relative risk of vertebral fracture by 44 to 47%. Statin therapy reduced the relative risk of revascularization procedures in patients with hypercholesterolemia or atherosclerosis by 17 to 37%, and of fatal/nonfatal MI by 25 to 40%. Twelve independent studies in patients with epilepsy showed decreases in seizure risk of 38 to 87% with anticonvulsants as add-on therapy. Patients with superficial bladder cancer who underwent surgery and received treatment with bacillus Calmette-Guérin had a reduced risk for recurrent tumors ranging from 31 to 80%. Prophylaxis with potassium and alkali citrates, allopurinol, and indapamide decreased the risk of recurrent stones in patients with a history of renal calculi. The risk reductions of 57% for AUR and 55% for BPH-related surgery compare favorably with those obtained in other therapeutic areas.2 PTCA = percutaneous transluminal coronary angioplasty; CABG = coronary artery bypass graft; BCG = bacillus Calmette-Guérin Adapted from Roehrborn CG et al Urology 2000;56:9-18. McConnell et al N Eng J Med 1998;338(9): Slide V.7 References 1. Roehrborn CG, Dolte KS, Ross KS et al. Incidence and risk reduction of long-term outcomes: A comparison of benign prostatic hyperplasia with several other disease areas. Urology 2000;56:9-18. 2. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

PSA and PROSCAR™ In PLESS, PROSCAR did not mask prostate cancer detected by PSA Predictably reduces PSA by 50% in men with BPH Multiplication of PSA values by 2 in men treated for 6 months preserves predictive value of PSA measurements Slide V.8 PROSCAR™ predictably reduces PSA by approximately 50% in men with BPH, even in the presence of prostate cancer.1 A subanalysis of PLESS evaluated the effects of therapy with PROSCAR on the predictive value of PSA measurements in the detection of prostate cancer. Prostate cancer detection rates in PLESS were similar in the groups treated with PROSCAR and placebo when PSA values were multiplied by 2. The authors concluded that multiplying PSA by 2 in patients treated with PROSCAR for six months or more preserves the test’s value in the detection of prostate cancer.1 Slide V.8 Reference 1. Andriole GL, Guess HA, Epstein JI et al. Treatment with finasteride preserved usefulness of prostate-specific antigen in the detection of prostate cancer: Results of a randomized, double-blind, placebo-controlled clinical trial. Urology 1998;52(2): PSC 2001-W SS

Time-Tested Clinical Benefits of PROSCAR™: Summary
Evidence-based medicine calls for clinical studies of individual drugs that investigate efficacy and disease outcomes. Outcomes studies with drugs for clinical BPH should evaluate effects on AUR and BPH-related surgery. Multicenter, double-blind, placebo-controlled trials of up to 6 years’ duration have established the effects of PROSCAR: Durable improvements in symptoms, prostate volume, and maximum urinary flow (p0.05) over 1 to 4 years vs. placebo Significant reductions in the risk of AUR and BPH-related surgery (p<0.001) at 4 years vs. placebo in PLESS No other therapy—including alpha blockers—proven to reduce AUR Slide V.9 Evidence-based medicine calls for clinical studies of individual drugs that investigate effects on efficacy and disease outcomes.1,2 Outcomes studies of drugs for clinical BPH should evaluate the effects of therapy on AUR and BPH-related surgery.2,3 Several multicenter, double-blind, placebo-controlled trials of up to six years’ duration have established the clinical efficacy and effects on disease outcomes of PROSCAR™. Durable improvements in symptoms, prostate volume, and maximum urinary flow (p0.05) were demonstrated over one to four years of treatment.4-9 Significant reductions in the risk of AUR and BPH-related surgery (p<0.001) occurred at four years in PLESS and were confirmed in a post hoc analysis of earlier one- to four-year trials.3,10 These reductions compare favorably with risk reductions seen with interventions for other diseases, including osteoporosis, atherosclerosis, epilepsy, bladder cancer, and renal calculi.3,11 No other therapy—including alpha blockers—has been proved to reduce AUR in men with clinical BPH in outcome studies.3,12 Moreover, PROSCAR does not mask the presence of prostate cancer; multiplying PSA values by 2 in men treated with PROSCAR for longer than six months preserves the usefulness of these measurements in the detection of prostate cancer.13 References 1. McAlister FA, Laupacis A, Wells GA et al. Users’ Guides to the Medical Literature: XIX. Applying clinical trials results B. Guidelines for determining whether a drug is exerting (more than) a class effect. JAMA 1999;282(14): 2. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 3. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): 4. Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327(17): 5. Andersen JT, Ekman P, Wolf H et al for the Scandinavian BPH Study Group. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 1995;46(5): 6. Nickel JC, Fradet Y, Boake RC et al for the PROSPECT Study Group. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: Results of a 2-year randomized controlled trial (the PROSPECT Study). Can Med Assoc J 1996;155(9): 7. Marberger MJ for the PROWESS Study Group. Long-term effects of finasteride in men with benign prostatic hyperplasia: A double-blind, placebo-controlled, multicenter study. Urology 1998;51: 8. Hudson PB, Boake R, Trachtenberg J et al for the North American Finasteride Study Group. Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. Urology 1999;53: 9. Ekman P for the Scandinavian Finasteride Study Group. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years. Follow-up of the Scandinavian Open-Extension Study. Eur Urol 1998;33: 10. Andersen JT, Nickel JC, Marshall VR et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49(6): 11. Roehrborn CG, Dolte KS, Ross KS et al. Incidence and risk reduction of long-term outcomes: A comparison of benign prostatic hyperplasia with several other disease areas. Urology 2000;56:9-18. 12. Roehborn CG. Reporting of acute urinary retention in BPH treatment trials: Importance of patient follow-up after discontinuation and case definitions. Urology 2002;59: 13. Andriole GL, Guess HA, Epstein JI et al. Treatment with finasteride preserved usefulness of prostate-specific antigen in the detection of prostate cancer: Results of a randomized, double-blind, placebo-controlled clinical trial. Urology 1998;52(2): Slide V.9 PSC 2001-W SS

New Data on the Long-Term Efficacy and Tolerability of PROSCAR™ Section VI
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Long-Term Experience with PROSCAR™
Sustained improvements over 7 years of therapy Reductions in symptom scores Sustained reductions in prostate volume Ö 25% reduction at year 7 Sustained increases in urinary flow Ö 2.5 ml/sec increase at year 7 Consistent safety and tolerability profile over 8 years of therapy Slide VI.1 The results from two extensions of double-blind, placebo-controlled trials in men 40 to 80 years of age with BPH have recently been reported, representing seven to eight years of treatment with PROSCAR™. Pooled efficacy data through year 7 of these studies are available for 61 of the 190 patients who entered the extensions; pooled safety data are available for 46 patients. This analysis represents the longest follow-up of men receiving any medical therapy for BPH in randomized clinical trials.1 Reductions in symptom scores achieved by year 1 were sustained or improved through year 7. Decreases of approximately 25% from baseline in prostate volume were maintained through year 7. Median improvements in urinary flow rate also were maintained, with an increase from baseline of 2.5 ml/sec at year 7.1 The safety and tolerability profile of PROSCAR during the extensions was consistent with that observed during the initial double-blind periods of both trials. Continuous long-term exposure to PROSCAR was well tolerated; drug-related adverse experiences did not increase over time.1 This analysis showed the effectiveness and tolerability of PROSCAR in the long-term management of men with BPH.1 Data on file, MSD. Slide VI.1 Reference 1. Data on file, MSD ______. PSC 2001-W SS

Efficacy of PROSCAR™ in Younger vs
Efficacy of PROSCAR™ in Younger vs. Older Men with Clinical BPH (PLESS Subanalysis) Younger men (<65 years) Older men (65 years) 20 18 16 14 12 10 8 6 4 2 20 18 16 14 12 10 8 6 4 2 Placebo (n=742) 51% risk reduction (p<0.001) Slide VI.2 A subanalysis of PLESS evaluated the safety profile and efficacy of PROSCAR™ in older (65 years) versus younger men (45 to <65 years) with BPH. At baseline, older men generally had larger prostates and higher symptom scores.1 Although older men had a higher risk of AUR and/or BPH-related surgery (as demonstrated by the incidence of these events in each cohort’s placebo group), treatment with PROSCAR significantly reduced the risk of these outcomes by 51% (p<0.001) in both older and younger men.1 The safety profile of PROSCAR was similar in older and younger men. No clinically important drug interactions were identified in either age group—a reassuring finding given the use of multiple medications by many older people.1 Placebo (n=774) Four-year probability of AUR and/or needing surgery 51% risk reduction (p<0.001) Four-year probability of AUR and/or needing surgery PROSCAR (n=738) PROSCAR (n=786) 1 2 3 4 1 2 3 4 Year Year PROSCAR significantly reduced the incidence of AUR and BPH-related surgery in younger and older patients at 4 years (p<0.001). Adapted from Kaplan SA et al Urology 2001;57(6): Slide VI.2 Reference 1. Kaplan SA, Holtgrewe HL, Bruskewitz R et al for the Proscar Long-term Efficacy and Safety Study Group. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001;57(6): PSC 2001-W SS

Yearly % of AUR and/or BPH-related surgery
Rapid and Sustained Reduction in the Risk of Long-Term Outcomes with PROSCAR™ Double-blind study Open-label extension Placebo (n=1503) PROSCAR 5 mg (n=1513) Placebo  PROSCAR 5 mg (n=858) PROSCAR 5 mg  PROSCAR 5 mg (n=979) 5 4 3 2 1 4.4 3.7 Slide VI.3 In PLESS,* a four-year, randomized, double-blind, placebo-controlled trial involving 3040 men with symptomatic BPH, PROSCAR™ 5 mg per day significantly reduced the risk of AUR and BPH-related surgery versus placebo (p<0.001) at four years.1 At the conclusion of the original study, 1000 men from the arm receiving PROSCAR and 883 men from the placebo arm entered a two-year open extension in which all patients received PROSCAR. Of these, 979 men from the arm receiving PROSCAR and 858 men from the placebo arm completed the extension.2 As the slide shows, the risk of AUR and/or BPH-related surgery remained low in patients who continued on PROSCAR during the extension, and decreased in patients who were switched from placebo to PROSCAR during the extension. By the end of the second year, these events occurred at similar rates with PROSCAR and placebo. These results demonstrated that PROSCAR provided rapid and sustained reductions in the risk of BPH-related complications.2 *PLESS = Proscar Long-term Efficacy and Safety Study 3.3 3.0 Yearly % of AUR and/or BPH-related surgery 2.1 2.0 1.9 1.4 1.3 1.0 1.0 0.7 1 2 3 4 5 6 Study year n values indicate number of patients completing each trial phase Adapted from Roehrborn CG et al. Poster 419. Slide VI.3 References 1. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): 2. Roehrborn CG for the PLESS Study Group. Rapid reduction in risk of AUR and/or surgery with finasteride in men with benign prostatic hyperplasia. Poster European Association of Urology meeting, Birmingham, UK, February 25, 2002. PSC 2001-W SS

PROSCAR™ Significantly Reduced Bother Over Long-Term Therapy (4 Years) (PLESS Substudy)
–1 –2 –3 –4 Overall bother score*,** By baseline PSA tertile (ng/ml) Placebo (n=1503) PROSCAR 5 mg (n=1513) PSA: 0–12 PSA: 0–1.3 PSA: 1.4–3.2 PSA: 3.3–12 Slide VI.4 A substudy of PLESS investigated the long-term effects of PROSCAR™ on bother and other health-related quality-of-life aspects due to BPH symptoms. The effects of PROSCAR became evident early: Mean overall bother scores were significantly reduced at every time point after four months up to one year (p<0.05 vs. placebo) and at every time point thereafter (p<0.001 vs. placebo). The separation between groups widened over time. Final improvements from baseline at four years were 3.0±0.16 points with PROSCAR versus 12±0.16 points with placebo (p<0.001 between groups).1,* In addition, bother scores for nearly all individual symptoms were significantly reduced by PROSCAR compared with placebo at every time point from year 1 through the end of the trial (p<0.001 for most comparisons).1 A subgroup analysis of the magnitude of treatment effects was performed according to baseline PSA. The highest tertile represented men with baseline PSA between 3.3 and 12 ng/ml; the middle tertile, men with baseline PSA between 1.4 and 3.2 ng/ml; and the lowest tertile, men with baseline PSA between 0 and 1.3 ng/ml.1 In this analysis, the effects of PROSCAR on bother scores were significantly greater in men with larger prostate volumes versus placebo at baseline (p=0.005 across tertiles) at four years. Bother scores in men with smaller volumes at baseline who received placebo persistently improved (a placebo effect) so that they did not approach baseline even after four years. However, men with larger volumes (higher PSA values) at baseline who received placebo experienced a gradual but consistent deterioration in bother scores (more bother) after an initial improvement during the first year of the study.1 These improvements in symptom bother corroborated the significant improvements in symptom scores with PROSCAR previously reported in PLESS (p<0.001 vs. placebo) at four years. Improvements in symptoms were evident during the first eight months of therapy with PROSCAR and became even more pronounced throughout the remainder of the four-year study.2 *Evaluation of the effects of PROSCAR on bother and other health-related quality-of-life aspects in 3040 men with BPH treated for four years Mean (±SE) change in bother score from baseline Year of follow-up *p<0.05 PROSCAR vs. placebo at every time point after 4 months to 1 year and p<0.001 PROSCAR vs. placebo every 4 months, years 1 to 4 **Significant improvement vs. baseline with PROSCAR and placebo at 4 years, p<0.001 PSA = prostate-specific antigen Adapted from Bruskewitz R et al Urology 1999;54: Slide VI.4 References 1. Bruskewitz R, Girman CJ, Fowler J et al for the PLESS Study Group. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. Urology 1999;54: 2. McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338(9): PSC 2001-W SS

PROSCAR™ Had No Effect on Bone Mineral Density (BMD) (PLESS Substudy)
1.15 1.14 1.13 1.12 1.11 1.10 1.09 1.08 PROSCAR (n=63) Placebo (n=54) 1.14 1.13 Slide VI.5 In a substudy of PLESS, 117 men who received PROSCAR™ or placebo for four years underwent dual-energy x-ray absorptiometry (DEXA) of the lumbar spine at baseline and at years 2, 3, and 4. During four years of therapy, bone mineral density (BMD) values remained stable in both groups, with no significant between-group differences. Moreover, the risk of osteoporotic fracture of the hip, wrist, and vertebrae did not differ significantly between groups. These results demonstrate that long-term type II 5-reductase inhibition does not adversely affect BMD in older men with BPH.1 1.12 BMD (g/cm2) 1.10 Baseline End of study p = NS between treatments Adapted from Matsumoto AM et al J Urol 2002;167: Slide VI.5 Reference 1. Matsumoto AM, Tenover L, McClung M et al. The long-term effect of specific type II 5 -reductase inhibition with finasteride on bone mineral density in men: Results of a 4 year placebo controlled trial. J Urol 2002;167: PSC 2001-W SS

New Data on the Long-Term Efficacy and Tolerability of PROSCAR™: Summary
PROSCAR maintains clinical improvements over long-term therapy Sustained reductions in symptom scores and prostate volume and increases in urinary flow over 7 years Durable effects up to 10 years Similar effects in older vs. younger men Reductions in risk of outcomes maintained over 6 years Significant reductions in bother due to BPH symptoms at 4 years (p<0.001 vs. placebo) PROSCAR is well tolerated over long-term therapy Consistent safety/tolerability profile through year 7 No effect on BMD Slide VI.6 Data from clinical studies demonstrate that PROSCAR™ maintains clinical improvements over long-term therapy. In a pooled analysis of extensions of two double-blind, placebo-controlled trials, reductions in symptom scores and prostate volume and increases in urinary flow during the initial double-blind period were sustained over seven years.1 In the four-year PLESS trial, the ability of PROSCAR to reduce the risk of negative BPH outcomes (AUR and/or BPH-related surgery), relieve symptoms, and decrease prostate volume was similar in older versus younger men.2 PLESS additionally showed that reductions in the risk of outcomes with PROSCAR were maintained over six years.3 In PLESS, PROSCAR also significantly reduced bother due to BPH symptoms (p<0.001 vs. placebo at four years).4 The consistent safety and tolerability profile of PROSCAR has been well characterized by extension data from eight years of therapy.1 In a subanalysis of PLESS, PROSCAR had no effect on BMD.5 Slide VI.6 References 1. Data on file, MSD ______. 2. Kaplan SA, Holtgrewe HL, Bruskewitz R et al for the Proscar Long-term Efficacy and Safety Study Group. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001;57(6): 3. Roehrborn CG for the PLESS Study Group. Rapid reduction in risk of AUR and/or surgery with finasteride in men with benign prostatic hyperplasia. Poster European Association of Urology meeting, Birmingham, UK, February 25, 2002. 4. Bruskewitz R, Girman CJ, Fowler J et al for the PLESS Study Group. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. Urology 1999;54: 5. Matsumoto AM, Tenover L, McClung M et al. The long-term effect of specific type II 5 -reductase inhibition with finasteride on bone mineral density in men: Results of a 4 year placebo controlled trial. J Urol 2002;167: PSC 2001-W SS

The Patient-Physician Connection Section VII
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Patient Satisfaction Is Important in the Treatment of Clinical BPH
Treatment selection in BPH should take into account Patient’s perception of the impact of BPH on quality of life Patient’s ability to deal with bother caused by symptoms Patient’s attitudes toward risk of possible complications Slide VII.1 In addition to safety and efficacy, the individual’s sense of well-being is important in assessing the benefit of different treatments.1 In particular, the patient’s perception of the impact of clinical BPH on quality of life,2 ability to deal with the degree of bother caused by symptoms,3 and attitudes toward the risk of possible complications2 should play a role in therapeutic decision making. A recent survey of 124 German men 40 to 80 years of age (mean, 61 years) receiving PROSCAR™ for the treatment of clinical BPH confirmed these considerations as key factors in the choice of medication. Specifically, the following characteristics were judged to be “very important” in a BPH medication: “improvement of symptoms” (92% of respondents), “reducing the risk of surgery” (85%), and “improvement in quality of life” (78%).4 Slide VII.1 References 1. Kaplan SA, Olsson CA. Patient satisfaction with finasteride in the treatment of symptomatic benign prostatic hyperplasia. Clin Ther 1996;18(1):73-83. 2. Garraway WM, Kirby RS. Benign prostatic hyperplasia: Effects on quality of life and impact on treatment decisions. Urology 1994;44(5): 3. Girman CJ, Kolman C, Liss CL et al for the Finasteride Study Group. Effects of finasteride on health-related quality of life in men with symptomatic benign prostatic hyperplasia. Prostate 1996;29:83-90. 4. Data on file, MSD ______. PSC 2001-W SS

The Physician’s Role in Patient Education
Physicians should involve patients with BPH in the choice of therapy Patient education should include discussions of The natural history of BPH (including potential for serious complications) Benefits, risks, and costs of alternative approaches Slide VII.2 Guidelines issued by the ICBPH recommend that physicians involve their patients in the choice of therapy for BPH (shared decision making).1 Patient preference is shaped by many factors, such as information learned from the Internet.2 To ensure that decisions are based on reliable data, the physician should educate patients about the natural history of BPH, including the potential for serious complications, as well as the benefits, risks, and costs of treatments.1,2 Slide VII.2 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. Roehrborn CG, Bartsch C, Kirby R et al. Guidelines for the diagnosis and treatment of benign prostatic hyperplasia: A comparative, international overview. Urology 2001;58(5): PSC 2001-W SS

Combination Therapy for Clinical BPH Section VIII
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Combined Therapy with PROSCAR™ and an Alpha Blocker (terazosin) for Clinical BPH
20 18 16 14 12 10 8 PROSCAR 5 mg/day Terazosin titrated to 5 mg Combination Slide VIII.1 Combination therapy with PROSCAR™ and an alpha blocker is a popular option for men with symptomatic BPH that is supported by clinical research. In one study, PROSCAR 5 mg/day plus terazosin titrated to 5 mg produced significantly greater relief of symptoms than occurred with either agent used alone at 12 months (p<0.05).1,* *Evaluation of comparative efficacy of PROSCAR, terazosin, or combination therapy in 195 men with BPH (mean age, 69 years) Mean IPSS 2 4 6 8 10 12 Time (months) p<0.05 PROSCAR + terazosin vs. either agent used alone at 12 months Adapted from Savage SJ et al Can J Urol 1998;5(3): Slide VIII.1 Reference 1. Savage SJ, Spungen AM, Galea G et al. Combination medical therapy for symptomatic benign prostatic hyperplasia. Can J Urol 1998;5(3): PSC 2001-W SS

Discontinuation of Alpha Blockade After Combined Therapy with PROSCAR™ and an Alpha Blocker (doxazosin) for BPH 100 80 60 40 20 Doxazosin 2 mg (n=25) Doxazosin 4 mg (n=20) Doxazosin 8 mg (n=15) 87 84 84 85 80 73 Slide VIII.2 As demonstrated by a recent clinical trial in men with enlarged prostates and BPH symptoms, discontinuation of doxazosin after three to 12 months of combination therapy did not lead to a clinically important deterioration in symptoms, regardless of the dosage used. Over the year following discontinuation, rates of success (stable or improved symptom scores and no desire to resume doxazosin) increased steadily in all dosage groups.1,* *Evaluation of the effect of discontinuing an alpha blocker on symptoms in 272 men (average age, 66 years) with BPH who initially received both PROSCAR and alpha-blocker therapy Success rates after discontinuation (% of patients) 48 45 40 20 15 13 3 months 6 months 9 months 12 months Time after discontinuation Adapted from Baldwin KC et al Urology 2001;58(2): Slide VIII.2 Reference 1. Baldwin KC, Ginsberg PC, Roehrborn CG et al. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001;58(2): PSC 2001-W SS

Combined Therapy with PROSCAR™ and an Alpha Blocker for Clinical BPH: Summary
Enhanced relief of symptoms After withdrawal of alpha blocker Satisfaction (success) rates maintained Ö 87% after 12 months in one study Slide VIII.3 For men with symptomatic BPH, combination therapy with PROSCAR™ and an alpha blocker is supported by clinical research.1 For example, a study of combination therapy showed significantly greater relief of symptoms with terazosin (titrated to 5 mg/day) plus PROSCAR than with either agent alone (p<0.05 at 12 months).1 One year after discontinuation of doxazosin (titrated to 8 mg) by patients receiving concomitant therapy with PROSCAR, the success rate was 87% in one study, demonstrating the durability of success with finasteride after discontinuation of an alpha blocker.2 Slide VIII.3 References 1. Savage SJ, Spungen AM, Galea G et al. Combination medical therapy for symptomatic benign prostatic hyperplasia. Can J Urol 1998;5(3): 2. Baldwin KC, Ginsberg PC, Roehrborn CG et al. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001;58(2): PSC 2001-W SS

Other Emerging Uses of PROSCAR™ Section IX
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PROSCAR™ Decreases the Risk of Hematuria
70 60 50 40 30 20 10 Control (n=27) PROSCAR (n=28) 63 Slide IX.1 The effect of PROSCAR™ on hematuria was prospectively evaluated in a multicenter, randomized trial in 55 men with BPH and chronic hematuria. After one year, four of the 28 men treated with PROSCAR (14%) had mild hematuria. Seven of the 27 men who underwent “watchful waiting” (63%) had heavier bleeding. Seven men in the control group (26%) but no men receiving PROSCAR required surgery (TURP or cystoscopy) for hematuria.1 PROSCAR is not indicated for treatment of BPH-related hematuria. % of men 26 14 Hematuria* at 1 year Hematuria requiring surgery at 1 year *p<0.05 between groups PROSCAR is not indicated for treatment of BPH-related hematuria. Adapted from Foley SJ et al J Urol 2000;163: Slide IX.1 Reference 1. Foley SJ, Soloman LZ, Wedderburn AW et al. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163: PSC 2001-W SS

% of patients with bleeding
Pretreatment with PROSCAR™ Decreases Perioperative Bleeding Associated with TURP* 40 35 30 25 20 15 10 5 Placebo PROSCAR 14 36.8 Slide IX.2 Bleeding requiring transfusion is one of the most common complications of TURP, even in the hands of experienced resectionists.1 In light of emerging evidence that PROSCAR™ may reduce the risk of BPH-related hematuria,2 a prospective study compared the incidence of perioperative bleeding in 25 patients pretreated with PROSCAR for two to four months before TURP with that of 50 control patients.1 In the month following surgery, perioperative bleeding (defined as the need for perioperative blood transfusion or a return visit to the emergency room for clot retention and/or gross hematuria) occurred in 4% of the men receiving PROSCAR versus 14% of the untreated controls. The risk reduction was even greater in the subset of patients with 30 g or more of prostate resected—8.3% with PROSCAR and 36.8% with no treatment. These results were supported by the findings of a six-month double-blind, randomized, placebo-controlled pilot study of the effects of three months of pretreatment with PROSCAR 5 mg daily (n=26) versus no treatment (n=29) on blood loss during TURP. During surgery, blood was collected through a suprapubic catheter placed in the bladder. Subsequently, the hemoglobin content of the fluid was measured by photometry, and total blood loss was calculated as the sum of the hemoglobin content in the perioperative fluid divided by the preoperative blood hemoglobin concentration. Blood loss did not differ between the groups as a whole but on subgroup analysis was significantly lower (p0.01) in patients treated with PROSCAR (median, 324 ml) than in untreated controls (median, 547 ml) when resected tissue weighed 18.6 g or more.3 PROSCAR is not indicated for pretreatment before prostate surgery. % of patients with bleeding 8.3 4 (n=50) (n=25) (n=31) (n=13) (n=19) (n=12) Total group <30 g resected 30 g resected *PROSCAR was given 2–4 months before TURP. PROSCAR is not indicated for pretreatment before prostate surgery. Adapted from Hagerty JA et al Urology 2000;55: Slide IX.2 References 1. Hagerty JA, Ginsberg PC, Harmon JD et al. Pretreatment with finasteride decreases perioperative bleeding associated with transurethral resection of the prostate. Urology 2000;55: 2. Foley SJ, Soloman LZ, Wedderburn AW et al. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163: 3. Sandfeldt L, Bailey DM, Hahn RG. Blood loss during transurethral resection of the prostate after 3 months of treatment with finasteride. Urology 2001;58: PSC 2001-W SS

Other Emerging Uses of PROSCAR™: Summary
Extended benefits of PROSCAR in men with BPH Reduced risk of hematuria and hematuria-related surgery Improved outcomes when used prior to BPH-related surgery PROSCAR is not currently indicated for these uses. Slide IX.3 Extended benefits of PROSCAR™ in men with BPH include a reduced risk of hematuria and need for surgery due to hematuria,1 and improved outcomes when used prior to BPH surgery.2,3 PROSCAR is not indicated for the above-mentioned uses. MSD does not advocate any use of PROSCAR outside approved label. PROSCAR is not currently indicated for these uses. Slide IX.3 References 1. Foley SJ, Soloman LZ, Wedderburn AW et al. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163: 2. Sandfeldt L, Bailey DM, Hahn RG. Blood loss during transurethral resection of the prostate after 3 months of treatment with finasteride. Urology 2001;58: 3. Hagerty JA, Ginsberg PC, Harmon JD et al. Pretreatment with finasteride decreases perioperative bleeding associated with transurethral resection of the prostate. Urology 2000;55: PSC 2001-W SS

Summary Section X Section X PSC 2001-W SS

Overall Summary and Conclusions
BPH, a multifactorial disorder characterized by an enlarged prostate, LUTS, and BOO, can lead to serious clinical outcomes (AUR and BPH-related surgery). PROSCAR™ is a competitive and specific inhibitor of type II 5-reductase, which mediates the conversion of testosterone to DHT. PROSCAR reduces BPH symptoms and prostate size, improves urinary flow, and decreases the risk of AUR and BPH-related surgery. PROSCAR slows the progression of BPH. The clinical effects of PROSCAR have been established in clinical trials of up to 7 years’ duration. Slide X.1 BPH, a multifactorial disorder characterized by an enlarged prostate, LUTS, and BOO, can lead to serious clinical outcomes, including AUR and BPH-related surgery.1,2 PROSCAR™ is a competitive and specific inhibitor of type II 5-reductase, the principal enzyme involved in the conversion of testosterone to the more potent prostatic androgen DHT.3,4 As such, PROSCAR targets the underlying cause of BPH. In light of results from large, controlled clinical studies, PROSCAR is indicated to reduce BPH symptoms and prostate size, improve urinary flow, and decrease the risk of AUR and BPH-related surgery in men with symptomatic BPH and enlarged prostates. The studies reviewed in this slide kit demonstrate that the effects of PROSCAR on prostate size, symptoms, and urinary flow are maintained for up to seven years of treatment.5 Most important, the ability of PROSCAR to prevent serious outcomes of BPH (AUR and BPH-related surgery) is sustained for up to six years of therapy.6 Before prescribing, please consult the prescribing information. Slide X.1 References 1. Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: 2. Lieber MM, Jacobsen SJ, Roberts RO et al. Prostate volume and prostate-specific antigen in the absence of prostate cancer: A review of the relationship and prediction of long-term outcomes. Prostate 2001;49(2): 3. Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5-alpha-reductase inhibition in human benign prostate hyperplasia. Eur Urol 2000;37(4): 4. Rittmaster RS. 5-Alpha-reductase inhibitors. J Androl 1997;18(6): 5. Data on file, MSD ______. 6. Roehrborn CG for the PLESS Study Group. Rapid reduction in risk of AUR and/or surgery with finasteride in men with benign prostatic hyperplasia. Poster European Association of Urology meeting, Birmingham, UK, February 25, 2002. PSC 2001-W SS

Bibliography See Notes page Bibliography
Andersen JT, Ekman P, Wolf H et al for the Scandinavian BPH Study Group. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebo-controlled study. Urology 1995;46(5): Andersen JT, Nickel JC, Marshall VR et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49(6): Andriole GL, Guess HA, Epstein JI et al. Treatment with finasteride preserved usefulness of prostate-specific antigen in the detection of prostate cancer: Results of a randomized, double-blind, placebo-controlled clinical trial. Urology 1998;52(2): Baldwin KC, Ginsberg PC, Roehrborn CG et al. Discontinuation of alpha-blockade after initial treatment with finasteride and doxazosin in men with lower urinary tract symptoms and clinical evidence of benign prostatic hyperplasia. Urology 2001;58(2): Bartsch G, Rittmaster RS, Klocker H. Dihydrotestosterone and the concept of 5-alpha-reductase inhibition in human benign prostate hyperplasia. Eur Urol 2000;37(4): Beers MH, Berkow R, eds. Prostate disease. In Merck Manual of Diagnosis and Therapy. 17th ed. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1999: Berry SJ, Coffey DS, Walsh PC et al. The development of human benign prostatic hyperplasia with age. J Urol 1984;132: Boesch ST, Curvin S, Zhang J et al. Modulation of the differentiation status of cultured prostatic smooth muscle cells by an alpha1-adrenergic receptor antagonist. Prostate 1999;39: Boyle P. Epidemiology and natural history. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001:17-68. Bruskewitz R, Girman CJ, Fowler J et al for the PLESS Study Group. Effect of finasteride on bother and other health-related quality of life aspects associated with benign prostatic hyperplasia. Urology 1999;54: Chon JK, Borkowski A, Partin AW et al. Alpha1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with BPH. J Urol 1999;161: Data on file, MSD ______. De la Rosette JJMCH, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol 2001;40: Ekman P for the Scandinavian Finasteride Study Group. Maximum efficacy of finasteride is obtained within 6 months and maintained over 6 years. Follow-up of the Scandinavian Open-Extension Study. Eur Urol 1998;33: Fifth International Consultation 2001 on BPH. Recommendations of the International Scientific Committee: Evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Foley SJ, Soloman LZ, Wedderburn AW et al. A prospective study of the natural history of hematuria associated with benign prostatic hyperplasia and the effect of finasteride. J Urol 2000;163: Garraway WM, Kirby RS. Benign prostatic hyperplasia: Effects on quality of life and impact on treatment decisions. Urology 1994;44(5): Girman CJ, Jacobsen SJ, Guess HA et al. Natural history of prostatism: Relationship among symptoms, prostate volume and peak urinary flow rate. J Urol 1995;153: Girman CJ, Jacobsen SJ, Rhodes T et al. Association of health-related quality of life and benign prostatic enlargement. Eur Urol 1999;35(4): Girman CJ, Kolman C, Liss CL et al for the Finasteride Study Group. Effects of finasteride on health-related quality of life in men with symptomatic benign prostatic hyperplasia. Prostate 1996;29:83-90. Gnanapragasam VJ, Robson CN, Leung HY et al. Androgen receptor signaling in the prostate. BJU Int 2000;86: Gormley GJ, Stoner E, Bruskewitz RC et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327(17): Guyatt GH, Haynes RB, Jaeschke RZ et al. Users’ Guides to the Medical Literature: XXV. Evidence-based medicine: Principles for applying the Users’ Guides to patient care. JAMA 2000;284(24): Hagerty JA, Ginsberg PC, Harmon JD et al. Pretreatment with finasteride decreases perioperative bleeding associated with transurethral resection of the prostate. Urology 2000;55: Holtgrewe HL. The medical management of lower urinary tract symptoms and benign prostatic hyperplasia. Urol Clin North Am 1998;25(4): Hudson PB, Boake R, Trachtenberg J et al for the North American Finasteride Study Group. Efficacy of finasteride is maintained in patients with benign prostatic hyperplasia treated for 5 years. Urology 1999;53: Imperato-McGinley J, Guerrero L, Gautier T et al. Steroid 5-alpha-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 1974;186(4170): Imperato-McGinley J. 5-Alpha-metabolism in finasteride-treated subjects and male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. A review. Eur Urol 1991;20(suppl 1):78-81. Jacobsen SJ, Jacobson DJ, Girman CJ et al. Natural history of prostatism: Risk factors for acute urinary retention. J Urol 1997;158: Jacobsen SJ, Jacobson DJ, Girman CJ et al. Treatment for benign prostatic hyperplasia among community-dwelling men: The Olmsted County Study of Urinary Symptoms and Health Status Among Men. J Urol 1999;162: Jardin A, Andersson K-E, Chapple C et al. Alpha1-adrenoceptor antagonists in the treatment of BPH. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Kaplan SA, Olsson CA. Patient satisfaction with finasteride in the treatment of symptomatic benign prostatic hyperplasia. Clin Ther 1996;18(1): Kaplan SA, Holtgrewe HL, Bruskewitz R et al for the Proscar™ Long-term Efficacy and Safety Study Group. Comparison of the efficacy and safety of finasteride in older versus younger men in benign prostatic hyperplasia. Urology 2001;57(6): Kirby RS. Clinical pharmacology of 1-adrenoceptor antagonists. Eur Urol 1999;36(suppl 1):48-53. Laupacis A. The future of evidence-based medicine. Can J Clin Pharmacol 2001;8(suppl A):6A-9A. Lee C, Cockett A, Cussenot O et al. Regulation of prostate growth. In: Chatelain C, Denis L, Foo KT et al, eds. Benign Prostatic Hyperplasia. Plymouth, United Kingdom: Health Publication, 2001: Lieber MM, Jacobsen SJ, Roberts RO et al. Prostate volume and prostate-specific antigen in the absence of prostate cancer: A review of the relationship and prediction of long-term outcomes. Prostate 2001;49(2): Bibliography See Notes page PSC 2001-W SS

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Marberger MJ for the PROWESS Study Group. Long-term effects of finasteride in men with benign prostatic hyperplasia: A double-blind, placebo- controlled, multicenter study. Urology 1998;51: Matsumoto AM, Tenover L, McClung M et al. The long-term effect of specific type II 5 -reductase inhibition with finasteride on bone mineral density in men: Results of a 4 year placebo controlled trial. J Urol 2002;167: McAlister FA, Laupacis A, Wells GA et al. Users’ Guides to the Medical Literature: XIX. Applying clinical trials results B. Guidelines for determining whether a drug is exerting (more than) a class effect. JAMA 1999;282(14): McConnell JD, Wilson JD, George FW et al. Finasteride, an inhibitor of 5 -reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab 1992;74(3): McConnell JD, Bruskewitz R, Walsh P et al for the PLESS Study Group. 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Clinical BPH and Its Management A Comprehensive Slide Kit
Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturer’s prescribing information. Before prescribing any of the products mentioned in this slide presentation, please consult the manufacturers’ prescribing information. Copyright © 2002 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved PSC 2001-W SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT Copyright © 2002 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved PSC 2001-W SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT PSC 2001-W SS

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