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/SECOND ADD -- PH011 -- MERCK'S PROSCAR/

 /SECOND ADD -- PH011 -- MERCK'S PROSCAR/
 /Note on Graphs: The following prescribing information for Proscar


(finasteride) contains a chemical structure and four figures (graphs) that are not reproducible over PR Newswire. Their location is identified in the text. If you would like a copy of this information, please call 215-661-6681, and the company will fax them to you./
 PROSCAR
 (Finasteride)
 Tablets
 DESCRIPTION
 PROSCAR (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid 5(alpha)-reductase, an intracellular enzyme that converts testosterone into the potent androgen 5(alpha)- dihydrotestosterone (DHT).
 Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1- dimethylethyl)-3-oxo-,(5(alpha),17)-. The empirical formula of finasteride is C(subscript 23)H(subscript 36)N(subscript 2)O(subscript 2) and its molecular weight is 372.55. Its structural formula is:
 (See "Note on Graphs" above)
 Finasteride is a white crystalline powder with a melting point near 250 degrees Celsius. It is freely soluble in chloroform and in lower alcohol solvents, but is practically insoluble in water.
 PROSCAR (finasteride) tablets for oral administration are film- coated tablets that contain 5 mg of finasteride and the following inactive ingredients: docusate sodium, FD&C Blue 2 aluminum lake, hydrous lactose, hydroxypropyl cellulose LF, hydroxypropylmethyl cellulose, magnesium stearate, microcrystal-line cellulose, pregelatinized starch, purified water, sodium starch glycolate, talc, titanium dioxide and yellow iron oxide.
 CLINICAL PHARMACOLOGY
 Progressive enlargement of the prostate gland is often associated with urinary symptoms and a decrease in urine flow, although a precise correlation between increased gland size and symptoms has not been demonstrated. Benign prostatic hyperplasia (BPH) produces symptoms in the majority of men over the age of 50 and its prevalence increases with age.
 The development of the prostate gland is dependent on the potent androgen, 5(alpha)-dihydrotestosterone (DHT). The enzyme 5(alpha)- reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.
 Finasteride is a competitive and specific inhibitor of 5(alpha)-red- uctase. This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5(alpha)-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.
 In man, a single 5-mg oral dose of PROSCAR produces a rapid reduction in serum DHT concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of PROSCAR at 5 mg/day for up to 24 months has been shown to reduce the serum DHT concentration by approximately 70 percent. The median circulating level of testosterone increased by 10 percent but remained within the physiologic range.
 Adult males with genetically inherited 5(alpha)-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to 5(alpha)-reductase deficiency have been observed in these individuals. These individuals have a small prostate gland throughout life and do not develop BPH.
 In patients with BPH treated with finasteride (1-100 mg/day) for 7- 10 days prior to prostatectomy, an approximate 80 percent lower DHT content was measured in prostatic tissue removed at surgery, compared to placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative to placebo. Intraprostatic content of prostate-specific antigen (PSA) was also decreased.
 In healthy male volunteers treated with PROSCAR for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks.
 In patients with BPH, PROSCAR had no effect on circulating levels of cortisol, estradiol, prolactin, thyroid-stimulating hormone, or thyroxine. Nor did it affect the plasma lipid profile (i.e. total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) of 56 patients receiving PROSCAR for 12 weeks. The effects of long-term administration of PROSCAR on the plasma lipid profile are unknown. Increases of about 10 percent were observed in luteinizing hormone (LH), follicle-st-imulating hormone (FSH) and testosterone levels in patients receiving PROSCAR, but levels remained within the normal range.
 In healthy volunteers, treatment with PROSCAR did not alter the response of LH and FSH to gonadotropin-releasing hormone, indicating that the hypothalamic-pituitary-testicular axis was not affected.
 Pharmacokinetics
 Following an oral dose of (superscript 14)C-finasteride in man, a mean of 39 percent (range, 32-46 percent) of the dose was excreted in the urine in the form of metabolites; 57 percent (range, 51-64 percent) was excreted in the feces. The major compound isolated from urine was the monocarboxylic acid metabolite; virtually no unchanged drug was recovered. The t-butyl side chain monohydroxylated metabolite has been isolated from plasma. These metabolites possess no more than 20 percent of the 5(alpha)-reductase inhibitory activity of finasteride.
 In a study in 15 healthy male subjects, the mean bioavailability of a 5-mg PROSCAR tablet was 63 percent (range, 34-108 percent), based on the ratio of AUC relative to a 5-mg intravenous dose infused over 60 minutes. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1 to 2 hours postdose. The mean plasma half-life of elimination was 6 hours (range, 3-16 hours). Following the intravenous infusion, mean plasma clearance was 165 mLe bioavailability of finasteride was not affected by food.
 Approximately 90 percent of circulating finasteride is bound to plasma proteins. Finasteride has been found to cross the blood-brain barrier.
 There is a slow accumulation phase for finasteride after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of finasteride were 47 percent and 54 percent higher than after the first dose in men 45-60 years old (n-12) and greater than or equal to years old (n-12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4-9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively in the two age groups. Although steady state was not reached in this study, mean trough plasma concentration in another study in patients with BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n-22) after over a year of dosing.
 The elimination rate of finasteride is decreased in the elderly, but no dosage adjustment is necessary. The mean terminal half-life of finasteride in subjects greater than or equal to years of age was approximately 8 hours (range, 6-15 hours) compared to 6 hours (range, 4-12 hours) in subjects 45-60 years of age. As a result, mean AUC (0-24 hr) after 17 days of dosing was 15 percent higher in subjects greater than or equal to years of age (p-0.02).
 No dosage adjustment is necessary in patients with renal insufficiency. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, area under the curve, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60 percent increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks where exposure of these patients to metabolites would presumably be much greater.
 In 16 subjects receiving PROSCAR 5 mg/day, finasteride concentrations in semen ranged from undetectable (<1 ng/mL) to 21 ng/mL. Based on a 5 mL ejaculate volume, the amount of finasteride in ejaculate was estimated to be less than 1/50 of the dose of finasteride (5 micrograms) that had no effect on circulating DHT levels in adults.
 Clinical Studies
 Twelve-Month Controlled Clinical Trials
 In a North American and in an international multicenter, double- blind, placebo-controlled, 12-month study in patients with BPH treated with PROSCAR 5 mg/day, statistically significant regression of the enlarged prostate gland was noted at the first evaluation at 3 months and was maintained during the studies (Table 1). In both studies, the maximum urinary flow rates showed statistically significant increases from baseline in patients treated with PROSCAR from week 2 throughout the 12-month studies. Compared to placebo, statistically significant increases in maximum urinary flow rates were maintained in the North American study from month 4 through 12 in patients treated with PROSCAR. The maximum urinary flow rates in the international study were statistically significantly greater than placebo at months 7, 8, 11 and 12 (Figures 1-3 and Table 2).
 TABLE 1
 Median Percent Change in Prostate Volume(A) from Baseline
 North American Study International Study
 PROSCAR Placebo PROSCAR Placebo
 5 mg 5 mg
 (n-297)(B) (n-300)(B) (n-246)(B) (n-255)(B)
 Baseline
 volume(cc) 52.1 50.0 45.5 41.5
 Percent Percent Percent Percent
 Month 3 -12.1(C) -2.4 -19.1(C) -6.0
 Month 6 -17.4(C) -2.8 -21.9(C) -5.5
 Month 12 -19.2(C) -3.0 -24.0(C) -6.1
 (A) Prostate volume was measured by magnetic resonance imaging (N. Am.) and ultrasound (Int'l.). (Prostate volume was not measured at month 9.)
 (B) Enrolled at baseline
 (C) p < 0.001 vs. placebo
 FIGURE 1
 Maximum Urinary Flow Rate
 (see "Note on Graphs" above)
 TABLE 2


Mean Increase in Maximum Urinary Flow Rate (mL/sec)(A) from Base-line
 North American Study International Study
 PROSCAR 5 mg Placebo PROSCAR 5 mg Placebo
 (n-297) (n-300) (n-246) (n-255)
 Baseline
 flow rate
 (mL/sec) 9.6 9.6 9.2 8.6
 Week 2 0.5(B) -0.2 0.6 0.2
 Month 1 0.5 0.2 0.7 0.3
 Month 2 0.9(B) 0.3 1.1 0.6
 Month 3 0.8 0.3 0.8 0.2
 Month 4 1.0(B) 0.4 1.0 0.6
 Month 5 1.0(C) 0.2 0.9 0.8
 Month 6 0.8(B) 0.1 1.1 0.7
 Month 7 1.2(C) 0.4 1.3(B) 0.4
 Month 8 1.4(D) 0.3 1.3(B) 0.5
 Month 9 1.3(C) 0.3 1.2 0.4
 Month 10 1.5(D) 0.5 1.3 0.7
 Month 11 1.4(D) 0.3 1.5(C) 0.4
 Month 12 1.6(D) 0.2 1.3(B) 0.4
 (A) Maximum urinary flow rates (voided volumes greater than or equal to 150 mL) were measured with a non-invasive urinary flow meter.
 (B), (C), (D) p < 0.05, p < 0.01, p < 0.001 vs placebo, respectively
 FIGURE 2
 Mean Increase in Maximum Urinary Flow Rate (mL/sec) (Pooled Data)
 (see "Note on Graphs" above)
 FIGURE 3
 Percent of Patients with a Maximum Urinary Flow Rate Increase
 Greater than or Equal to 3 mL/sec
 (see "Note on Graphs" above)
 /delval/
 -0- 6/22/92 AB PH011
 /CONTACT: Jan D. Weiner or Gary M. Bruell, 215-661-6681, both of Merck & Co. Inc./
 /THIRD ADD -- MERCK'S PROSCAR -- TO FOLLOW/
 (MRK) CO: Merck & Co. Inc. ST: Pennsylvania IN: MTC SU: PDT


CC-JS -- PH011B -- 2417 06/22/92 12:49 EDT
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Copyright 1992 Gale, Cengage Learning. All rights reserved.

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Date:Jun 22, 1992
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