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

 /THIRD ADD -- PH011 -- MERCK'S PROSCAR/
 Symptomatic improvement was also evaluated in these multicenter


studies. Obstructive and total symptom scores were calculated based on patient responses to a validated questionnaire. The obstructive symptoms evaluated were hesitancy, feeling of incomplete bladder emptying, interruption of urinary stream, impairment of size and force of urinary stream and terminal urinary dribbling. The total symptom score also included straining to start urinary flow, dysuria, frequency of clothes wetting and urgency to urinate. On a scale of 0 (absence of all symptoms) to 36 (worst response for all symptoms), the mean baseline total symptom scores for the North American and international studies were 10.1 and 10.6, respectively.
 The mean total symptom scores of patients in the North American and international studies decreased from baseline starting at week 2 of treatment with either PROSCAR or placebo; from week 2 the scores of the patients treated with PROSCAR were numerically lower than those of placebo and remained so throughout the 12-month study. These scores became statistically significantly lower than placebo (p<0.05) starting at month 7 in the international study and at month 10 in the North American study (Figure 4). Similar results were observed with the obstructive symptom scores.
 FIGURE 4
 Mean Change in Total Symptom Scores From Baseline
 (see "Note on Graphs" above)
 Blinded global assessments of overall urinary function and symptoms were performed. Greater improvement in patients treated with PROSCAR as compared to placebo was demonstrated by both the investigator's assessment (N.Am. and Int'l, ps0.01) and the patient's own assessment (N.Am., ps0.01; Int'l, ps0.1).
 In both of these 12-month studies, patients treated with PROSCAR 5 mg had progressively decreasing prostate volumes, increasing maximum urinary flow rates and improvement of symptoms associated with BPH, suggesting an arrest in the disease process.
 Controlled clinical data beyond 12 months are not available.
 Long-Term Open Extensions
 In long-term uncontrolled extensions of these studies in approximately 300 patients receiving PROSCAR 5 mg/day for 24 months, prostate volume was reduced by a median of 25.5 percent (base-line, 52.2 cc), maximum flow rate increased by a mean of 2.2 mL/sec (baseline, 11.3 mL/sec) and the total symptom score improved by a mean of 3.4 points (baseline, 9.6 points).
 In addition, regression of the enlarged prostate gland and a decrease in PSA levels were maintained in approximately 50 patients who were treated with PROSCAR for 36 months.
 INDICATIONS AND USAGE
 PROSCAR is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH). Although there is a rapid regression of the enlarged prostate gland in most treated patients, less than 50 percent of patients experience an increase in urinary flow and improvement in symptoms of BPH when treated with PROSCAR for 12 months. (See CLINICAL PHARMACOLOGY.)
 The long-term effects of PROSCAR on the incidence of surgery, acute urinary obstruction or other complications of BPH are yet to be determined.
 A minimum of 6 months treatment may be necessary to determine whether an individual will respond to PROSCAR. It is not possible to identify prospectively those patients who will respond.
 Prior to initiating therapy with PROSCAR, appropriate evaluation should be performed to identify other conditions, such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic disorders, that might mimic BPH.
 CONTRAINDICATIONS
 PROSCAR is contraindicated in the following:
 Hypersensitivity to any component of this medication.
 Pregnancy. Finasteride is contraindicated in women who are or may become pregnant. Because of the ability of 5 alpha-reductase inhibitors to inhibit the conversion of testosterone to DHT, finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. (See also WARNINGS, Exposure of Women - Risk to Male Fetus and PRECAUTIONS, Information for Patients and Pregnancy.) In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.
 WARNINGS
 PROSCAR is not indicated for use in children (see PRECAUTIONS, Pediatric Use) or women (see also CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Information for Patients and Pregnancy; and HOW SUPPLIED).
 Exposure of Women - Risk to Male Fetus
 It is not known whether the amount of finasteride that could potentially be absorbed by a pregnant woman through either direct contact with crushed PROSCAR tablets or from the semen of a patient taking PROSCAR can adversely affect a developing male fetus (see CLINICAL PHARMACOLOGY, Pharmacokinetics; CONTRAINDICATIONS; PRECAUTIONS, Information for Patients and Pregnancy; and HOW SUPPLIED). Therefore, because of the potential risk to a male fetus, a woman who is pregnant or who may become pregnant should not handle crushed PROSCAR tablets; in addition, when the patient's sexual partner is or may become pregnant, the patient should either avoid exposure of his partner to semen or he should discontinue PROSCAR.
 PRECAUTIONS
 General
 Digital rectal examinations, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with PROSCAR and periodically thereafter. Although currently not indicated for this purpose, serum PSA is being increasingly used as one of the components of the screening process to detect prostate cancer (Catalona, W.J.; Smith, D.S.; Ratliff, T.l.; Dodds, K.M.; Coplen, M.D.; Yuan, J.J.J.; Petros, J.A.; Andriole, G.L.: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer, N.Eng.J.Med. 324(17): 1156-1161, April 25, 1991.).
 Generally, a baseline PSA >10 ng/mL (Hybritech) prompts further evaluation and consideration of biopsy; for PSA levels between 4 and 10 ng/mL, further evaluation is generally considered advisable. The physician should be aware that a baseline PSA <4 ng/mL does not exclude the diagnosis of prostate cancer.
 PROSCAR causes a decrease in serum PSA levels in patients with BPH even in the presence of prostate cancer (see Drug/Laboratory Test Interactions). This reduction of PSA levels should be considered when evaluating PSA laboratory data and does not suggest a beneficial effect of PROSCAR on prostate cancer. In controlled clinical trials PROSCAR did not appear to alter the rate of prostate cancer detection.
 Any sustained increases in PSA levels while on PROSCAR should be carefully evaluated, including consideration of non-compliance to therapy with PROSCAR (see Drug/Laboratory Test Interactions).
 Since not all patients demonstrate a response to PROSCAR, patients with a large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for this therapy.
 Caution should be used in the administration of PROSCAR in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.
 Information for Patients
 Crushed PROSCAR tablets should not be handled by a woman who is pregnant or who may become pregnant because of the potential for absorption of finasteride and the subsequent potential risk to the male fetus. Similarly, when the patient's sexual partner is or may become pregnant, the patient should either avoid exposure of his partner to semen or he should discontinue PROSCAR (see CLINICAL PHARMACOLOGY, Pharmacokinetics; CONTRAINDICATIONS; WARNINGS, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Pregnancy; and HOW SUPPLIED).
 Physicians should inform patients that the volume of ejaculate may be decreased in some patients during treatment with PROSCAR. This decrease does not appear to interfere with normal sexual function. However, impotence and decreased libido may occur in patients treated with PROSCAR (see ADVERSE REACTIONS, Twelve-Month Controlled Clinical Trials).
 Drug/Laboratory Test Interactions
 When PSA laboratory determinations are evaluated, consideration should be given to the fact that PSA levels are decreased in patients treated with PROSCAR. In controlled clinical trials in patients with BPH treated with PROSCAR, PSA levels decreased from baseline by a median of 41 percent (95 percent confidence interval of the median: 38-45 percent) at month 6 and by a median of 48 percent (95 percent confidence interval of the median: 45-52 percent) at month 12.
 Drug Interactions
 Antipyrine: Antipyrine is used as a model for drugs that are metabolized by the same isoenzymatic cytochrome P450 system. In 12 subjects receiving PROSCAR 10 mg/day for 28 days, PROSCAR had no effect on the pharmacokinetic parameters of antipyrine or its metabolites.
 Propranolol: In 19 normal volunteers receiving PROSCAR 5 mg/day for 10 days, PROSCAR did not affect the beta-adrenergic blocking activity or plasma concentrations of propranolol enantiomers after a single dose of propranolol.
 Digoxin: In 17 normal volunteers receiving PROSCAR 5 mg/day for 10 days, concomitant administration of multiple doses of PROSCAR and a single dose of digoxin resulted in no effect on plasma concentrations of digoxin and its immunoreactive metabolites.
 Theophylline: In 12 normal volunteers receiving PROSCAR 5 mg/day for 8 days, PROSCAR significantly increased theophylline clearance by 7 percent and decreased its half-life by 10 percent after intravenous administration of aminophylline. These changes were not clinically significant.
 Warfarin: In 12 patients chronically treated with warfarin, the prothrombin times and plasma concentrations of warfarin enantiomers were not altered after treatment with PROSCAR 5 mg/day for 14 days.
 Other Concomitant Therapy: Although specific interaction studies were not performed, PROSCAR was concomitantly used in clinical studies with alpha-blockers, angiotensin-converting enzyme (ACE) inhibitors, analgesics, anti-convulsants, beta-adrenergic blocking agents, diuretics, calcium channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, H(subscript 2) antagonists and quinolone antiinfectives without evidence of clinically significant adverse interactions.
 Carcinogenesis, Mutagenesis, Impairment of Fertility
 No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC(0-24hr) for animals and mean AUC(0-24hr) for man (0.4 ug.hr/mL).
 In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p s0.05) increase in the incidence of testicular Leydig cell adenomas was observed at a dose of 250 mg/kg/day (228 times the human exposure). In mice at a dose of 25 mg/kg/day (23 times the human exposure, estimated) and in rats at a dose of >or equal to 40 mg/kg/day (39 times the human exposure) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2-3 fold above control) has been demonstrated in both rodent species treated with high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated with finasteride for 1 year at doses of 20 mg/kg/day and 45 mg/kg/day (30 and 350 times, respectively, the human exposure) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (2.3 times the human exposure, estimated).
 No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, when Chinese hamster ovary cells were treated with high concentrations (450-550 fmol) of finasteride, there was a slight increase in chromosome aberrations. These concentrations correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg. Further, the concentrations (450-550 fmol) used in in vitro studies are not achievable in a biological system. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the human exposure) as determined in the carcinogenicity studies.
 In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (543 times the human exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 80 mg/kg/day of finasteride (61 times the human exposure), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man.
 Pregnancy Pregnancy Category X See CONTRAINDICATIONS.
 PROSCAR is not indicated for use in women.
 Administration of finasteride to pregnant rats at doses ranging from 100 ug/kg/day to 100 mg/kg/day (1-1000 times the recommended human dose) resulted in dose-dependent development of hypospadias in 3.6 to 100 percent of male offspring. Pregnant rats produced male offspring with decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development when given finasteride at > or equal to 30 ug/kg/day (> or equal to 3/10 of the recommended human dose) and decreased anogenital distance when given finasteride at > or equal to 3 ug/kg/day (> or equal to 3/100 of the recommended human dose). The critical period during which these effects can be induced in male rats has been defined to be days 16-17 of gestation. The changes described above are expected pharmacological effects of drugs belonging to the class of 5 alpha-reductase inhibitors and are similar to those reported in male infants with a genetic deficiency of 5 alpha-reductase. No abnormalities were observed in female offspring exposed to any dose of finasteride in utero.
 No developmental abnormalities have been observed in first filial generation (F(subscript 1)) male or female offspring resulting from mating finasteride-treated male rats (80 mg/kg/day; 61 times the human exposure) with untreated females. Administration of finasteride at 3 mg/kg/day (30 times the recommended human dose) during the late gestation and lactation period resulted in slightly decreased fertility in F(subscript 1) male offspring. No effects were seen in female offspring. No evidence of malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6-18 of gestation at doses up to 100 mg/kg/day (1000 times the recommended human dose). However, effects on male genitalia would not be expected since the rabbits were not exposed during the critical period of genital system development.
 Nursing Mothers -- PROSCAR is not indicated for use in women.
 It is not known whether finasteride is excreted in human milk.
 Pediatric Use -- PROSCAR is not indicated for use in children.
 Safety and effectiveness in children have not been established.
 ADVERSE REACTIONS
 PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient.
 Twelve-Month Controlled Clinical Trials
 In North American and international clinical trials, 543 patients were treated with 5 mg of PROSCAR for 12 months. Seven of these patients (1.3 percent) were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related; only 1 of these patients (0.2 percent) discontinued therapy with PROSCAR because of a sexual adverse experience.
 The following clinical adverse reactions were reported as possibly, probably or definitely drug-related in > or equal to 1 percent of patients treated for 12 months with 5 mg/day of PROSCAR or placebo, respectively: impotence (3.7 percent, 1.1 percent), decreased libido (3.3 percent, 1.6 percent), decreased volume of ejaculate (2.8 percent, 0.9 percent).
 The adverse experience profile for an additional 547 patients treated with 1 mg/day of PROSCAR for 12 months was similar to that observed in patients treated for 12 months with 5 mg/day of PROSCAR.
 Long-Term Open Extensions
 The adverse experience profile for approximately 300 patients who were maintained on PROSCAR 5 mg/day for 24 months was similar to that observed in the controlled studies. In addition, a similar safety profile was observed in 50 patients treated with PROSCAR 5 mg/day for 36 months.
 OVERDOSAGE
 Patients have received single doses of PROSCAR up to 400 mg and multiple doses of PROSCAR up to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific treatment for an overdose with PROSCAR can be recommended.
 Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m(superscript 2) (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m(superscript 2) (400 mg/kg) and 5900 mg/m(superscript 2) (1000 mg/kg), respectively.
 DOSAGE AND ADMINISTRATION
 The recommended dose is 5 mg once a day.
 Although early improvement may be seen, at least 6-12 months of therapy with PROSCAR may be necessary in some patients to assess whether a beneficial response has been achieved. Periodic follow-up evaluations should be performed to determine whether a clinical response has occurred.
 PROSCAR may be administered with or without meals.
 No dosage adjustment is necessary for patients with renal impairment or for the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics).
 HOW SUPPLIED
 No. 3094 -- PROSCAR tablets 5 mg are blue, modified apple-shaped, film-coated tablets, with the code MSD 72 on one side and PROSCAR on the other. They are supplied as follows:
 NDC 0006-0072-31 unit of use bottles of 30
 NDC 0006-0072-58 unit of use bottles of 100
 NDC 0006-0072-28 unit dose packages of 100.
 Storage and Handling
 Store at room temperatures below 30xC (86xF). Protect from light and keep container tightly closed.
 If the film coating of PROSCAR tablets has been broken (e.g., crushed), the tablets should not be handled by a woman who is pregnant or who may become pregnant because of the potential for absorption of finasteride and the subsequent potential risk to a male fetus (see CLINICAL PHARMACOLOGY, Pharmacokinetics; WARNINGS, Exposure of Women -- Risk to Male Fetus; and PRECAUTIONS, Information for Patients and Pregnancy).
 Distributed by: MERCK SHARP & DOHME, DIVISION OF MERCK & CO., INC., WEST POINT, PA 19486 USA
 Manufactured by: MERCK SHARP & DOHME Ltd., Hoddesdon, Harts, U.K., EN11 9BU.
 /delval/
 -0- 6/22/92 AC PH011
 /CONTACT: Jan D. Weiner or Gary M. Bruell, 215-661-6681, both of Merck & Co. Inc./
 /END THIRD AND FINAL ADD/
 (MRK) CO: Merck & Co. Inc. ST: Pennsylvania IN: MTC SU: PDT


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Date:Jun 22, 1992
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