Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action The development and enlargement of the prostate gland is dependent on the potent androgen, 5α- dihydrotestosterone (DHT). Type II 5α-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 Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½ ~ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride. Pharmacodynamics 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 4 years has been shown to reduce the serum DHT concentration by approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range. In patients receiving PROSCAR 5 mg/day, increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 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. In patients with BPH, PROSCAR has no effect on circulating levels of cortisol, prolactin, thyroidstimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral density. Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related to Type II 5α-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% 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 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 treated for three months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately three months of discontinuation of therapy. Pharmacokinetics Absorption In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63% (range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food. Distribution Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of circulating finasteride is bound to plasma proteins. 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 and 54% higher than after the first dose in men 45-60 years old (n=12) and ≥70 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. Finasteride has been shown to cross the blood brain barrier but does not appear to distribute preferentially to the CSF. In 2 studies of healthy subjects (n=69) receiving PROSCAR 5 mg/day for 6-24 weeks, finasteride concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PROSCAR 5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume, the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride (5 μg) that had no effect on circulating DHT levels in men [see also Use In Specific Populations]. Metabolism Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of finasteride. Excretion In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces. The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of age. As a result, mean AUC(0-24 hr) after 17 days of dosing was 15% higher in subjects ≥70 years of age than in subjects 45-60 years of age (p=0.02). Table 3: Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15) Mean (± SD) Bioavailability 63% (34-108%)* Clearance (mL/min) 165 (55) Volume of Distribution (L) 76 (14) Half-Life (hours) 6.2 (2.1) *Range Pediatric Finasteride pharmacokinetics have not been investigated in patients <18 years of age. Finasteride is not indicated for use in pediatric patients [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Gender Finasteride is not indicated for use in women [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations, HOW SUPPLIED/Storage And Handling and PATIENT INFORMATION]. Geriatric No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is decreased in the elderly, these findings are of no clinical significance. [See Pharmacokinetics and Use In Specific Populations.] Table 4: Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men Mean (± SD) 45-60 years old (n=12) ≥70 years old (n=12) AUC (ng•hr/mL) 389 (98) 463 (186) Peak Concentration (ng/mL) 46.2 (8.7) 48.4 (14.7) Time to Peak (hours) 1.8 (0.7) 1.8 (0.6) Half-Life (hours)* 6.0 (1.5) 8.2 (2.5) *First-dose values; all other parameters are last-dose values Race The effect of race on finasteride pharmacokinetics has not been studied. Hepatic Impairment The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of PROSCAR in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. Renal Impairment No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, 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% 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. Clinical Studies Monotherapy PROSCAR 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their 5-year open extensions. PROSCAR was further evaluated in the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016 patients were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride group, 883 in the placebo group). Effect On Symptom Score Symptoms were quantified using a score similar to the American Urological Association Symptom Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to 4 scale for one symptom, for a total possible score of 34. Patients in PLESS had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0-34 point scale). Patients randomized to PROSCAR who remained on therapy for 4 years had a mean (± 1 SD) decrease in symptom score of 3.3 (± 5.8) points compared with 1.3 (± 5.6) points in the placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at 1 year in patients treated with PROSCAR vs placebo (–2.3 vs –1.6), and this improvement continued through Year 4. Figure 1: Symptom Score in PLESS Results seen in earlier studies were comparable to those seen in PLESS. Although an early improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was generally necessary to assess whether a beneficial response in symptom relief had been achieved. The improvement in BPH symptoms was seen during the first year and maintained throughout an additional 5 years of open extension studies. Effect On Acute Urinary Retention And The Need For Surgery In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical intervention and acute urinary retention requiring catheterization. Complete event information was available for 92% of the patients. The following table (Table 5) summarizes the results. Table 5: All Treatment Failures in PLESS Event Patients (%)* Placebo N=1503 Finasteride N=1513 Relative Risk† 95% CI P Value† All Treatment Failures 37.1 26.2 0.68 (0.57 to 0.79) <0.001 Surgical Interventions for BPH 10.1 4.6 0.45 (0.32 to 0.63) <0.001 Acute Urinary Retention Requiring Catheterization 6.6 2.8 0.43 (0.28 to 0.66) <0.001 Two consecutive symptom scores≥20 9.2 6.7 Bladder Stone 0.4 0.5 Incontinence 2.1 1.7 Renal Failure 0.5 0.6 UTI 5.7 4.9 Discontinuation due to worsening of BPH, lack of improvement, or to receive other medical treatment 21.8 13.3 *patients with multiple events may be counted more than once for each type of event †Hazard ratio based on log rank test Compared with placebo, PROSCAR was associated with a significantly lower risk for acute urinary retention or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PROSCAR; 51% reduction in risk, 95% CI: (34 to 63%)]. Compared with placebo, PROSCAR was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for PROSCAR; 55% reduction in risk, 95% CI: (37 to 68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for PROSCAR; 57% reduction in risk, 95% CI: (34 to 72%)]; see Figures 2 and 3. Figure 2: Percent of Patients Having Surgery for BPH, Including TURP Figure 3: Percent of Patients Developing Acute Urinary Retention (Spontaneous and Precipitated) Effect On Maximum Urinary Flow Rate In the patients in PLESS who remained on therapy for the duration of the study and had evaluable urinary flow data, PROSCAR increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2 mL/sec in the placebo group. There was a clear difference between treatment groups in maximum urinary flow rate in favor of PROSCAR by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1- year studies, increase in maximum urinary flow rate was comparable to PLESS and was maintained through the first year and throughout an additional 5 years of open extension studies. Effect On Prostate Volume In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients. In patients treated with PROSCAR who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. PROSCAR decreased prostate volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1% (from 51.3 cc to 58.5 cc) in the placebo group (p<0.001). (See Figure 4.) Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at baseline ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and maintained throughout an additional five years of open extension studies. Figure 4 : Prostate Volume in PLESS Prostate Volume As A Predictor Of Therapeutic Response A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with PROSCAR, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline. Combination With Alpha-Blocker Therapy The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized, placebocontrolled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant's final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered once per day, at bedtime. The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and 49 mL in 66% of patients. The primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: a ≥4 point confirmed increase from baseline in symptom score, acute urinary retention, BPHrelated renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with PROSCAR, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with PROSCAR alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001). (See Table 6.) Table 6: Count and Percent Incidence of Primary Outcome Events by Treatment Group in MTOPS Event Treatment Group Placebo Doxazosin Finasteride Combination Total N=737 N (%) N=756 N (%) N=768 N (%) N=786 N (%) N=3047 N (%) AUA 4-point rise 100 (13.6) 59 (7.8) 74 (9.6) 41 (5.2) 274 (9.0) Acute urinary retention 18 (2.4) 13 (1.7) 6 (0.8) 4 (0.5) 41 (1.3) Incontinence 8 (1.1) 11 (1.5) 9 (1.2) 3 (0.4) 31 (1.0) Recurrent UTI/ urosepsis 2 (0.3) 2 (0.3) 0 (0.0) 1 (0.1) 5 (0.2) Creatinine rise 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Total Events 128 (17.4) 85 (11.2) 89 (11.6) 49 (6.2) 351 (11.5) The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score, referred to as symptom score progression. The risk of symptom score progression was reduced by 30% (p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PROSCAR, doxazosin, or the combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy significantly reduced the risk of symptom score progression compared to the effect of PROSCAR alone (p<0.001) and compared to doxazosin alone (p=0.037). Figure 5: Cumulative Incidence of a 4 -Point Rise in AUA Symptom Score by Treatment Group Treatment with PROSCAR, doxazosin or the combination of PROSCAR with doxazosin, reduced the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA symptom score by treatment group for patients who remained on therapy for four years. Table 7: Change From Baseline in AUA Symptom Score by Treatment Group at Year 4 in MTOPS Placebo N=534 Doxazosin N=582 Finasteride N=565 Combination N=598 Baseline Mean (SD) 16.8 (6.0) 17.0 (5.9) 17.1 (6.0) 16.8 (5.8) Mean Change AUA Symptom Score (SD) -4.9 (5.8) -6.6 (6.1) -5.6 (5.9) -7.4 (6.3) Comparison to Placebo (95% CI) -1.8 (-2.5, -1.1) -0.7 (-1.4, 0.0) -2.5 (-3.2, -1.8) Comparison to Doxazosin alone (95% CI) -0.7 (-1.4, 0.0) Comparison to Finasteride alone (95% CI) -1.8 (-2.5, -1.1) The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS [see Monotherapy] in that treatment with PROSCAR reduces the risk of acute urinary retention and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was reduced by 67% in patients treated with PROSCAR compared to patients treated with placebo (0.8% for PROSCAR and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with PROSCAR compared to patients treated with placebo (2.0% for PROSCAR and 5.4% for placebo). Summary Of Clinical Studies The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate volume, suggest that PROSCAR arrests the disease process of BPH in men with an enlarged prostate.

CLINICAL PHARMACOLOGY Mechanism Of Action Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into DHT. Two distinct isozymes are found in mice, rats, monkeys, and humans: Type I and II. Each of these isozymes is differentially expressed in tissues and developmental stages. In humans, Type I 5α-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver. Type I 5α-reductase is responsible for approximately one-third of circulating DHT. The Type II 5α-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT. In humans, the mechanism of action of finasteride is based on its preferential inhibition of the Type II isozyme. Using native tissues (scalp and prostate), in vitro binding studies examining the potential of finasteride to inhibit either isozyme revealed a 100-fold selectivity for the human Type II 5α-reductase over Type I isozyme (IC50=500 and 4.2 nM for Type I and II, respectively). For both isozymes, the inhibition by finasteride is accompanied by reduction of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex). Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant decreases in serum and tissue DHT concentrations. In men with male pattern hair loss (androgenetic alopecia), the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Administration of finasteride decreases scalp and serum DHT concentrations in these men. The relative contributions of these reductions to the treatment effect of finasteride have not been defined. By this mechanism, finasteride appears to interrupt a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Pharmacodynamics Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a 1-mg tablet. Mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range. Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. In studies with finasteride, no clinically meaningful changes in luteinizing hormone (LH), follicle-stimulating hormone (FSH) or prolactin were detected. In healthy volunteers, treatment with finasteride did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected. Finasteride had no effect on circulating levels of cortisol, thyroid-stimulating hormone, or thyroxine, nor did it affect the plasma lipid profile (e.g., total cholesterol, low-density lipoproteins, high-density lipoproteins and triglycerides) or bone mineral density. Pharmacokinetics Absorption In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26-170%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. At steady state following dosing with 1 mg/day (n=12), maximum finasteride plasma concentration averaged 9.2 ng/mL (range, 4.9-13.7 ng/mL) and was reached 1 to 2 hours postdose; AUC(0-24 hr) was 53 ng•hr/mL (range, 20-154 ng•hr/mL). Bioavailability of finasteride was not affected by food. Distribution Mean steady-state volume of distribution was 76 liters (range, 44-96 liters; n=15). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride after multiple dosing. Finasteride has been found to cross the blood-brain barrier. Semen levels have been measured in 35 men taking finasteride 1 mg/day for 6 weeks. In 60% (21 of 35) of the samples, finasteride levels were undetectable (<0.2 ng/mL). The mean finasteride level was 0.26 ng/mL and the highest level measured was 1.52 ng/mL. Using the highest semen level measured and assuming 100% absorption from a 5-mL ejaculate per day, human exposure through vaginal absorption would be up to 7.6 ng per day, which is 650-fold less than the dose of finasteride (5 µg) that had no effect on circulating DHT levels in men. [See Use In Specific Populations] Metabolism Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of finasteride. Excretion Following intravenous infusion in healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-279 mL/min). Mean terminal half-life in plasma was 4.5 hours (range, 3.3- 13.4 hours; n=12). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39% (range, 32- 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces. Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age. TABLE 3: Mean (SD) Pharmacokinetic Parameters in Healthy Men (ages 18-26) Mean (±SD) n=15 Bioavailability 65% (26-170%)* Clearance (mL/min) 165 (55) Volume of Distribution (L) 76 (14) *Range TABLE 4: Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 1 mg/day in Healthy Men (ages 19-42) Mean (± SD) (n=12) AUC (ng•hr/mL) 53 (33.8) Peak Concentration (ng/mL) 9.2 (2.6) Time to Peak (hours) 1.3 (0.5) Half-Life (hours)* 4.5 (1.6) *First-dose values; all other parameters are last-dose values Renal Impairment No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to those 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% increase in total radioactivity AUC). However, finasteride has been tolerated in men 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. Hepatic Impairment The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be used in the administration of PROPECIA in patients with liver function abnormalities, as finasteride is metabolized extensively in the liver. Clinical Studies Studies In Men The efficacy of PROPECIA was demonstrated in men (88% Caucasian) with mild to moderate androgenetic alopecia (male pattern hair loss) between 18 and 41 years of age. In order to prevent seborrheic dermatitis which might confound the assessment of hair growth in these studies, all men, whether treated with finasteride or placebo, were instructed to use a specified, medicated, tar-based shampoo (Neutrogena T/Gel® Shampoo) during the first 2 years of the studies. There were three double-blind, randomized, placebo-controlled studies of 12-month duration. The two primary endpoints were hair count and patient self-assessment; the two secondary endpoints were investigator assessment and ratings of photographs. In addition, information was collected regarding sexual function (based on a self-administered questionnaire) and non-scalp body hair growth. The three studies were conducted in 1879 men with mild to moderate, but not complete, hair loss. Two of the studies enrolled men with predominantly mild to moderate vertex hair loss (n=1553). The third enrolled men having mild to moderate hair loss in the anterior mid-scalp area with or without vertex balding (n=326). Studies In Men With Vertex Baldness Of the men who completed the first 12 months of the two vertex baldness trials, 1215 elected to continue in double-blind, placebo-controlled, 12-month extension studies. There were 547 men receiving PROPECIA for both the initial study and first extension periods (up to 2 years of treatment) and 60 men receiving placebo for the same periods. The extension studies were continued for 3 additional years, with 323 men on PROPECIA and 23 on placebo entering the fifth year of the study. In order to evaluate the effect of discontinuation of therapy, there were 65 men who received PROPECIA for the initial 12 months followed by placebo in the first 12-month extension period. Some of these men continued in additional extension studies and were switched back to treatment with PROPECIA, with 32 men entering the fifth year of the study. Lastly, there were 543 men who received placebo for the initial 12 months followed by PROPECIA in the first 12-month extension period. Some of these men continued in additional extension studies receiving PROPECIA, with 290 men entering the fifth year of the study (see Figure 1 below). Hair counts were assessed by photographic enlargements of a representative area of active hair loss. In these two studies in men with vertex baldness, significant increases in hair count were demonstrated at 6 and 12 months in men treated with PROPECIA, while significant hair loss from baseline was demonstrated in those treated with placebo. At 12 months there was a 107-hair difference from placebo (p<0.001, PROPECIA [n=679] vs placebo [n=672]) within a 1-inch diameter circle (5.1 cm2). Hair count was maintained in those men taking PROPECIA for up to 2 years, resulting in a 138-hair difference between treatment groups (p<0.001, PROPECIA [n=433] vs placebo [n=47]) within the same area. In men treated with PROPECIA, the maximum improvement in hair count compared to baseline was achieved during the first 2 years. Although the initial improvement was followed by a slow decline, hair count was maintained above baseline throughout the 5 years of the studies. Furthermore, because the decline in the placebo group was more rapid, the difference between treatment groups also continued to increase throughout the studies, resulting in a 277-hair difference (p<0.001, PROPECIA [n=219] vs placebo [n=15]) at 5 years (see Figure 1 below). Patients who switched from placebo to PROPECIA (n=425) had a decrease in hair count at the end of the initial 12-month placebo period, followed by an increase in hair count after 1 year of treatment with PROPECIA. This increase in hair count was less (56 hairs above original baseline) than the increase (91 hairs above original baseline) observed after 1 year of treatment in men initially randomized to PROPECIA. Although the increase in hair count, relative to when therapy was initiated, was comparable between these two groups, a higher absolute hair count was achieved in patients who were started on treatment with PROPECIA in the initial study. This advantage was maintained through the remaining 3 years of the studies. A change of treatment from PROPECIA to placebo (n=48) at the end of the initial 12 months resulted in reversal of the increase in hair count 12 months later, at 24 months (see Figure 1 below). At 12 months, 58% of men in the placebo group had further hair loss (defined as any decrease in hair count from baseline), compared with 14% of men treated with PROPECIA. In men treated for up to 2 years, 72% of men in the placebo group demonstrated hair loss, compared with 17% of men treated with PROPECIA. At 5 years, 100% of men in the placebo group demonstrated hair loss, compared with 35% of men treated with PROPECIA. Figure 1 Patient self-assessment was obtained at each clinic visit from a self-administered questionnaire, which included questions on their perception of hair growth, hair loss, and appearance. This self-assessment demonstrated an increase in amount of hair, a decrease in hair loss, and improvement in appearance in men treated with PROPECIA. Overall improvement compared with placebo was seen as early as 3 months (p<0.05), with improvement maintained over 5 years. Investigator assessment was based on a 7-point scale evaluating increases or decreases in scalp hair at each patient visit. This assessment showed significantly greater increases in hair growth in men treated with PROPECIA compared with placebo as early as 3 months (p<0.001). At 12 months, the investigators rated 65% of men treated with PROPECIA as having increased hair growth compared with 37% in the placebo group. At 2 years, the investigators rated 80% of men treated with PROPECIA as having increased hair growth compared with 47% of men treated with placebo. At 5 years, the investigators rated 77% of men treated with PROPECIA as having increased hair growth, compared with 15% of men treated with placebo. An independent panel rated standardized photographs of the head in a blinded fashion based on increases or decreases in scalp hair using the same 7-point scale as the investigator assessment. At 12 months, 48% of men treated with PROPECIA had an increase as compared with 7% of men treated with placebo. At 2 years, an increase in hair growth was demonstrated in 66% of men treated with PROPECIA, compared with 7% of men treated with placebo. At 5 years, 48% of men treated with PROPECIA demonstrated an increase in hair growth, 42% were rated as having no change (no further visible progression of hair loss from baseline) and 10% were rated as having lost hair when compared to baseline. In comparison, 6% of men treated with placebo demonstrated an increase in hair growth, 19% were rated as having no change and 75% were rated as having lost hair when compared to baseline. A 48-week, placebo-controlled study designed to assess by phototrichogram the effect of PROPECIA on total and actively growing (anagen) scalp hairs in vertex baldness enrolled 212 men with androgenetic alopecia. At baseline and 48 weeks, total and anagen hair counts were obtained in a 1-cm2 target area of the scalp. Men treated with PROPECIA showed increases from baseline in total and anagen hair counts of 7 hairs and 18 hairs, respectively, whereas men treated with placebo had decreases of 10 hairs and 9 hairs, respectively. These changes in hair counts resulted in a between-group difference of 17 hairs in total hair count (p<0.001) and 27 hairs in anagen hair count (p<0.001), and an improvement in the proportion of anagen hairs from 62% at baseline to 68% for men treated with PROPECIA. Other Results In Vertex Baldness Studies A sexual function questionnaire was self-administered by patients participating in the two vertex baldness trials to detect more subtle changes in sexual function. At Month 12, statistically significant differences in favor of placebo were found in 3 of 4 domains (sexual interest, erections, and perception of sexual problems). However, no significant difference was seen in the question on overall satisfaction with sex life. In one of the two vertex baldness studies, patients were questioned on non-scalp body hair growth. PROPECIA did not appear to affect non-scalp body hair. Study In Men With Hair Loss In The Anterior Mid-Scalp Area A study of 12-month duration, designed to assess the efficacy of PROPECIA in men with hair loss in the anterior mid-scalp area, also demonstrated significant increases in hair count compared with placebo. Increases in hair count were accompanied by improvements in patient self-assessment, investigator assessment, and ratings based on standardized photographs. Hair counts were obtained in the anterior mid-scalp area, and did not include the area of bitemporal recession or the anterior hairline. Summary Of Clinical Studies In Men Clinical studies were conducted in men aged 18 to 41 with mild to moderate degrees of androgenetic alopecia. All men treated with PROPECIA or placebo received a tar-based shampoo (Neutrogena T/Gel® Shampoo) during the first 2 years of the studies. Clinical improvement was seen as early as 3 months in the patients treated with PROPECIA and led to a net increase in scalp hair count and hair regrowth. In clinical studies for up to 5 years, treatment with PROPECIA slowed the further progression of hair loss observed in the placebo group. In general, the difference between treatment groups continued to increase throughout the 5 years of the studies. Ethnic Analysis Of Clinical Data From Men In a combined analysis of the two studies on vertex baldness, mean hair count changes from baseline were 91 vs -19 hairs (PROPECIA vs placebo) among Caucasians (n=1185), 49 vs -27 hairs among Blacks (n=84), 53 vs -38 hairs among Asians (n=17), 67 vs 5 hairs among Hispanics (n=45) and 67 vs -15 hairs among other ethnic groups (n=20). Patient self-assessment showed improvement across racial groups with PROPECIA treatment, except for satisfaction of the frontal hairline and vertex in Black men, who were satisfied overall. Study In Women In a study involving 137 postmenopausal women with androgenetic alopecia who were treated with PROPECIA (n=67) or placebo (n=70) for 12 months, effectiveness could not be demonstrated. There was no improvement in hair counts, patient self-assessment, investigator assessment, or ratings of standardized photographs in the women treated with PROPECIA when compared with the placebo group [see INDICATIONS AND USAGE].

Find Lowest Prices on PROSCAR® (finasteride) Tablets for Oral Administration DESCRIPTION PROSCAR (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α- dihydrotestosterone (DHT). Finasteride is 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5α,17ß)-. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: Finasteride is a white crystalline powder with a melting point near 250°C. 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: hydrous lactose, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow iron oxide.

Find Lowest Prices on PROPECIA®(finasteride) Film-coated Tablets DESCRIPTION PROPECIA (finasteride) tablets contain finasteride as the active ingredient. Finasteride, a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT). The chemical name of finasteride is N-tert-Butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55. Its structural formula is: Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in chloroform and in lower alcohol solvents but is practically insoluble in water. PROPECIA (finasteride) tablets are film-coated tablets for oral administration. Each tablet contains 1 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, yellow ferric oxide, and red ferric oxide.

INDICATIONS Monotherapy PROSCAR® is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: Improve symptoms Reduce the risk of acute urinary retention Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy. Combination With Alpha-Blocker PROSCAR administered in combination with the alpha-blocker doxazosin is indicated to reduce the risk of symptomatic progression of BPH (a confirmed ≥4 point increase in American Urological Association (AUA) symptom score). Limitations Of Use PROSCAR is not approved for the prevention of prostate cancer. DOSAGE AND ADMINISTRATION PROSCAR may be administered with or without meals. Monotherapy The recommended dose of PROSCAR is one tablet (5 mg) taken once a day [see Clinical Studies]. Combination With Alpha-Blocker The recommended dose of PROSCAR is one tablet (5 mg) taken once a day in combination with the alpha-blocker doxazosin [see Clinical Studies]. HOW SUPPLIED Dosage Forms And Strengths 5-mg blue, modified apple-shaped, film-coated tablets, with the code MSD 72 on one side and PROSCAR on the other. Storage And Handling 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. Storage And Handling Store at room temperatures below 30°C (86°F). Protect from light and keep container tightly closed. Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and PATIENT INFORMATION]. Distributed by: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: Sep 2015

INDICATIONS PROPECIA® is indicated for the treatment of male pattern hair loss (androgenetic alopecia) in MEN ONLY. Efficacy in bitemporal recession has not been established. PROPECIA is not indicated for use in women. DOSAGE AND ADMINISTRATION PROPECIA may be administered with or without meals. The recommended dose of PROPECIA is one tablet (1 mg) taken once daily. In general, daily use for three months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit, which should be re-evaluated periodically. Withdrawal of treatment leads to reversal of effect within 12 months. HOW SUPPLIED Dosage Forms And Handling PROPECIA tablets (1 mg) are tan, octagonal, film-coated convex tablets with “stylized P” logo on one side and PROPECIA on the other. Storage And Handling No. 6642 — PROPECIA tablets, 1 mg, are tan, octagonal, film-coated convex tablets with “stylized P” logo on one side and PROPECIA on the other. They are supplied as follows: NDC 0006-0071-31 bottles of 30 (with desiccant) NDC 0006-0071-54 PROPAK® bottles of 90 (with desiccant). Storage And Handling Store at room temperature, 15-30°C (59-86°F). Keep container closed and protect from moisture. Women should not handle crushed or broken PROPECIA tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. PROPECIA tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets are not broken or crushed [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and Patient Counseling Information]. Distributed by: MERCK & Co.,INC., Whitehouse Station, NJ 08889, USA. Revised: Jan 2014

PATIENT INFORMATION PROPECIA (Pro-pee-sha) (finasteride) Tablets PROPECIA® is for use by MEN ONLY and should NOT be used by women or children. Read this Patient Information before you start taking PROPECIA and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. What is PROPECIA? PROPECIA is a prescription medicine used for the treatment of male pattern hair loss (androgenetic alopecia). It is not known if PROPECIA works for a receding hairline on either side of and above your forehead (temporal area). PROPECIA is not for use by women and children. Who should not take PROPECIA? Do not take PROPECIA if you: are pregnant or may become pregnant. PROPECIA may harm your unborn baby. PROPECIA tablets are coated and will prevent contact with the medicine during handling, as long as the tablets are not broken or crushed. Females who are pregnant or who may become pregnant should not come in contact with broken or crushed PROPECIA tablets. If a pregnant woman comes in contact with crushed or broken PROPECIA tablets, wash the contact area right away with soap and water. If a woman who is pregnant comes into contact with the active ingredient in PROPECIA, a healthcare provider should be consulted. If a woman who is pregnant with a male baby swallows or comes in contact with the medicine in PROPECIA, the male baby may be born with sex organs that are not normal. are allergic to any of the ingredients in PROPECIA. See the end of this leaflet for a complete list of ingredients in PROPECIA. What should I tell my healthcare provider before taking PROPECIA? Before taking PROPECIA, tell your healthcare provider if you: have any other medical conditions, including problems with your prostate or liver Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take PROPECIA? Take PROPECIA exactly as your healthcare provider tells you to take it. You may take PROPECIA with or without food. If you forget to take PROPECIA, do not take an extra tablet. Just take the next tablet as usual. PROPECIA will not work faster or better if you take it more than once a day. What are the possible side effects of PROPECIA? decrease in your blood Prostate Specific Antigen (PSA) levels. PROPECIA can affect a blood test called PSA (Prostate-Specific Antigen) for the screening of prostate cancer. If you have a PSA test done you should tell your healthcare provider that you are taking PROPECIA because PROPECIA decreases PSA levels. Changes in PSA levels will need to be evaluated by your healthcare provider. Any increase in follow-up PSA levels from their lowest point may signal the presence of prostate cancer and should be evaluated, even if the test results are still within the normal range for men not taking PROPECIA. You should also tell your healthcare provider if you have not been taking PROPECIA as prescribed because this may affect the PSA test results. For more information, talk to your healthcare provider. There may be an increased risk of a more serious form of prostate cancer in men taking finasteride at 5 times the dose of PROPECIA. The most common side effects of PROPECIA include: decrease in sex drive trouble getting or keeping an erection a decrease in the amount of semen The following have been reported in general use with PROPECIA: breast tenderness and enlargement. Tell your healthcare provider about any changes in your breasts such as lumps, pain or nipple discharge. depression; decrease in sex drive that continued after stopping the medication; allergic reactions including rash, itching, hives and swelling of the lips, tongue, throat, and face; problems with ejaculation that continued after stopping medication; testicular pain; difficulty in achieving an erection that continued after stopping the medication; male infertility and/or poor quality of semen. in rare cases, male breast cancer. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of PROPECIA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088. How should I store PROPECIA? Store PROPECIA at room temperature between 59°F to 86°F (15°C to 30°C). Keep PROPECIA in a closed container and keep PROPECIA tablets dry (protect from moisture). Keep PROPECIA and all medicines out of the reach of children. General information about the safe and effective use of PROPECIA. Medicines are sometimes prescribed for purposes other than those listed in this Patient Information leaflet. Do not use PROPECIA for a condition for which it was not prescribed. Do not give PROPECIA to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about PROPECIA. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PROPECIA that is written for health professionals. For more information, call 1-888-637-2522. What are the ingredients in PROPECIA? Active ingredient: finasteride. Inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, yellow ferric oxide, and red ferric oxide. This Patient Information has been approved by the U.S. Food and Drug Administration.

SIDE EFFECTS Clinical Trials Experience PROSCAR is generally well tolerated; adverse reactions usually have been mild and transient. 4-Year Placebo-Controlled Study (PLESS) In PLESS, 1524 patients treated with PROSCAR and 1516 patients treated with placebo were evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were related to sexual function. 3.7% (57 patients) treated with PROSCAR and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo over the 4 years of the study. In years 2-4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder. Table 1: Drug-Related Adverse Experiences Year 1 (%) Years 2, 3 and 4* (%) Finasteride Placebo Finasteride Placebo Impotence 8.1 3.7 5.1 5.1 Decreased Libido 6.4 3.4 2.6 2.6 Decreased Volume of Ejaculate 3.7 0.8 1.5 0.5 Ejaculation Disorder 0.8 0.1 0.2 0.1 Breast Enlargement 0.5 0.1 1.8 1.1 Breast Tenderness 0.4 0.1 0.7 0.3 Rash 0.5 0.2 0.5 0.1 N = 1524 and 1516, finasteride vs placebo, respectively *Combined Years 2-4 Phase III Studies And 5-Year Open Extensions The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open extensions, and PLESS were similar. Medical Therapy Of Prostatic Symptoms (MTOPS) Study In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive PROSCAR 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PROSCAR 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies.] The incidence rates of drug-related adverse experiences reported by ≥2% of patients in any treatment group in the MTOPS Study are listed in Table 2. The individual adverse effects which occurred more frequently in the combination group compared to either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido, rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum of the incidences of this adverse experience reported for the two monotherapies. Combination therapy with finasteride and doxazosin was associated with no new clinical adverse experience. Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were on finasteride only and one was on combination therapy. [See Long-Term Data.] The MTOPS Study was not specifically designed to make statistical comparisons between groups for reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study and previous studies of the single agents may not be appropriate based upon differences in patient population, dosage or dose regimen, and other procedural and study design elements. Table 2: Incidence ≥2% in One or More Treatment Groups Drug-Related Clinical Adverse Experiences in MTOPS Adverse Experience Placebo Doxazosin 4 mg or 8 mg* Finasteride Combination (N=737) (%) (N=756) (%) (N=768) (%) (N=786) (%) Body as a whole Asthenia 7.1 15.7 5.3 16.8 Headache 2.3 4.1 2.0 2.3 Cardiovascular Hypotension 0.7 3.4 1.2 1.5 Postural Hypotension 8.0 16.7 9.1 17.8 Metabolic and Nutritional Peripheral Edema 0.9 2.6 1.3 3.3 Nervous Dizziness 8.1 17.7 7.4 23.2 Libido Decreased 5.7 7.0 10.0 11.6 Somnolence 1.5 3.7 1.7 3.1 Respiratory Dyspnea 0.7 2.1 0.7 1.9 Rhinitis 0.5 1.3 1.0 2.4 Urogenital Abnormal Ejaculation 2.3 4.5 7.2 14.1 Gynecomastia 0.7 1.1 2.2 1.5 Impotence 12.2 14.4 18.5 22.6 Sexual Function Abnormal 0.9 2.0 2.5 3.1 *Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4 . Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the study. Long-Term Data High-Grade Prostate Cancer The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received either PROSCAR (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%) [see INDICATIONS AND USAGE and WARNINGS AND PRECAUTIONS]. In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART), similar results for Gleason score 8-10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR. Breast Cancer During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. During the 7- year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. Sexual Function There is no evidence of increased sexual adverse experiences with increased duration of treatment with PROSCAR. New reports of drug-related sexual adverse experiences decreased with duration of therapy. Postmarketing Experience The following additional adverse events have been reported in postmarketing experience with PROSCAR. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hypersensitivity reactions, such as pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face) testicular pain sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, decreased libido and ejaculation disorders (e.g. reduced ejaculate volume). These events were reported rarely in men taking PROSCAR for the treatment of BPH. Most men were older and were taking concomitant medications and/or had co-morbid conditions. The independent role of PROSCAR in these events is unknown. male infertility and/or poor seminal quality were reported rarely in men taking PROSCAR for the treatment of BPH. Normalization or improvement of poor seminal quality has been reported after discontinuation of finasteride. The independent role of PROSCAR in these events is unknown. depression male breast cancer The following additional adverse event related to sexual dysfunction that continued after discontinuation of treatment has been reported in postmarketing experience with finasteride at lower doses used to treat male pattern baldness. Because the event is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure: orgasm disorders DRUG INTERACTIONS Cytochrome P450-Linked Drug Metabolizing Enzyme System No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. Other Concomitant Therapy Although specific interaction studies were not performed, PROSCAR was concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-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, H2 antagonists and quinolone anti-infectives without evidence of clinically significant adverse interactions.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Studies For PROPECIA (Finasteride 1 mg) In The Treatment Of Male Pattern Hair Loss In three controlled clinical trials for PROPECIA of 12-month duration, 1.4% of patients taking PROPECIA (n=945) were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related (1.6% for placebo; n=934). Clinical adverse experiences that were reported as possibly, probably or definitely drug-related in ≥1% of patients treated with PROPECIA or placebo are presented in Table 1. TABLE 1: Drug-Related Adverse Experiences for PROPECIA (finasteride 1 mg) in Year 1 (%) MALE PATTERN HAIR LOSS PROPECIA N=945 Placebo N=934 Decreased Libido 1.8 1.3 Erectile Dysfunction 1.3 0.7 Ejaculation Disorder (Decreased Volume of Ejaculate) 1.2 (0.8) 0.7 (0.4) Discontinuation due to drug-related sexual adverse experiences 1.2 0.9 Integrated analysis of clinical adverse experiences showed that during treatment with PROPECIA, 36 (3.8%) of 945 men had reported one or more of these adverse experiences as compared to 20 (2.1%) of 934 men treated with placebo (p=0.04). Resolution occurred in men who discontinued therapy with PROPECIA due to these side effects and in most of those who continued therapy. The incidence of each of the above adverse experiences decreased to ≤0.3% by the fifth year of treatment with PROPECIA. In a study of finasteride 1 mg daily in healthy men, a median decrease in ejaculate volume of 0.3 mL (- 11%) compared with 0.2 mL (-8%) for placebo was observed after 48 weeks of treatment. Two other studies showed that finasteride at 5 times the dosage of PROPECIA (5 mg daily) produced significant median decreases of approximately 0.5 mL (-25%) compared to placebo in ejaculate volume, but this was reversible after discontinuation of treatment. In the clinical studies with PROPECIA, the incidences for breast tenderness and enlargement, hypersensitivity reactions, and testicular pain in finasteride-treated patients were not different from those in patients treated with placebo. Controlled Clinical Trials And Long-Term Open Extension Studies For PROSCAR® (Finasteride 5 mg) And AVODART (Dutasteride) In The Treatment Of Benign Prostatic Hyperplasia In the PROSCAR Long-Term Efficacy and Safety Study (PLESS), a 4-year controlled clinical study, 3040 patients between the ages of 45 and 78 with symptomatic BPH and an enlarged prostate were evaluated for safety over a period of 4 years (1524 on PROSCAR 5 mg/day and 1516 on placebo). 3.7% (57 patients) treated with PROSCAR 5 mg and 2.1% (32 patients) treated with placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the most frequently reported adverse reactions. Table 2 presents the only clinical adverse reactions considered possibly, probably or definitely drug related by the investigator, for which the incidence on PROSCAR was ≥1% and greater than placebo over the 4 years of the study. In years 2-4 of the study, there was no significant difference between treatment groups in the incidences of impotence, decreased libido and ejaculation disorder. TABLE 2: Drug-Related Adverse Experiences for PROSCAR (finasteride 5 mg) BENIGN PROSTATIC HYPERPLASIA Year 1 (%) Years 2, 3 and 4* (%) Finasteride 5 mg Placebo Finasteride 5 mg Placebo Impotence 8.1 3.7 5.1 5.1 Decreased Libido 6.4 3.4 2.6 2.6 Decreased Volume of Ejaculate 3.7 0.8 1.5 0.5 Ejaculation Disorder 0.8 0.1 0.2 0.1 Breast Enlargement 0.5 0.1 1.8 1.1 Breast Tenderness 0.4 0.1 0.7 0.3 Rash 0.5 0.2 0.5 0.1 *Combined Years 2-4 N = 1524 and 1516, finasteride vs placebo, respectively The adverse experience profiles in the 1-year, placebo-controlled, Phase III BPH studies and the 5-year open extensions with PROSCAR 5 mg and PLESS were similar. There is no evidence of increased sexual adverse experiences with increased duration of treatment with PROSCAR 5 mg. New reports of drug-related sexual adverse experiences decreased with duration of therapy. During the 4- to 6-year placebo- and comparator-controlled Medical Therapy of Prostatic Symptoms (MTOPS) study that enrolled 3047 men, there were 4 cases of breast cancer in men treated with PROSCAR but no cases in men not treated with PROSCAR. During the 4-year placebo-controlled PLESS study that enrolled 3040 men, there were 2 cases of breast cancer in placebo-treated men, but no cases were reported in men treated with PROSCAR. During the 7-year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1 case of breast cancer in men treated with PROSCAR, and 1 case of breast cancer in men treated with placebo. The relationship between long-term use of finasteride and male breast neoplasia is currently unknown. The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882 healthy men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received either PROSCAR (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with finasteride (1.8%) than in those treated with placebo (1.1%). In a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor [AVODART (dutasteride)], similar results for Gleason score 8-10 prostate cancer were observed (1% dutasteride vs 0.5% placebo). The clinical significance of these findings with respect to use of PROPECIA by men is unknown. No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR. PROSCAR is not approved to reduce the risk of developing prostate cancer. Postmarketing Experience The following adverse reactions have been identified during post approval use of PROPECIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hypersensitivity Reaction hypersensitivity reactions such as rash, pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face); Reproductive System sexual dysfunction that continued after discontinuation of treatment, including erectile dysfunction, libido disorders, ejaculation disorders, and orgasm disorders; male infertility and/or poor seminal quality (normalization or improvement of seminal quality has been reported after discontinuation of finasteride); testicular pain. [See Clinical Trials Experience] Neoplasms male breast cancer; Breast Disorders breast tenderness and enlargement; Nervous System/Psychiatric depression DRUG INTERACTIONS Cytochrome P450-Linked Drug Metabolizing Enzyme System No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug-metabolizing enzyme system. Compounds that have been tested in man include antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. Other Concomitant Therapy Although specific interaction studies were not performed, finasteride doses of 1 mg or more were concomitantly used in clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, analgesics, angiotensin-converting enzyme (ACE) inhibitors, anticonvulsants, benzodiazepines, beta blockers, calcium-channel blockers, cardiac nitrates, diuretics, H2 antagonists, HMG-CoA reductase inhibitors, prostaglandin synthetase inhibitors (also referred to as NSAIDs), and quinolone anti-infectives without evidence of clinically significant adverse interactions.

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Effects On Prostate Specific Antigen(PSA) And The Use Of PSA In Prostate Cancer Detection In clinical studies, PROSCAR reduced serum PSA concentration by approximately 50% within six months of treatment. This decrease is predictable over the entire range of PSA values in patients with symptomatic BPH, although it may vary in individuals. For interpretation of serial PSAs in men taking PROSCAR, a new PSA baseline should be established at least six months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on PROSCAR may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α- reductase inhibitor. Non-compliance with PROSCAR therapy may also affect PSA test results. To interpret an isolated PSA value in patients treated with PROSCAR for six months or more, PSA values should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the utility of PSA to detect prostate cancer in men treated with PROSCAR. PROSCAR may also cause decreases in serum PSA in the presence of prostate cancer. The ratio of free to total PSA (percent free PSA) remains constant even under the influence of PROSCAR. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing finasteride therapy, no adjustment to its value appears necessary. Increased Risk Of High-Grade Prostate Cancer Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See INDICATIONS AND USAGE and ADVERSE REACTIONS.] Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established. Exposure Of Women — Risk To Male Fetus Women should not handle crushed or broken PROSCAR tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. [See CONTRAINDICATIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY, HOW SUPPLIED/Storage And Handling and Patient Counseling Information.] Pediatric Patients And Women PROSCAR is not indicated for use in pediatric patients [see Use In Specific Populations see CLINICAL PHARMACOLOGY] or women [see also Exposure Of Women — Risk To Male Fetus, Use In Specific Populations, CLINICAL PHARMACOLOGY, HOW SUPPLIED/Storage And Handling and Patient Counseling Information]. Effect On Semen Characteristics Treatment with PROSCAR for 24 weeks to evaluate semen parameters in healthy male volunteers revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL (22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate was observed. These parameters remained within the normal range and were reversible upon discontinuation of therapy with an average time to return to baseline of 84 weeks. Consideration Of Other Urological Conditions Prior to initiating treatment with PROSCAR, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist. Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy. Patient Counseling Information See FDA-Approved Patient Labeling (PATIENT INFORMATION). Increased Risk Of High-Grade Prostate Cancer Patients should be informed that there was an increase in high-grade prostate cancer in men treated with 5α-reductase inhibitors indicated for BPH treatment, including PROSCAR, compared to those treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS]. Exposure Of Women — Risk To Male Fetus Physicians should inform patients that women who are pregnant or may potentially be pregnant should not handle crushed or broken PROSCAR tablets because of the possibility of absorption of finasteride and the subsequent potential risk to the male fetus. PROSCAR tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and water [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations, HOW SUPPLIED/Storage And Handling]. Additional Instructions 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]. Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been reported [see ADVERSE REACTIONS]. Physicians should instruct their patients to read the patient package insert before starting therapy with PROSCAR and to reread it each time the prescription is renewed so that they are aware of current information for patients regarding PROSCAR. Nonclinical Toxicology 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(0-24 hr) for animals and mean AUC(0-24 hr) for man (0.4 μg•hr/mL). In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250 mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times the human exposure (40 mg/kg/day) 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- to 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 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day). 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, using Chinese hamster ovary cells, 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. 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 543 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), 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. Use In Specific Populations Pregnancy Pregnancy Category X [See CONTRAINDICATIONS.] PROSCAR is contraindicated for use in women who are or may become pregnant. PROSCAR is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. Abnormal male genital development is an expected consequence when conversion of testosterone to 5α- dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or broken PROSCAR tablets or semen from a male partner taking PROSCAR. With regard to finasteride exposure through the skin, PROSCAR tablets are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. Women who are pregnant or may become pregnant should not handle crushed or broken PROSCAR tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken PROSCAR tablets, the contact area should be washed immediately with soap and water. With regard to potential finasteride exposure through semen, two studies have been conducted in men receiving PROSCAR 5 mg/day that measured finasteride concentrations in semen [see CLINICAL PHARMACOLOGY]. In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride. No developmental abnormalities were observed in the offspring of untreated females mated with finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions. No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at maternal oral doses up to 100 mg/kg/day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. The fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20-100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose. 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 pediatric patients. Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75 and over, respectively. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly [see CLINICAL PHARMACOLOGY and Clinical Studies]. Hepatic Impairment Caution should be exercised in the administration of PROSCAR in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver [see CLINICAL PHARMACOLOGY]. Renal Impairment No dosage adjustment is necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY].

WARNINGS Included as part of the "PRECAUTIONS" Section PRECAUTIONS Exposure Of Women — Risk To Male Fetus PROPECIA is not indicated for use in women. Women should not handle crushed or broken PROPECIA tablets when they are pregnant or may potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. PROPECIA tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. [See INDICATIONS AND USAGE, CONTRAINDICATIONS, Use In Specific Populations, HOW SUPPLIED and PATIENT INFORMATION] Effects On Prostate Specific Antigen (PSA) In clinical studies with PROPECIA (finasteride, 1 mg) in men 18-41 years of age, the mean value of serum prostate specific antigen (PSA) decreased from 0.7 ng/mL at baseline to 0.5 ng/mL at Month 12. Further, in clinical studies with PROSCAR (finasteride, 5 mg) when used in older men who have benign prostatic hyperplasia (BPH), PSA levels are decreased by approximately 50%. Other studies with PROSCAR showed it may also cause decreases in serum PSA in the presence of prostate cancer. These findings should be taken into account for proper interpretation of serum PSA when evaluating men treated with finasteride. Any confirmed increase from the lowest PSA value while on PROPECIA may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5α-reductase inhibitor. Non-compliance to therapy with PROPECIA may also affect PSA test results. Increased Risk Of High-Grade Prostate Cancer With 5α-Reductase Inhibitors Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking finasteride 5 mg/day (5 times the dose of PROPECIA) in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See ADVERSE REACTIONS] Similar results were observed in a 4-year placebo-controlled clinical trial with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α- reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results of these studies has not been established. Pediatric Patients PROPECIA is not indicated for use in pediatric patients [see Use In Specific Populations]. Patient Counseling Information See FDA-approved patient labeling (PATIENT INFORMATION). Exposure Of Women — Risk To Male Fetus Physicians should inform patients that women who are pregnant or may potentially be pregnant should not handle crushed or broken PROPECIA tablets because of the possibility of absorption of finasteride and the subsequent potential risk to a male fetus. PROPECIA tablets are coated and will prevent contact with the active ingredient during normal handling, provided that the tablets have not been broken or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or broken PROPECIA tablets, the contact area should be washed immediately with soap and water [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Use In Specific Populations and HOW SUPPLIED]. Increased Risk Of High-Grade Prostate Cancer Patients should be informed that there was an increase in high-grade prostate cancer in men treated with 5α-reductase inhibitors indicated for BPH treatment, compared to those treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Additional Instructions Physicians should instruct their patients to promptly report any changes in their breasts such as lumps, pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have been reported [see ADVERSE REACTIONS]. Nonclinical Toxicology 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 888 and 2192 times those observed in man receiving the recommended human dose of 1 mg/day. All exposure calculations were based on calculated AUC(0-24 hr) for animals and mean AUC(0-24 hr) for man (0.05µg•hr/mL). In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the incidence of testicular Leydig cell adenomas was observed at 1824 times the human exposure (250 mg/kg/day). In mice at 184 times the human exposure, estimated (25 mg/kg/day) and in rats at 312 times the human exposure (≥40 mg/kg/day) 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- to 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 240 and 2800 times (20 mg/kg/day and 45 mg/kg/day, respectively), or in mice treated for 19 months at 18.4 times the human exposure, estimated (2.5 mg/kg/day). 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, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. 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 (1824 times the human exposure) as determined in the carcinogenicity studies. In sexually mature male rabbits treated with finasteride at 4344 times the human exposure (80 mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 488 times the human exposure (80 mg/kg/day), 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 but is not relevant in man. Use In Specific Populations Pregnancy Pregnancy Category X [see CONTRAINDICATIONS] PROPECIA is contraindicated for use in women who are or may become pregnant. PROPECIA is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. In animal studies, finasteride caused abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the male fetus. Abnormal male genital development is an expected consequence when conversion of testosterone to 5α- dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride through contact with crushed or broken PROPECIA tablets or semen from a male partner taking PROPECIA. With regard to finasteride exposure through the skin, PROPECIA tablets are coated and will prevent skin contact with finasteride during normal handling if the tablets have not been crushed or broken. Women who are pregnant or may become pregnant should not handle crushed or broken PROPECIA tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact with crushed or broken PROPECIA tablets, the contact area should be washed immediately with soap and water. With regard to potential finasteride exposure through semen, a study has been conducted in men receiving PROPECIA 1 mg/day that measured finasteride concentrations in semen [see CLINICAL PHARMACOLOGY]. In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 1 to 684 times the recommended human dose (RHD) of 1 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.2 times the RHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.02 times the RHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring exposed to any dose of finasteride in utero. No developmental abnormalities were observed in the offspring of untreated females mated with finasteride-treated male rats that received approximately 488 times the RHD (based on AUC at animal dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of about 20 times the RHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions. No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at maternal doses up to 100 mg/kg/day (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit. The fetal effects of maternal finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20-100), in a species and development period more predictive of specific effects in humans than the studies in rats and rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 930 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 1 mg/day) resulted in no abnormalities in male fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral administration of a dose of finasteride (2 mg/kg/day or approximately 120,000 times the highest estimated blood levels of finasteride from semen of men taking 1 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteriderelated abnormalities were observed in female fetuses at any dose. Nursing Mothers PROPECIA is not indicated for use in women. It is not known whether finasteride is excreted in human milk. Pediatric Use PROPECIA is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical efficacy studies with PROPECIA did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the elderly for PROPECIA [see CLINICAL PHARMACOLOGY]. However the efficacy of PROPECIA in the elderly has not been established. Hepatic Impairment Caution should be exercised in the administration of PROPECIA in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver [see CLINICAL PHARMACOLOGY]. Renal Impairment No dosage adjustment is necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY].