003078 Finasteride

COST OF THERAPY: 70.97 (BPH; Proscar; 5 mg; 1 tablet/day/day; 30 days)

COST OF THERAPY: 49.35 (Male Pattern Hair Loss; Proscar; 1 mg; 1 tablet/day/day; 30 days)

DESCRIPTION

Note:

Propecia

Propecia (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-,17β)-. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55.

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 tablets for oral administration are film-coated tablets that contain 1 mg of finasteride and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, docusate sodium, magnesium stearate, hydroxypropyl methylcellulose 2910, hydroxypropyl cellulose, titanium dioxide, talc, yellow ferric oxide, and red ferric oxide.

Proscar

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,17β)-. The empirical formula of finasteride is C23H36N2O2 and its molecular weight is 372.55.

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, hydroxypropylmethyl cellulose, titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C blue 2 aluminum lake and yellow iron oxide.

CLINICAL PHARMACOLOGY

Propecia

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 (T½ approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex).

Finasteride has no affinity for the androgen receptor and has no androgenic, antiandrogenic, estrogenic, antiestrogenic, or progestational effects. Inhibition of Type II 5α-reductase blocks the peripheral conversion of testosterone to DHT, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a 1 mg tablet.

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.

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. In studies with finasteride, no clinically meaningful changes in luteinizing hormone (LH) or follicle-stimulating hormone (FSH) 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. Mean circulating levels of testosterone and estradiol were increased by approximately 15% as compared to baseline, but these remained within the physiologic range.

Pharmacokinetics

Following an oral dose of 14C-finasteride in man, 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 major compound isolated from urine was the monocarboxylic acid metabolite; virtually no unchanged drug was recovered. The t-butyl side chain monohydroxylated metabolite has been isolated from plasma. These metabolites possessed no more than 20% of the 5α-reductase inhibitory activity of finasteride.

In a study in 15 healthy male subjects, the mean bioavailability of finasteride 1 mg tablets was 65% (range 26-170%), based on the ratio of AUC relative to a 5 mg intravenous dose infused over 60 minutes. Following intravenous infusion, mean plasma clearance was 165 ml/min (range, 70-279 ml/min) and mean steady-state volume of distribution was 76 L (range, 44-96 L). In a separate study, the bioavailability of finasteride was not affected by food.

Approximately 90% of circulating finasteride is bound to plasma proteins. Finasteride has been found to cross the blood-brain barrier.

There is a slow accumulation phase for finasteride after multiple dosing. At steady state following dosing with 1 mg/day, maximum finasteride plasma concentration averaged 9.2 ng/ml (range, 4.9-13.7 ng/ml) and was reached 1-2 hours postdose; AUC(0-24h) was 53 ng.h/ml (range, 20-154 ng.h/ml) and mean terminal half-life of elimination was 4.8 hours (range, 3.3-13.4 hours).

Semen levels have been measured in 35 men taking finasteride 1 mg daily for 6 weeks. In 60% (21 of 35) of the samples, finasteride levels were undetectable. The mean finasteride level was 0.26 ng/ml and the highest level measured was 1.52 ng/ml. Using this 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/day, which is 750 times lower than the exposure from the no-effect dose for developmental abnormalities in Rhesus monkeys (see PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X).

The elimination rate of finasteride decreases somewhat with age. 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. These findings are of no clinical significance, and a reduction in dosage in the elderly is not warranted.

No dosage adjustment is necessary in patients with renal insufficiency. In patients with chronic renal impairment (creatinine clearance ranging from 9.0 to 55 ml/min), the values for 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). Furthermore, finasteride has been well 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.

Proscar

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.

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.

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 prostate-specific antigen (PSA) was also decreased.

In healthy male volunteers treated with Proscar for 14 days, discontinuation of therapy resulted in a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for 3 months, prostate volume, which declined by approximately 20%, returned to close to baseline value after approximately 3 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 L (range, 44-96 L). 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 PRECAUTIONS, Proscar, Pregnancy Category X).

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 (0-24h) 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).

Special Populations

Pediatric

Finasteride pharmacokinetics have not been investigated in patients <18 years of age.

Gender

Finasteride pharmacokinetics in women are not available.

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 also Pharmacokinetics, Excretion; PRECAUTIONS, Proscar, Geriatric Use; and DOSAGE AND ADMINISTRATION, Proscar.

Race

The effect of race on finasteride pharmacokinetics has not been studied.

Renal Insufficiency

No dosage adjustment is necessary in patients with renal insufficiency. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 ml/min, 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.

Hepatic Insufficiency

The effect of hepatic insufficiency on finasteride pharmacokinetics has not been studied. Caution should be used in the administration of Proscar in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Drug Interactions

Also see DRUG INTERACTIONS, Proscar.

No drug interactions of clinical importance have been identified. Finasteride does not appear to affect the cytochrome P450-linked drug metabolism enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin, and no clinically meaningful interactions were found.

CLINICAL STUDIES

Propecia

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 (controlled phase and extensions), all men, whether treated with finasteride or placebo, were instructed to use a specified, medicated, tar-based shampoo (Neutrogena T/Gel Shampoo).

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. 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).

Two Studies on 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 and extension periods (up to 24 months) and 60 men receiving placebo for the same periods. In addition, there were 65 men who received Propecia for the initial 12 months followed by placebo in the 12 month extension period, and 543 men who received placebo for the initial 12 months followed by Propecia in the 12 month extension period.

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 evaluable men] vs placebo [n=672 evaluable men]) within a 1 inch diameter circle (5.1 cm2). Hair count was maintained in those men taking Propecia (n=433 evaluable men) for up to 24 months, while the placebo group (n=47 evaluable men) continued to show progressive hair loss. At 24 months, this resulted in a 138-hair difference between treatment groups (p <0.001) within the same area. Patients who switched from placebo to Propecia (n=426 evaluable men) at the end of the initial 12 months had an increase in hair count at 24 months. A change of treatment from Propecia to placebo (n=48 evaluable men) at the end of the initial 12 months resulted in reversal of the increase in hair count 12 months later, at 24 months.

At 12 months, 14% of men treated with Propecia had hair loss (defined as any decrease in hair count from baseline) compared with 58% of men in the placebo group. In men treated for up to 24 months, 17% of those treated with Propecia demonstrated hair loss compared with 72% of those in the placebo group.

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 continued improvement over 24 months.

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 24 months, the investigators rated 80% of men treated with Propecia as having increased hair growth compared with 47% of men treated with placebo.

Standardized photographs of the head were assessed in a blinded fashion, at the beginning of the study and at 6, 12, 18 and 24 months. An independent panel rated increases or decreases in scalp hair on 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 24 months, an increase in hair growth was demonstrated in 66% of men treated with Propecia compared with 7% of men treated with placebo. Based on this assessment, continued treatment with Propecia resulted in further improvement. These results were observed in the context of no further increase in hair count between month 12 and month 24.

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 on Hair Loss in the Anterior Mid-Scalp Area

A third 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

Clinical studies were conducted in men aged 18-41 with mild to moderate degrees of androgenetic alopecia. All men treated with Propecia or placebo received a tar-based shampoo (Neutrogena T/Gel Shampoo). 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 addition, clinical studies demonstrated slowing of hair loss with Propecia by patient self-assessment. These effects were maintained through the second year of treatment. Maintenance of or improvement in clinical efficacy has also been demonstrated in controlled and open-extension studies for up to 3 years.

Ethnic Analysis of Clinical Data

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.

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.

Proscar

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. 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.

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. TABLE 3 summarizes the results.

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: (34-63%)].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: (37-68%)] 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: (34-72%)].

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).

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 5 years of open extension studies.

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.

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.

INDICATIONS AND USAGE

Propecia

Propecia is indicated for the treatment of male pattern hair loss (androgenetic alopecia) in MEN ONLY. Safety and efficacy were demonstrated in men between 18-41 years of age with mild to moderate hair loss of the vertex and anterior mid-scalp area (see CLINICAL STUDIES, Propecia).

Efficacy in bitemporal recession has not been established.

Propecia is not indicated in women (see CONTRAINDICATIONS, Propecia).

Propecia is not indicated in children (see PRECAUTIONS, Propecia, Pediatric Use).

Proscar

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.

CONTRAINDICATIONS

Propecia

Propecia is contraindicated in the following:

Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of 5α-reductase inhibitors to inhibit the conversion of testosterone to DHT, finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. (See also WARNINGS, Propecia, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Propecia, Information for the Patient; and PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X.) In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.

Hypersensitivity to any component of this medication.

Proscar

Proscar is contraindicated in the following:

Hypersensitivity to any component of this medication.

Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of testosterone to DHT, finasteride may cause abnormalities of the external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman should be apprised of the potential hazard to the male fetus. (See also WARNINGS, Proscar, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Proscar, Information for the Patient; and PRECAUTIONS, Proscar, Pregnancy Category X.) In female rats, low doses of finasteride administered during pregnancy have produced abnormalities of the external genitalia in male offspring.

WARNINGS

Propecia

Propecia is not indicated for use in pediatric patients (see INDICATIONS AND USAGE, Propecia; and PRECAUTIONS, Propecia, Pediatric Use) or women (see also PRECAUTIONS, Propecia, Information for the Patient; PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X; and HOW SUPPLIED, Propecia, Storage and Handling).

Exposure of Women - Risk to Male Fetus

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 also CONTRAINDICATIONS, Propecia; PRECAUTIONS, Propecia, Information for the Patient; PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X; and HOW SUPPLIED, Propecia, Storage and Handling.)

Proscar

Proscar is not indicated for use in pediatric patients (see PRECAUTIONS, Proscar, Pediatric Use) or women (see also WARNINGS, Proscar, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Proscar, Information for the Patient; PRECAUTIONS, Proscar, Pregnancy Category X; and HOW SUPPLIED, Proscar).

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, Proscar; PRECAUTIONS, Proscar, Information for the Patient; PRECAUTIONS, Proscar, Pregnancy Category X; and HOW SUPPLIED, Proscar.)

PRECAUTIONS

Propecia

General

Caution should be used in the administration of Propecia in patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Information for the Patient

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 also CONTRAINDICATIONS, Propecia; WARNINGS, Propecia, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X; and HOW SUPPLIED, Propecia, Storage and Handling.) See also the Patient Package Insert which is available with the prescription.

Drug/Laboratory Test Interactions

In clinical studies with Propecia 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. When finasteride is used in older men who have benign prostatic hyperplasia (BPH), PSA levels are decreased by approximately 50%. Until further information is gathered in men >41 years of age without BPH, consideration should be given to doubling the PSA level in men undergoing this test while taking Propecia.

Carcinogenesis, Mutagenesis, and 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(0-24h) for animals and mean AUC(0-24h) for man (0.05 μg.h/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 a dose of 250 mg/kg/day (1824 times the human exposure). In mice at a dose of 25 mg/kg/day (184 times the human exposure, estimated) and in rats at a dose of ≥40 mg/kg/day (312 times the human exposure) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2- 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 doses of 20 mg/kg/day and 45 mg/kg/day (240 and 2800 times, respectively, the human exposure) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (18.4 times the human exposure).

No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, when Chinese hamster ovary cells were treated with high concentrations (450-550 μmol) of finasteride, there was a slight increase in chromosome aberrations. These concentrations correspond to 18,000-22,000 times the peak plasma levels in man given a total dose of 1 mg. Further, the concentrations (450-550 μmol) used in in vitro studies are not achievable in a biological system. In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (1824 times the human exposure, estimated) as determined in the carcinogenicity studies.

In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (4344 times the estimated human exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 80 mg/kg/day of finasteride (488 times the estimated human exposure), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity, and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats but is not relevant in man.

Pregnancy, Teratogenic Effects, Pregnancy Category X

See CONTRAINDICATIONS, Propecia.

Propecia is not indicated for use in women.

Administration of finasteride to pregnant rats at doses ranging from 100 μg/kg/day to 100 mg/kg/day (5-5000 times the recommended human dose of 1 mg/day) resulted in dose-dependent development of hypospadias in 3.6 to 100% of male offspring. Pregnant rats produced male offspring with decreased prostatic and seminal vesicular weights, delayed preputial separation, and transient nipple development when given finasteride at ≥30 μg/kg/day ≥1.5 times the recommended human dose of 1 mg/day) and decreased anogenital distance when given finasteride at ≥3 μg/kg/day (one-fifth the recommended human dose of 1 mg/day). The critical period during which these effects can be induced in male rats has been defined to be days 16-17 of gestation. The changes described above are expected pharmacological effects of drugs belonging to the class of Type II 5α-reductase inhibitors and are similar to those reported in male infants with a genetic deficiency of Type II 5α-reductase. No abnormalities were observed in female offspring exposed to any dose of finasteride in utero.

No developmental abnormalities have been observed in first filial generation (F1 ) male or female offspring resulting from mating finasteride-treated male rats (80 mg/kg/day; 488 times the human exposure) with untreated females. Administration of finasteride at 3 mg/kg/day (150 times the recommended human dose of 1 mg/day) during the late gestation and lactation period resulted in slightly decreased fertility in F1 male offspring. No effects were seen in female offspring. No evidence of malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6-18 of gestation at doses up to 100 mg/kg/day (5000 times the recommended human dose of 1 mg/day). However, effects on male genitalia would not be expected since the rabbits were not exposed during the critical period of genital system development.

The in utero effects of finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20-100), a species more predictive of human development than rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (at least 750 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 very high dose of finasteride (2 mg/kg/day; 100 times the recommended human dose of 1 mg/day or approximately 12 million times the highest estimated exposure to 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 finasteride-related 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 pharmacokinetics, no dosage adjustment is necessary in the elderly (see CLINICAL PHARMACOLOGY, Propecia, Pharmacokinetics).

Proscar

General

Prior to initiating therapy with Proscar, appropriate evaluation should be performed to identify other conditions such as infection, prostate cancer, stricture disease, hypotonic bladder or other neurogenic disorders that might mimic BPH.

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.

Caution should be used in the administration of Proscar in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Effects on PSA and Prostate Cancer Detection

No clinical benefit has been demonstrated in patients with prostate cancer treated with Proscar. Patients with BPH and elevated PSA were monitored in controlled clinical studies with serial PSAs and prostate biopsies. In these studies, Proscar did not appear to alter the rate of prostate cancer detection. The overall incidence of prostate cancer was not significantly different in patients treated with Proscar or placebo.

Proscar causes a decrease in serum PSA levels by approximately 50% in patients with BPH, even in the presence of prostate cancer. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Analysis of PSA data from over 3000 patients in PLESS confirmed that in typical patients treated with Proscar for 6 months or more, PSA values should be doubled for comparison with normal ranges in untreated men. This adjustment preserves the sensitivity and specificity of the PSA assay and maintains its ability to detect prostate cancer.

Any sustained increases in PSA levels while on Proscar should be carefully evaluated, including consideration of non-compliance to therapy with Proscar.

Percent free PSA (free to total PSA ratio) is not significantly decreased by Proscar. The ratio of free to total 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.

Information for the Patient

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 the male fetus (see CONTRAINDICATIONS, Proscar; WARNINGS, Proscar, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Proscar, Pregnancy Category X; and HOW SUPPLIED, Proscar).

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, Proscar).

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.

Drug/Laboratory Test Interactions

In patients with BPH, Proscar has no effect on circulating levels of cortisol, estradiol, prolactin, thyroid-stimulating 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. Increases of about 10% were observed in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in patients receiving Proscar, but levels remained within the normal range. In healthy volunteers, treatment with Proscar did not alter the response of LH and FSH to gonadotropin-releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.

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.

Carcinogenesis, Mutagenesis, and 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(0-24h) for animals and mean AUC (0-24h) for man (0.4 μg.h/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 a dose of 250 mg/kg/day (228 times the human exposure). In mice at a dose of 25 mg/kg/day (23 times the human exposure, estimated) and in rats at a dose of ≥40 mg/kg/day (39 times the human exposure) an increase in the incidence of Leydig cell hyperplasia was observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in serum LH levels (2- 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 doses of 20 mg/kg/day and 45 mg/kg/day (30 and 350 times, respectively, the human exposure) or in mice treated for 19 months at a dose of 2.5 mg/kg/day (2.3 times the human exposure, estimated).

No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration assay, 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 80 mg/kg/day (543 times the human exposure) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In sexually mature male rats treated with 80 mg/kg/day of finasteride (61 times the human exposure), there were no significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within 6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The seminal plug is essential for normal fertility in rats and is not relevant in man.

Pregnancy Category X

See CONTRAINDICATIONS, Proscar.

Proscar is not indicated for use in women.

Administration of finasteride to pregnant rats at doses ranging from 100 μg/kg/day to 100 mg/kg/day (1-1000 times the recommended human dose of 5 mg/day) resulted in dose-dependent development of hypospadias in 3.6 to 100% of male offspring. Pregnant rats produced male offspring with decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development when given finasteride at ≥30 μg/kg/day ≥3/10 of the recommended human dose of 5 mg/day) and decreased anogenital distance when given finasteride at ≥3 μg/kg/day ≥3/100 of the recommended human dose of 5 mg/day). The critical period during which these effects can be induced in male rats has been defined to be days 16-17 of gestation. The changes described above are expected pharmacological effects of drugs belonging to the class of Type II 5α-reductase inhibitors and are similar to those reported in male infants with a genetic deficiency of Type II 5α-reductase. No abnormalities were observed in female offspring exposed to any dose of finasteride in utero.

No developmental abnormalities have been observed in first filial generation (F1) male or female offspring resulting from mating finasteride-treated male rats (80 mg/kg/day; 61 times the human exposure) with untreated females. Administration of finasteride at 3 mg/kg/day (30 times the recommended human dose of 5 mg/day) during the late gestation and lactation period resulted in slightly decreased fertility in F1 male offspring. No effects were seen in female offspring. No evidence of malformations has been observed in rabbit fetuses exposed to finasteride in utero from days 6-18 of gestation at doses up to 100 mg/kg/day (1000 times the recommended human dose of 5 mg/day). However, effects on male genitalia would not be expected since the rabbits were not exposed during the critical period of genital system development.

The in utero effects of finasteride exposure during the period of embryonic and fetal development were evaluated in the rhesus monkey (gestation days 20-100), a species more predictive of human development than rats or rabbits. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (at least 60-120 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; 20 times the recommended human dose of 5 mg/day or approximately 1-2 million times the highest estimated exposure to 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, Proscar, Pharmacokinetics and CLINICAL STUDIES, Proscar).

DRUG INTERACTIONS

Propecia

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 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, 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 (NSAIDs), and quinolone anti-infectives without evidence of clinically significant adverse interactions.

Proscar

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.

ADVERSE REACTIONS

Propecia

Clinical Studies for Propecia (finasteride 1 mg) in the Treatment of Male Pattern Hair Loss

In controlled clinical trials for Propecia of 12 month duration, 1.4% of the patients were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related (1.6% for placebo); 1.2% of patients on Propecia and 0.9% of patients on placebo discontinued therapy because of a drug-related sexual adverse experience. The following clinical adverse reactions were reported as possibly, probably or definitely drug-related in ≥1% of patients treated for 12 months with Propecia or placebo, respectively: decreased libido (1.8%, 1.3%), erectile dysfunction (1.3%, 0.7%) and ejaculation disorder (1.2%, 0.7%; primarily decreased volume of ejaculate: [0.8%, 0.4%]). 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 all men who discontinued therapy with Propecia due to these side effects and in 58% of those who continued therapy.

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.

Postmarketing Experience for Propecia (finasteride 1 mg)

Breast tenderness and enlargement; hypersensitivity reactions including rash, pruritus, urticaria, and swelling of the lips and face; and testicular pain.

Controlled Clinical Trials and Long-Term Open Extension Studies for Proscar (finasteride 5 mg) in the Treatment of Benign Prostatic Hyperplasia

In controlled clinical trials for Proscar of 12 month duration, 1.3% of the patients were discontinued due to adverse experiences that were considered to be possibly, probably or definitely drug-related (0.9% for placebo); only 1 patient on Proscar (0.2%) and 1 patient on placebo (0.2%) discontinued therapy because of a drug-related sexual adverse experience. The following clinical adverse reactions were reported as possibly, probably or definitely drug-related in ≥1% of patients treated for 12 months with Proscar or placebo, respectively: erectile dysfunction (3.7%, 1.1%), decreased libido (3.3%, 1.6%) and decreased volume of ejaculate (2.8%, 0.9%). The adverse experience profiles for patients treated with finasteride 1 mg/day for 12 months and those maintained on Proscar for 24-48 months were similar to that observed in the 12 month controlled studies with Proscar. Sexual adverse experiences resolved with continued treatment in over 60% of patients who reported them.

Proscar

Proscar is generally well tolerated; adverse reactions usually have been mild and transient.

4 Year Placebo-Controlled Study

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 4 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.

Phase 3 Studies and 5 Year Open Extensions

The adverse experience profile in the 1 year, placebo-controlled, Phase 3 studies, the 5 year open extensions, and PLESS were similar.

There is no evidence of increased adverse experiences with increased duration of treatment with Proscar. New reports of drug-related sexual adverse experiences decreased with duration of therapy.

The following additional adverse effects have been reported in post-marketing experience:

Hypersensitivity reactions, including pruritus, urticaria, and swelling of the lips and face.

Testicular pain.

OVERDOSAGE

Propecia

In clinical studies, single doses of finasteride up to 400 mg and multiple doses of finasteride up to 80 mg/day for 3 months did not result in adverse reactions. Until further experience is obtained, no specific treatment for an overdose with finasteride can be recommended.

Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg), respectively.

Proscar

Patients have received single doses of Proscar up to 400 mg and multiple doses of Proscar up to 80 mg/day for 3 months without adverse effects. Until further experience is obtained, no specific treatment for an overdose with Proscar can be recommended.

Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m2 (500 mg/kg) and in female and male rats at single oral doses of 2360 mg/m2 (400 mg/kg) and 5900 mg/m2 (1000 mg/kg), respectively.

DOSAGE AND ADMINISTRATION

Propecia

The recommended dosage is 1 mg once a day.

Propecia may be administered with or without meals.

In general, daily use for 3 months or more is necessary before benefit is observed. Continued use is recommended to sustain benefit. Withdrawal of treatment leads to reversal of effect within 12 months.

Proscar

The recommended dose is 5 mg orally once a day.

Proscar may be administered with or without meals.

No dosage adjustment is necessary for patients with renal impairment or for the elderly (see CLINICAL PHARMACOLOGY, Proscar, Pharmacokinetics).

HOW SUPPLIED

Propecia

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

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, Propecia, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Propecia, Information for the Patient; and PRECAUTIONS, Propecia, Pregnancy, Teratogenic Effects, Pregnancy Category X.)

Proscar

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.

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, Proscar, Exposure of Women - Risk to Male Fetus; PRECAUTIONS, Proscar, Information for the Patient; and PRECAUTIONS, Proscar, Pregnancy Category X).