Finasteride 1 mg Tablet, Film Coated, 30-count — NDC 68071-3094-3 (Billing 68071-3094-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 (IC 50 =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 (t 1/2 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics Absorption In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26 to 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 to 13.7 ng/mL) and was reached 1 to 2 hours postdose ; AUC (0 to 24 hr) was 53 ng•hr/mL (range, 20 to 154 ng•hr/mL). Bioavailability of finasteride was not affected by food.

Distribution Mean steady-state volume of distribution was 76 liters (range, 44 to 96 liters; n=15). Approximately 90% of circulating finasteride is bound to plasma proteins. There is a slow accumulation ph… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 (IC 50 =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 (t 1/2 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.

12.3Pharmacokinetics Absorption In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was 65% (range 26 to 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 to 13.7 ng/mL) and was reached 1 to 2 hours postdose ; AUC (0 to 24 hr) was 53 ng•hr/mL (range, 20 to 154 ng•hr/mL). Bioavailability of finasteride was not affected by food.

Distribution Mean steady-state volume of distribution was 76 liters (range, 44 to 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 mcg) that had no effect on circulating DHT levels in men. [ See Use in Specific Populations (8.1) .] 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 to 279 mL/min). Mean terminal half-life in plasma was 4.5 hours (range, 3.3 to 13.4 hours; n=12).

Following an oral dose of 14 C-finasteride in man (n=6), a mean of 39% (range, 32 to 46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51 to 64%) was excreted in the feces. Mean terminal half-life is approximately 5 to 6 hours in men 18 to 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 to 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 Dosesof 1 mg/ day inHealthy Men (ages 19 to 42) AUC (ng· hr/mL) Mean (± SD) (n=12) 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 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14 C-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 finasteride tablets USP in patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES

14.1Studies in Men The efficacy of finasteride tablets USP 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 finasteride tablets USP, 1 mg 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 finasteride tablets USP, 1 mg 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 finasteride tablets USP 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 finasteride tablets USP, 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 finasteride tablets USP in the first 12-month extension period. Some of these men continued in additional extension studies receiving finasteride tablets USP, 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 finasteride tablets USP, 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, finasteride tablets USP [n=679] vs placebo [n=672]) within a 1-inch diameter circle (5.1 cm 2 ).

Hair count was maintained in those men taking finasteride tablets USP for up to 2 years, resulting in a 138-hair difference between treatment groups (p<0.001, finasteride tablets USP [n=433] vs placebo [n=47]) within the same area. In men treated with finasteride tablets USP, 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, finasteride tablets USP [n=219] vs placebo [n=15]) at 5 years (see Figure 1 below). Patients who switched from placebo to finasteride tablets USP (n=425) had a decrease in hair count at the end of the initial 12-month placebo period, followed by an increase in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis & 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 to 24 hr) for animals and mean AUC (0 to 24 hr) for man (0.05 mcg•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.