Finasteride 5 mg Tablet, Film Coated, 90-count — NDC 67877-288-90 (Billing 67877-0288-90)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 (t ½ ~ 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.

12.2Pharmacodynamics In man, a single 5-mg oral dose of finasteride tablets 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 finasteride tablets 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 to 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 finasteride tablets 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 finasteride tablets 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, finasteride tablets have no effect on circulating levels of cortisol, 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.

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 to 100 mg/day) for 7 to 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 finasteride tablets 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.

12.3Pharmacokinetics Absorption In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63% (range 34 to 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 to 49 ng/mL) and was reached 1 to 2 hours postdose. Bioavailability of finasteride was not affected by food.

Distribution Mean steady-state volume of distribution was 76 liters (range, 44 to 96… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 (t ½ ~ 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.

12.3Pharmacokinetics Absorption In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63% (range 34 to 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 to 49 ng/mL) and was reached 1 to 2 hours postdose. Bioavailability of finasteride was not affected by food.

Distribution Mean steady-state volume of distribution was 76 liters (range, 44 to 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 to 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 to 9.8 ng/mL) and 8.1 ng/mL (range, 1.8 to 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 to 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 finasteride tablets 5 mg/day for 6 to 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 finasteride tablets 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 mcg) that had no effect on circulating DHT levels in men [see also 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 In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70 to 279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3 to 16 hours). 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. The mean terminal half-life of finasteride in subjects ≥70 years of age was approximately 8 hours (range, 6 to 15 hours; n=12), compared with 6 hours (range, 4 to 12 hours; n=12) in subjects 45 to 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 to 60 years of age (p=0.02). Table 3: Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15) Mean (±SD) Bioavailability 63% (34 to 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 (5.4) , Use in Specific Populations (8.4 )].

Gender Finasteride is not indicated for use in females [ see Contraindications (4) , Warnings and Precautions ( 5.3 and 5.4 ), Use in Specific Populations (8.1) , and How Supplied/Storage and Handling (16) ]. 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 Clinic… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In man, a single 5-mg oral dose of finasteride tablets 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 finasteride tablets 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 to 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 finasteride tablets 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 finasteride tablets 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, finasteride tablets have no effect on circulating levels of cortisol, 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.

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 to 100 mg/day) for 7 to 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 finasteride tablets 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.

14 CLINICAL STUDIES

14.1Monotherapy Finasteride tablets 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. Finasteride tablets was further evaluated in the finasteride tablets A Long-Term Efficacy and Safety Study, a double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3,040 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 (1,524 to finasteride, 1,516 to placebo) and 3,016 patients were evaluable for efficacy.

1,883 patients completed the 4-year study (1,000 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 A Long-Term Efficacy and Safety Study had moderate to severe symptoms at baseline (mean of approximately 15 points on a 0 to 34 point scale). Patients randomized to finasteride tablets 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 finasteride tablets vs placebo (-2.3 vs -1.6), and this improvement continued through Year 4.

Figure 1 Symptom Score in A Long-Term Efficacy and Safety Study Results seen in earlier studies were comparable to those seen in A Long-Term Efficacy and Safety Study. 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 A Long-Term Efficacy and Safety Study, 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 A Long-Term Efficacy and Safety Study Patients (%)* Event 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

6.7Bladder Stone 0.4

0.5Incontinence 2.1

1.7Renal Failure 0.5

0.6UTI 5.7

4.9Discontinuation 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, finasteride tablets 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 finasteride tablets; 51% reduction in risk, 95% CI: (34 to 63%)]. Compared with placebo, fi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 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 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). Mutagenesis 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 4,000 to 5,000 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. Impairment of Fertility 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.