12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The development and enlargement of the prostate gland is dependent on the potent androgen, 5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a stable enzyme complex. Turnover from this complex is extremely slow (t½∼ 30 days). This has been demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the 5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.

12.2 Pharmacodynamics

In man, a single 5-mg oral dose of finasteride tablets USP 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 USP 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 USP, 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 USP 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 USP has 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 USP 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.

12.3 Pharmacokinetics

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 USP 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 USP, 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 14C-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 to 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% (34-108%)*
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 women [see Contraindications (4), Warnings and Precautions (5.3 and 5.4), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient Counseling Information (17.2)]

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 Clinical Pharmacology (12.3) and Use in Specific Populations (8.5).]

Table 4 : Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men
	Mean (± SD)
	45-60 years old (n=12)	≥70 years old (n=12)
AUC (ng•hr/mL)	389 (98)	463 (186)
Peak Concentration (ng/mL)	46.2 (8.7)	48.4 (14.7)
Time to Peak (hours)	1.8 (0.7)	1.8 (0.6)
Half-Life (hours)*	6.0 (1.5)	8.2 (2.5 )

*First-dose values; all other parameters are last-dose values

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

Hepatic Impairment
The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution should be exercised in the administration of finasteride tablets USP in those patients with liver function abnormalities, as finasteride is metabolized extensively in the liver.

Renal Impairment
No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal impairment, with creatinine clearances ranging from 9.0 to 55 mL/min, AUC, maximum plasma concentration, half-life, and protein binding after a single dose of 14C-finasteride were similar to values obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60% increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to metabolites would presumably be much greater.

14 CLINICAL STUDIES

14.1 Monotherapy

Finasteride tablets USP, 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 USP was further evaluated in a long-term efficacy and safety study, 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 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 USP 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 USP 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 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 . Complete event information was available for 92% of the patients. The following table 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
Two consecutive symptom score ≥ 20	9.2	6.7
Bladder Stone	0.4	0.5
Incontinence	2.1	1.7
Renal Failure	0.5	0.6
UTI	5.7	4.9
Discontinuation due to worsening of BPH, lack of improvement, or to receive other medical treatment	21.8	13.3

*patients with multiple events may be counted more than once for each type of event
† Hazard ratio based on log rank test

Compared with placebo, finasteride tablets USP was associated with a significantly lower need for BPH-related surgery. Compared with placebo, finasteride tablets USP was associated with a significantly lower risk for surgery [10.1% for placebo vs 4.6% for finasteride tablets USP; 55% reduction in risk, 95% CI: (37 to 68%)]; see Figure 2.

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** Effect on Maximum Urinary Flow Rate**
In the patients in a long-term efficacy and safety study who remained on therapy for the duration of the study and had evaluable urinary flow data, finasteride tablets USP 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 finasteride tablets USP 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 a long-term efficacy and safety study and was maintained through the first year and throughout an additional 5 years of open extension studies.

Effect on Prostate Volume
In a long-term efficacy and safety study, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of patients. In patients treated with finasteride tablets USP who remained on therapy, prostate volume was reduced compared with both baseline and placebo throughout the 4-year study. Finasteride tablets USP decreased prostate volume by 17.9% (from 55.9 mL at baseline to 45.8 mL at 4 years) compared with an increase of 14.1% (from 51.3 mL to 58.5 mL) in the placebo group (p<0.001). (See Figure 3.)

Results seen in earlier studies were comparable to those seen in a long-term efficacy and safety study. Mean prostate volume at baseline ranged between 40 to 50 ml. The reduction in prostate volume was seen during the first year and maintained throughout an additional five years of open extension studies.

** Figure 3**
Prostate Volume in A Long-Term Efficacy and Safety Study

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 finasteride tablets USP, the magnitude of symptom response and degree of improvement in maximum urinary flow rate were greater in patients with an enlarged prostate at baseline.

14.2 Combination with Alpha-Blocker Therapy

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized, placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH, who were randomized to receive finasteride tablets USP, 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of finasteride tablets USP, 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The final doxazosin dose was administered once per day, at bedtime.

The mean patient age at randomization was 62.6 years (±7.3 years). Patients were Caucasian (82%), African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH symptoms was 4.7 years (±4.6 years). Patients had moderate to severe BPH symptoms at baseline with a mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was 10.5 mL/sec (±2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was 36.3 mL (±20.1 mL). Prostate volume was ≤20 mL in 16% of patients, ≥50 mL in 18% of patients and between 21 and 49 mL in 66% of patients.

The primary endpoint was a composite measure of the first occurrence of any of the following five outcomes: a ≥4 point confirmed increase from baseline in symptom score, BPH-related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence. Compared to placebo, treatment with finasteride tablets USP, doxazosin, or combination therapy resulted in a reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001), and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the primary endpoint compared to treatment with finasteride tablets USP alone (49%; p≤0.001) or doxazosin alone (46%; p≤0.001). (See Table 6.)
Table 6: Count and Percent Incidence of Primary Outcome Events by Treatment Group in MTOPS

	Treatment Group
	Placebo N=737	Doxazosin N=756	Finasteride N=768	Combination N=786	Total N=3047
Event	N (%)	N (%)	N (%)	N (%)	N (%)
AUA 4-point rise	100 (13.6)	59 (7.8)	74 (9.6)	41 (5.2)	274 (9.0)
Incontinence	8 (1.1)	11 (1.5)	9 (1.2)	3 (0.4)	31 (1.0)
Recurrent UTI/urosepsis	2 (0.3)	2 (0.3)	0 (0.0)	1 (0.1)	5 (0.2)
Creatinine rise	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Total Events	128 (17.4)	85 (11.2)	89 (11.6)	49 (6.2)	351 (11.5)

The majority of the events (274 out of 351; 78%) was a confirmed ≥4 point increase in symptom score, referred to as symptom score progression. The risk of symptom score progression was reduced by 30% (p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with finasteride tablets USP, doxazosin, or the combination, respectively, compared to patients treated with placebo (see Figure 4). Combination therapy significantly reduced the risk of symptom score progression compared to the effect of finasteride tablets USP alone (p<0.001) and compared to doxazosin alone (p=0.037).

Figure 4
Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group

Treatment with finasteride tablets USP, doxazosin or the combination of finasteride tablets USP with doxazosin, reduced the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for AUA symptom score by treatment group for patients who remained on therapy for four years.

Table 7:Change From Baseline in AUA Symptom Score by Treatment
** Group at Year 4 in MTOPS**

	** Placebo** N=534	Doxazosin N=582	Finasteride N=565	Combination ** N=598**
Baseline Mean (SD)	16.8 (6.0)	17.0 (5.9)	17.1 (6.0)	16.8 (5.8)
Mean Change AUA Symptom Score (SD)	-4.9 (5.8)	-6.6 (6.1)	-5.6 (5.9)	-7.4 (6.3)
Comparison to Placebo (95% CI)		-1.8 (-2.5, -1.1)	-0.7 (-1.4, 0.0)	-2.5 (-3.2, -1.8)
Comparison to Doxazosin alone (95% CI)				-0.7 (-1.4, 0.0)
Comparison to Finasteride alone (95% CI)				-1.8 (-2.5, -1.1)

The results of MTOPS are consistent with the findings of the 4-year, placebo- controlled study a long-term efficacy and safety study [see Clinical Studies (14.1)] in that treatment with finasteride tablets USP reduces the need for BPH-related surgery. Also, the risk of requiring BPH-related invasive therapy was reduced by 64% in patients treated with finasteride tablets USP compared to patients treated with placebo (2.0% for finasteride tablets USP and 5.4% for placebo).

14.3 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 finasteride tablets USP arrests the disease process of BPH in men with an enlarged prostate.