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9636003
PROPECIA
(finasteride)
Tablets, 1 mg
DESCRIPTION
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. Its structural formula is:
Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in
chloroform and in lower alcohol solvents but is practically insoluble in water.
PROPECIA 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, hydroxypropyl methylcellulose, hydroxypropyl cellulose LF, titanium dioxide,
magnesium stearate, talc, docusate sodium, yellow ferric oxide, and red ferric oxide.
CLINICAL PHARMACOLOGY
Finasteride is a competitive and specific inhibitor of Type II 5α-reductase, an intracellular enzyme that
converts the androgen testosterone into DHT. Two distinct isozymes are found in mice, rats, monkeys,
and humans: Type I and II. Each of these isozymes is differentially expressed in tissues and
developmental stages. In humans, Type I 5α-reductase is predominant in the sebaceous glands of most
regions of skin, including scalp, and liver. Type I 5α-reductase is responsible for approximately one-third
of circulating DHT. The Type II 5α-reductase isozyme is primarily found in prostate, seminal vesicles,
epididymides, and hair follicles as well as liver, and is responsible for two-thirds of circulating DHT.
In humans, the mechanism of action of finasteride is based on its preferential inhibition of the Type II
isozyme. Using native tissues (scalp and prostate), in vitro binding studies examining the potential of
finasteride to inhibit either isozyme revealed a 100-fold selectivity for the human Type II 5α-reductase
over Type I isozyme (IC50=500 and 4.2 nM for Type I and II, respectively). For both isozymes, the
inhibition by finasteride is accompanied by reduction of the inhibitor to dihydrofinasteride and adduct
formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the
Type II enzyme complex and 14 days for the Type I complex).
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. Mean circulating levels of testosterone and
* Registered trademark of MERCK & CO., Inc.
COPYRIGHT 1997 MERCK & CO., Inc.
All rights reserved
PROPECIA (Finasteride) Tablets, 1 mg 9636003
2
estradiol were increased by approximately 15% as compared to baseline, but these remained within the
physiologic range.
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.
A 48-week, placebo-controlled study designed to assess by phototrichogram the effect of PROPECIA
on total and actively growing (anagen) scalp hairs in vertex baldness enrolled 212 men with androgenetic
alopecia. At baseline and 48 weeks, total and anagen hair counts were obtained in a 1-cm2 target area of
the scalp. Men treated with PROPECIA showed increases from baseline in total and anagen hair counts
of 7 hairs and 18 hairs, respectively, whereas men treated with placebo had decreases of 10 hairs and 9
hairs, respectively. These changes in hair counts resulted in a between-group difference of 17 hairs in
total hair count (p<0.001) and 27 hairs in anagen hair count (p<0.001), and an improvement in the
proportion of anagen hairs from 62% at baseline to 68% for men treated with PROPECIA.
Pharmacokinetics
Absorption
In a study in 15 healthy young male subjects, the mean bioavailability of finasteride 1-mg tablets was
65% (range 26-170%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV)
reference dose. At steady state following dosing with 1 mg/day (n=12), maximum finasteride plasma
concentration averaged 9.2 ng/mL (range, 4.9-13.7 ng/mL) and was reached 1 to 2 hours postdose;
AUC(0-24 hr) was 53 ng•hr/mL (range, 20-154 ng•hr/mL). Bioavailability of finasteride was not affected by
food.
Distribution
Mean steady-state volume of distribution was 76 liters (range, 44-96 liters; n=15). Approximately 90%
of circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride
after multiple dosing.
Finasteride has been found to cross the blood-brain barrier.
Semen levels have been measured in 35 men taking finasteride 1 mg/day for 6 weeks. In 60% (21 of
35) of the samples, finasteride levels were undetectable (<0.2 ng/mL). The mean finasteride level was
0.26 ng/mL and the highest level measured was 1.52 ng/mL. Using the highest semen level measured
and assuming 100% absorption from a 5-mL ejaculate per day, human exposure through vaginal
absorption would be up to 7.6 ng per day, which is 750 times lower than the exposure from the no-effect
dose for developmental abnormalities in Rhesus monkeys and 650-fold less than the dose of finasteride
(5 μg) that had no effect on circulating DHT levels in men (see PRECAUTIONS, Pregnancy).
Metabolism
Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme
subfamily. Two metabolites, the t-butyl side chain monohydroxylated and monocarboxylic acid
metabolites, have been identified that possess no more than 20% of the 5α-reductase inhibitory activity of
finasteride.
Excretion
Following intravenous infusion in healthy young subjects (n=15), mean plasma clearance of
finasteride was 165 mL/min (range, 70-279 mL/min). Mean terminal half-life in plasma was 4.5 hours
(range, 3.3-13.4 hours; n=12). Following an oral dose of 14C-finasteride in man (n=6), a mean of 39%
(range, 32-46%) of the dose was excreted in the urine in the form of metabolites; 57% (range, 51-64%)
was excreted in the feces.
Mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more
than 70 years of age.
Special Populations
Pediatric: Finasteride pharmacokinetics have not been investigated in patients <18 years of age.
Gender: PROPECIA is not indicated for use in women.
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, and PRECAUTIONS, Geriatric Use sections.
Race: The effect of race on finasteride pharmacokinetics has not been studied.
PROPECIA (Finasteride) Tablets, 1 mg 9636003
3
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
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 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.
Hepatic Insufficiency: The effect of hepatic insufficiency on finasteride pharmacokinetics has not been
studied. Caution should be used in the administration of PROPECIA in patients with liver function
abnormalities, as finasteride is metabolized extensively in the liver.
Drug Interactions (also see PRECAUTIONS, Drug Interactions)
No drug interactions of clinical importance have been identified. Finasteride does not appear to affect
the cytochrome P450-linked drug-metabolizing enzyme system. Compounds that have been tested in
man include antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful
interactions were found.
Clinical Studies
Studies in Men
The efficacy of PROPECIA was demonstrated in men (88% Caucasian) with mild to moderate
androgenetic alopecia (male pattern hair loss) between 18 and 41 years of age. In order to prevent
seborrheic dermatitis which might confound the assessment of hair growth in these studies, all men,
whether treated with finasteride or placebo, were instructed to use a specified, medicated, tar-based
shampoo (Neutrogena T/Gel®** Shampoo) during the first 2 years of the studies.
There were three double-blind, randomized, placebo-controlled studies of 12-month duration. The two
primary endpoints were hair count and patient self-assessment; the two secondary endpoints were
investigator assessment and ratings of photographs. In addition, information was collected regarding
sexual function (based on a self-administered questionnaire) and non-scalp body hair growth. The three
studies were conducted in 1879 men with mild to moderate, but not complete, hair loss. Two of the
studies enrolled men with predominantly mild to moderate vertex hair loss (n=1553). The third enrolled
men having mild to moderate hair loss in the anterior mid-scalp area with or without vertex balding
(n=326).
Studies in Men with Vertex Baldness
Of the men who completed the first 12 months of the two vertex baldness trials, 1215 elected to
continue in double-blind, placebo-controlled, 12-month extension studies. There were 547 men receiving
PROPECIA for both the initial study and first extension periods (up to 2 years of treatment) and 60 men
** Registered trademark of Johnson & Johnson
Mean (SD) Pharmacokinetic Parameters
in Healthy Men (ages 18-26)
Mean (± SD)
n=15
Bioavailability 65% (26-170%)*
Clearance (mL/min) 165 (55)
Volume of Distribution (L) 76 (14)
*Range
Mean (SD) Noncompartmental Pharmacokinetic Parameters
After Multiple Doses of 1 mg/day in
Healthy Men (ages 19-42)
Mean (± SD)
(n=12)
AUC (ng•hr/mL) 53 (33.8)
Peak Concentration (ng/mL) 9.2 (2.6)
Time to Peak (hours) 1.3 (0.5)
Half-Life (hours)* 4.5 (1.6)
*First-dose values; all other parameters are last-dose values
PROPECIA (Finasteride) Tablets, 1 mg 9636003
4
receiving placebo for the same periods. The extension studies were continued for 3 additional years, with
323 men on PROPECIA and 23 on placebo entering the fifth year of the study.
In order to evaluate the effect of discontinuation of therapy, there were 65 men who received
PROPECIA for the initial 12 months followed by placebo in the first 12-month extension period. Some of
these men continued in additional extension studies and were switched back to treatment with
PROPECIA, with 32 men entering the fifth year of the study. Lastly, there were 543 men who received
placebo for the initial 12 months followed by PROPECIA in the first 12-month extension period. Some of
these men continued in additional extension studies receiving PROPECIA, with 290 men entering the fifth
year of the study (see Figure below).
Hair counts were assessed by photographic enlargements of a representative area of active hair loss.
In these two studies in men with vertex baldness, significant increases in hair count were demonstrated at
6 and 12 months in men treated with PROPECIA, while significant hair loss from baseline was
demonstrated in those treated with placebo. At 12 months there was a 107-hair difference from placebo
(p<0.001, PROPECIA [n=679] vs placebo [n=672]) within a 1-inch diameter circle (5.1 cm2). Hair count
was maintained in those men taking PROPECIA for up to 2 years, resulting in a 138-hair difference
between treatment groups (p<0.001, PROPECIA [n=433] vs placebo [n=47]) within the same area. In
men treated with PROPECIA, the maximum improvement in hair count compared to baseline was
achieved during the first 2 years. Although the initial improvement was followed by a slow decline, hair
count was maintained above baseline throughout the 5 years of the studies. Furthermore, because the
decline in the placebo group was more rapid, the difference between treatment groups also continued to
increase throughout the studies, resulting in a 277-hair difference (p<0.001, PROPECIA [n=219] vs
placebo [n=15]) at 5 years (see Figure below).
Patients who switched from placebo to PROPECIA (n=425) had a decrease in hair count at the end of
the initial 12-month placebo period, followed by an increase in hair count after 1 year of treatment with
PROPECIA. This increase in hair count was less (56 hairs above original baseline) than the increase (91
hairs above original baseline) observed after 1 year of treatment in men initially randomized to
PROPECIA. Although the increase in hair count, relative to when therapy was initiated, was comparable
between these two groups, a higher absolute hair count was achieved in patients who were started on
treatment with PROPECIA in the initial study. This advantage was maintained through the remaining 3
years of the studies. A change of treatment from PROPECIA to placebo (n=48) at the end of the initial 12
months resulted in reversal of the increase in hair count 12 months later, at 24 months (see Figure
below).
At 12 months, 58% of men in the placebo group had further hair loss (defined as any decrease in hair
count from baseline), compared with 14% of men treated with PROPECIA. In men treated for up to 2
years, 72% of men in the placebo group demonstrated hair loss, compared with 17% of men treated with
PROPECIA. At 5 years, 100% of men in the placebo group demonstrated hair loss, compared with 35%
of men treated with PROPECIA.
PROPECIA (Finasteride) Tablets, 1 mg 9636003
5
Patient self-assessment was obtained at each clinic visit from a self-administered questionnaire, which
included questions on their perception of hair growth, hair loss, and appearance. This self-assessment
demonstrated an increase in amount of hair, a decrease in hair loss, and improvement in appearance in
men treated with PROPECIA. Overall improvement compared with placebo was seen as early as 3
months (p<0.05), with improvement maintained over 5 years.
Investigator assessment was based on a 7-point scale evaluating increases or decreases in scalp hair
at each patient visit. This assessment showed significantly greater increases in hair growth in men
treated with PROPECIA compared with placebo as early as 3 months (p<0.001). At 12 months, the
investigators rated 65% of men treated with PROPECIA as having increased hair growth compared with
37% in the placebo group. At 2 years, the investigators rated 80% of men treated with PROPECIA as
having increased hair growth compared with 47% of men treated with placebo. At 5 years, the
investigators rated 77% of men treated with PROPECIA as having increased hair growth, compared with
15% of men treated with placebo.
An independent panel rated standardized photographs of the head in a blinded fashion based on
increases or decreases in scalp hair using the same 7-point scale as the investigator .