FINASTERIDE
DESCRIPTION:
FINAST* (finasteride), a synthetic 4-azasteroid compound, is a specific
inhibitor of steroid Type II 5alpha-reductase, an intracellular enzyme that
converts the androgen testosterone into 5alpha- dihydrotestosterone (DHT).
Finasteride is 4-azaandrost-1-ene- 17-carboxamide,N-(1,1-dimethylethyl) -3-oxo-
,(5alpha,17beta-. 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 deg C.
It is freely soluble in chloroform and in lower alcohol solvents but is
practically insoluble in water.
FINAST tablets for oral administration are film-coated tablets that contain 5
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.
ACTIONS/CLINICAL PHARMACOLOGY:
Finasteride is a competitive and specific inhibitor of Type II 5alpha-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 5alpha-reductase is predominant in the sebaceous
glands of most regions of skin, including scalp, and liver. Type I 5alpha-
reductase is responsible for approximately one- third of circulating DHT. The
Type II 5-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 5alpha-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 5alpha-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 5alpha-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 liters (range, 44-96 liters). 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 to 2
hours postdose; AUC(0-24 hr) was 53 ng*hr/mL (range, 20-154 ng*hr/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 per day, which is 750 times lower than the exposure from the no-
effect dose for developmental abnormalities in Rhesus monkeys (see PRECAUTIONS,
PREGNANCY).
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.
CLINICAL STUDIES:
The efficacy of FINAST 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(R)** Shampoo).
** Registered trademark of Johnson & Johnson
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 1,879 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=1,553). The third enrolled
men having mild to moderate hair loss in the anterior midscalp 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,
1,215 elected to continue in double-blind, placebo-controlled, 12-month
extension studies. There were 547 men receiving FINAST 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 FINAST 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 FINAST in the
12-month extension period (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 FINAST, 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, FINAST (n=679 evaluable men) vs placebo
(n=672 evaluable men)) within a 1-inch diameter circle (5.1 cm(squared)). Hair
count was maintained in those men taking FINAST (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 FINAST (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
FINAST 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. See figure below for combined study results.
At 12 months, 14% of men treated with FINAST 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 FINAST
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 FINAST. 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 FINAST
compared with placebo as early as 3 months (p<0.001). At 12 months, the
investigators rated 65% of men treated with FINAST as having increased hair
growth compared with 37% in the placebo group. At 24 months, the investigators
rated 80% of men treated with FINAST 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 FINAST 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 FINAST
compared with 7% of men treated with placebo. Based on this assessment,
continued treatment with FINAST 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. FINAST 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 FINAST
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 to 41 with mild to moderate
degrees of androgenetic alopecia. All men treated with FINAST or placebo
received a tar-based shampoo (Neutrogena T/Gel(R)** Shampoo). Clinical
improvement was seen as early as 3 months in the patients treated with FINAST
and led to a net increase in scalp hair count and hair regrowth. In addition,
clinical studies demonstrated slowing of hair loss with FINAST 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 (FINAST vs placebo) among
Caucasians (n=1,185), 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 FINAST 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.
INDICATIONS AND USAGE:
FINAST is indicated for the treatment of male pattern hair loss (androgenetic
alopecia) in MEN ONLY. Safety and efficacy were demonstrated in men between 18
to 41 years of age with mild to moderate hair loss of the vertex and anterior
mid-scalp area (See ACTIONS/CLINICAL PHARMACOLOGY, CLINICAL STUDIES).
Efficacy in bitemporal recession has not been established.
FINAST is not indicated in women (see CONTRAINDICATIONS).
FINAST is not indicated in children (see PRECAUTIONS, PEDIATRIC USE).
CONTRAINDICATIONS:
FINAST 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 5(alpha)-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, EXPOSURE OF WOMEN--RISK
TO MALE FETUS; and PRECAUTIONS, INFORMATION FOR PATIENTS and PREGNANCY.) 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.
WARNINGS:
FINAST is not indicated for use in pediatric patients (See INDICATIONS AND
USAGE; and PRECAUTIONS, PEDIATRIC USE) or women (See also PRECAUTIONS,
INFORMATION FOR PATIENTS and PREGNANCY; and HOW SUPPLIED, STORAGE AND HANDLING.)
EXPOSURE OF WOMEN--RISK TO MALE FETUS
Women should not handle crushed or broken FINAST 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. FINAST
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; PRECAUTIONS, INFORMATION FOR PATIENTS and PREGNANCY; and
HOW SUPPLIED, STORAGE AND HANDLING).
PRECAUTIONS:
GENERAL
Caution should be used in the administration of FINAST in patients with liver
function abnormalities, as finasteride is metabolized extensively in the liver.
INFORMATION FOR PATIENTS
Women should not handle crushed or broken FINAST 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. FINAST
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; WARNINGS, EXPOSURE OF WOMEN - RISK TO MALE FETUS;
PRECAUTIONS, PREGNANCY; and HOW SUPPLIED, STORAGE AND HANDLING.)
See also Patient Package Insert.
DRUG/LABORATORY TEST INTERACTIONS
In clinical studies with FINAST 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 FINAST.
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 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,
(alpha)-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.
CARCINOGENESIS, 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 2,192 times those observed in man receiving the recommended human
dose of 1 mg/day. All exposure calculations were based on calculated AUC(0-24
hr) for animals and mean AUC(0-24 hr) for man (0.05 Mu-g*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 a dose of 250 mg/kg/day (1,824 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 (2-3 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 2,800 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 Mu-mol) 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 Mu- mol) 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
(1,824 times the human exposure, estimated) as determined in the carcinogenicity
studies.
In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (4,344
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.
FINAST is not indicated for use in women.
Administration of finasteride to pregnant rats at doses ranging from 100 Mu-
g/kg/day to 100 mg/kg/day (5-5,000 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 Mu-g/kg/day ((>/=) 1.5 times the
recommended human dose of 1 mg/day) and decreased anogenital distance when given
finasteride at (>/=)3 Mu-g/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
5(alpha)-reductase inhibitors and are similar to those reported in male infants
with a genetic deficiency of Type II 5(alpha)-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
FINAST is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
PEDIATRIC USE
FINAST is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
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 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,
(alpha)-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.
(See also PRECAUTIONS)
ADVERSE REACTIONS:
CLINICAL STUDIES FOR FINAST (FINASTERIDE 1 MG) IN THE TREATMENT OF MALE
PATTERN HAIR LOSS
In controlled clinical trials for FINAST 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 FINAST 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 FINAST 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 FINAST, 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 FINAST 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 0.3mL (-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 FINAST (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 FINAST, the incidences for breast tenderness and
enlargement, and for hypersensitivity reactions in finasteride-treated patients
were not different from those in patients treated with placebo.
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 one
patient on PROSCAR (0.2%) and one 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 to 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.
ADVERSE EFFECTS REPORTED IN POST-MARKETING EXPERIENCE FOR PROSCAR (FINASTERIDE 5
MG)
Breast tenderness and enlargement, as well as hypersensitivity reactions,
including lip swelling and skin rash have been reported.
OVERDOSAGE:
In clinical studies, single doses of finasteride up to 400 mg and multiple doses
of finasteride up to 80 mg/day for three 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 1,500 mg/m(squared) (500 mg/kg) and in female and male rats at single oral
doses of 2,360 mg/m(squared) (400 mg/kg) and 5,900 mg/m(squared) (1,000 mg/kg),
respectively.
DOSAGE AND ADMINISTRATION:
The recommended dosage is 1 mg once a day.
FINAST may be administered with or without meals.
In general, daily use for three 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.
DESCRIPTION:
FINAST* (finasteride), a synthetic 4-azasteroid compound, is a specific
inhibitor of steroid Type II 5alpha-reductase, an intracellular enzyme that
converts the androgen testosterone into 5alpha- dihydrotestosterone (DHT).
Finasteride is 4-azaandrost-1-ene- 17-carboxamide,N-(1,1-dimethylethyl) -3-oxo-
,(5alpha,17beta-. 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 deg C.
It is freely soluble in chloroform and in lower alcohol solvents but is
practically insoluble in water.
FINAST tablets for oral administration are film-coated tablets that contain 5
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.
ACTIONS/CLINICAL PHARMACOLOGY:
Finasteride is a competitive and specific inhibitor of Type II 5alpha-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 5alpha-reductase is predominant in the sebaceous
glands of most regions of skin, including scalp, and liver. Type I 5alpha-
reductase is responsible for approximately one- third of circulating DHT. The
Type II 5-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 5alpha-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 5alpha-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 5alpha-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 liters (range, 44-96 liters). 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 to 2
hours postdose; AUC(0-24 hr) was 53 ng*hr/mL (range, 20-154 ng*hr/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 per day, which is 750 times lower than the exposure from the no-
effect dose for developmental abnormalities in Rhesus monkeys (see PRECAUTIONS,
PREGNANCY).
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.
CLINICAL STUDIES:
The efficacy of FINAST 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(R)** Shampoo).
** Registered trademark of Johnson & Johnson
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 1,879 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=1,553). The third enrolled
men having mild to moderate hair loss in the anterior midscalp 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,
1,215 elected to continue in double-blind, placebo-controlled, 12-month
extension studies. There were 547 men receiving FINAST 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 FINAST 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 FINAST in the
12-month extension period (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 FINAST, 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, FINAST (n=679 evaluable men) vs placebo
(n=672 evaluable men)) within a 1-inch diameter circle (5.1 cm(squared)). Hair
count was maintained in those men taking FINAST (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 FINAST (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
FINAST 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. See figure below for combined study results.
At 12 months, 14% of men treated with FINAST 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 FINAST
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 FINAST. 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 FINAST
compared with placebo as early as 3 months (p<0.001). At 12 months, the
investigators rated 65% of men treated with FINAST as having increased hair
growth compared with 37% in the placebo group. At 24 months, the investigators
rated 80% of men treated with FINAST 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 FINAST 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 FINAST
compared with 7% of men treated with placebo. Based on this assessment,
continued treatment with FINAST 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. FINAST 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 FINAST
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 to 41 with mild to moderate
degrees of androgenetic alopecia. All men treated with FINAST or placebo
received a tar-based shampoo (Neutrogena T/Gel(R)** Shampoo). Clinical
improvement was seen as early as 3 months in the patients treated with FINAST
and led to a net increase in scalp hair count and hair regrowth. In addition,
clinical studies demonstrated slowing of hair loss with FINAST 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 (FINAST vs placebo) among
Caucasians (n=1,185), 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 FINAST 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.
INDICATIONS AND USAGE:
FINAST is indicated for the treatment of male pattern hair loss (androgenetic
alopecia) in MEN ONLY. Safety and efficacy were demonstrated in men between 18
to 41 years of age with mild to moderate hair loss of the vertex and anterior
mid-scalp area (See ACTIONS/CLINICAL PHARMACOLOGY, CLINICAL STUDIES).
Efficacy in bitemporal recession has not been established.
FINAST is not indicated in women (see CONTRAINDICATIONS).
FINAST is not indicated in children (see PRECAUTIONS, PEDIATRIC USE).
CONTRAINDICATIONS:
FINAST 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 5(alpha)-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, EXPOSURE OF WOMEN--RISK
TO MALE FETUS; and PRECAUTIONS, INFORMATION FOR PATIENTS and PREGNANCY.) 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.
WARNINGS:
FINAST is not indicated for use in pediatric patients (See INDICATIONS AND
USAGE; and PRECAUTIONS, PEDIATRIC USE) or women (See also PRECAUTIONS,
INFORMATION FOR PATIENTS and PREGNANCY; and HOW SUPPLIED, STORAGE AND HANDLING.)
EXPOSURE OF WOMEN--RISK TO MALE FETUS
Women should not handle crushed or broken FINAST 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. FINAST
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; PRECAUTIONS, INFORMATION FOR PATIENTS and PREGNANCY; and
HOW SUPPLIED, STORAGE AND HANDLING).
PRECAUTIONS:
GENERAL
Caution should be used in the administration of FINAST in patients with liver
function abnormalities, as finasteride is metabolized extensively in the liver.
INFORMATION FOR PATIENTS
Women should not handle crushed or broken FINAST 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. FINAST
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; WARNINGS, EXPOSURE OF WOMEN - RISK TO MALE FETUS;
PRECAUTIONS, PREGNANCY; and HOW SUPPLIED, STORAGE AND HANDLING.)
See also Patient Package Insert.
DRUG/LABORATORY TEST INTERACTIONS
In clinical studies with FINAST 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 FINAST.
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 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,
(alpha)-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.
CARCINOGENESIS, 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 2,192 times those observed in man receiving the recommended human
dose of 1 mg/day. All exposure calculations were based on calculated AUC(0-24
hr) for animals and mean AUC(0-24 hr) for man (0.05 Mu-g*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 a dose of 250 mg/kg/day (1,824 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 (2-3 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 2,800 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 Mu-mol) 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 Mu- mol) 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
(1,824 times the human exposure, estimated) as determined in the carcinogenicity
studies.
In sexually mature male rabbits treated with finasteride at 80 mg/kg/day (4,344
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.
FINAST is not indicated for use in women.
Administration of finasteride to pregnant rats at doses ranging from 100 Mu-
g/kg/day to 100 mg/kg/day (5-5,000 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 Mu-g/kg/day ((>/=) 1.5 times the
recommended human dose of 1 mg/day) and decreased anogenital distance when given
finasteride at (>/=)3 Mu-g/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
5(alpha)-reductase inhibitors and are similar to those reported in male infants
with a genetic deficiency of Type II 5(alpha)-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
FINAST is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
PEDIATRIC USE
FINAST is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not been established.
DRUG INTERACTIONS:
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 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,
(alpha)-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.
(See also PRECAUTIONS)
ADVERSE REACTIONS:
CLINICAL STUDIES FOR FINAST (FINASTERIDE 1 MG) IN THE TREATMENT OF MALE
PATTERN HAIR LOSS
In controlled clinical trials for FINAST 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 FINAST 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 FINAST 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 FINAST, 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 FINAST 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 0.3mL (-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 FINAST (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 FINAST, the incidences for breast tenderness and
enlargement, and for hypersensitivity reactions in finasteride-treated patients
were not different from those in patients treated with placebo.
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 one
patient on PROSCAR (0.2%) and one 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 to 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.
ADVERSE EFFECTS REPORTED IN POST-MARKETING EXPERIENCE FOR PROSCAR (FINASTERIDE 5
MG)
Breast tenderness and enlargement, as well as hypersensitivity reactions,
including lip swelling and skin rash have been reported.
OVERDOSAGE:
In clinical studies, single doses of finasteride up to 400 mg and multiple doses
of finasteride up to 80 mg/day for three 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 1,500 mg/m(squared) (500 mg/kg) and in female and male rats at single oral
doses of 2,360 mg/m(squared) (400 mg/kg) and 5,900 mg/m(squared) (1,000 mg/kg),
respectively.
DOSAGE AND ADMINISTRATION:
The recommended dosage is 1 mg once a day.
FINAST may be administered with or without meals.
In general, daily use for three 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.