Caution should be used in the administration of PROPECIA in patients
with liver function abnormalities, as finasteride is metabolized
extensively in the liver.
Women should not handle crushed or broken PROPECIA 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. PROPECIA 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.
In clinical studies with PROPECIA 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 PROPECIA.
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, a-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.
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 mg•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 mmol ) 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 mmol ) 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.
Teratogenic Effects: Pregnancy Category X
See CONTRAINDICATIONS.
PROPECIA is not indicated for use in women.
Administration of finasteride to pregnant rats at doses
ranging from 100 mg/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 mg/kg/day ( >1.5
times the recommended human dose of 1 mg/day ) and
decreased anogenital distance when given finasteride at
>3 mg/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 5a-reductase inhibitors and are
similar to those reported in male infants with a genetic
deficiency of Type II 5a-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.
PROPECIA is not indicated for use in women.
It is not known whether finasteride is excreted in human milk.
PROPECIA is not indicated for use in pediatric patients.
Safety and effectiveness in pediatric patients have not
been established.
Clinical efficacy studies with PROPECIA did not include subjects
aged 65 and over. Based on the pharmacokinetics of
finasteride 5 mg, no dosage adjustment is necessary in the
elderly for PROPECIA ( see CLINICAL PHARMACOLOGY, Pharmacokinetics
). However the efficacy of PROPECIA in the elderly has
not been established.
