Caution should be used in administering dutasteride to patients taking potent, chronic CYP3A4
Avodart does not inhibit the in vitro metabolism of model substrates for the major human cytochrome P450
isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at a concentration of 1000 ng/mL, 25 times greater than
steady-state serum concentrations in humans. In vitro studies demonstrate that dutasteride does not displace
warfarin, diazepam, or phenytoin from plasma protein binding sites, nor do these model compounds displace
Digoxin: In a study of 20 healthy volunteers, Duagen did not alter the steady-state pharmacokinetics of
digoxin when administered concomitantly at a dose of 0.5 mg/day for 3 weeks.
Warfarin: In a study of 23 healthy volunteers, 3 weeks of treatment with Duagen 0.5 mg/day did not alter
the steady-state pharmacokinetics of the S- or R-warfarin isomers or alter the effect of warfarin on prothrombin time
when administered with warfarin.
Alpha adrenergic blocking agents: In a single sequence, cross-over study in healthy volunteers, the
administration of tamsulosin or terazosin in combination with Duagen had no effect on the steady-state
pharmacokinetics of either alpha adrenergic blocker. The percent change in DHT concentrations was similar for Duagen
alone compared with the combination treatment.
Calcium Channel Antagonists: In a population PK analysis, a decrease in clearance of dutasteride was noted
when co-administered with the CYP3A4 inhibitors verapamil (-37%, n = 6) and diltiazem (-44%, n = 5). In contrast, no
decrease in clearance was seen when amlodipine, another calcium channel antagonist that is not a CYP34A inhibitor,
was co-administered with dutasteride (+7%, n = 4).
Cholestyramine: Administration of a single 5-mg dose of Duagen followed 1 hour later by 12 g cholestyramine
did not affect the relative bioavailability of dutasteride in 12 normal volunteers.
Other Concomitant Therapy: Although specific interaction studies were not performed with other compounds,
approximately 90% of the subjects in the 3 Phase 111 pivotal efficacy studies receiving Duagen were taking other
medications concomitantly. No clinically significant adverse interactions could be attributed to the combination of
Duagen and concurrent therapy when Duagen was co-administered with anti-hyperlipidemics, angiotensin-converting
enzyme (ACE) inhibitors, beta-adrenergic blocking agents, calcium channel blockers, corticosteroids, diuretics,
nonsteroidal anti-inflammatory drugs (NSAIDs), phosphodiesterase Type V inhibitors, and quinolone
Drug/Laboratory Test Interactions: Effects on PSA: PSA levels generally decrease in patients treated with
Duagen as the prostate volume decreases. In approximately one-half of the subjects, a 20% decrease in PSA is seen
within the first month of therapy. After 6 months of therapy, PSA levels stabilize to a new baseline that is
approximately 50% of the pre-treatment value. Results of subjects treated with Duagen for up to two years indicate
this 50% reduction in PSA is maintained. Therefore, a new baseline PSA concentration should be established after 3 to
6 months of treatment with Duagen.
Hormone Levels: In healthy volunteers, 52 weeks of treatment with dutasteride 0.5 mg/day (n = 26) resulted
in no clinically significant change compared with placebo (n = 23) in sex hormone binding globulin, estradiol,
luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone. Statistically
significant, baseline-adjusted mean increases compared with placebo were observed for total testosterone at 8 weeks
(97.1 ng/dL, p<0.003) and thyroid-stimulating hormone (TSH) at 52 weeks (0.4 mcIU/mL, p<0.05). The median
percentage changes from baseline within the dutasteride group were 17.9% for testosterone at 8 weeks and 12.4% for
TSH at 52 weeks. In BPH patients treated with dutasteride in a large Phase ID trial, there was a median percent
increase in luteinizing hormone of 12% at 6 months and 19% at 12 months.
Reproductive Function: The effects of dutasteride 0.5 mg/day on reproductive function were evaluated in
normal volunteers aged 18 to 52 (n = 26) throughout 52 weeks of treatment. Semen characteristics were evaluated at 3
timepoints and indicated no clinically meaningful changes in sperm concentration, sperm motility, or sperm
morphology. A 0.8 mL (25%) mean decrease in ejaculate volume with a concomitant reduction in total sperm per
ejaculate was observed at 52 weeks. These parameters remained within the normal range.
CNS Toxicity: In rats and dogs, repeated oral administration of dutasteride resulted in some animals
showing signs of non-specific, reversible, centrally-mediated toxicity, without associated histopathological changes
at exposure 425- and 315-fold the expected clinical exposure (of parent drug), respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: In a 2-year carcinogenicity study in B6C3F1 mice, at doses of 3, 35, 250, and 500 mg/kg/day
for males and 3, 35, and 250 mg/kg/day for females. An increased incidence of benign hepatocellular adenomas was
noted at 250 mg/kg/day (290-fold the expected clinical exposure to a 0.5 mg daily dose) in females only. Two of the
three major human metabolites have been detected in mice. The exposure to these metabolites in mice is either lower
than in humans or is not known.
In a 2-year carcinogenicity study in Han Wistar rats, at doses of 1.5, 7.5, and 53 mg/kg/day for males and 0.8,
6.3, and 15 mg/kg/day for females there was an increase in Leydig cell adenomas in the testes at 53 mg/kg/day
(135-fold the expected clinical exposure). An increased incidence of Leydig cell hyperplasia was present at 7.5
mg/kg/day (52-fold the expected clinical exposure) and 53 mg/kg/day in male rats. A positive correlation between
proliferative changes in the Leydig cells and an increase in circulating luteinizing hormone levels has been
demonstrated with 5ct-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular
axis following 5ct-reductase inhibition. At tumorigenic doses in rats, luteinizing hormone levels in rats were
increased by 167%. In this study, the major human metabolites were tested for carcinogenicity at approximately 1 to 3
times the expected clinical exposure.
Mutagenesis: Avodart was tested for genotoxicity in a bacterial mutagenesis assay (Ames test), a
chromosomal aberration assay in CHO cells, and a micronucleus assay in rats. The results did not indicate any
genotoxic potential of the parent drug. Two major human metabolites were also negative in either the Ames test or an
abbreviated Ames test.
Impairment of Fertility: Treatment of sexually mature male rats with dutasteride at doses of 0.05, 10, 50,
and 500 mg/kg/day (0.1 to 110-fold the expected clinical exposure of parent drug) for up to 31 weeks resulted in
dose- and time-dependent decreases in fertility, reduced cauda epididymal sperm counts (at 50 and 500 mg/kg/day),
reduced weights of the epididymis, prostate and seminal vesicles, and microscopic changes in the male reproductive
organs. The fertility effects were reversed by recovery week 6 at all doses, and sperm counts were normal at the end
of a 14-week recovery period. The 5α-reductase-related changes consisted of cytoplasmic vacuolation of tubular
epithelium in the epididymides and decreased cytoplasmic content of epithelium, consistent with decreased secretory
activity in the prostate and seminal vesicles. The microscopic changes were no longer present at recovery week 14 in
the low-dose group and were partly recovered in the remaining treatment groups. Low levels of dutasteride (0.6 to 17
ng/mL) were detected in the serum of untreated female rats mated to males dosed at 10, 50, or 500 mg/kg/ day for 29
to 30 weeks.
In a fertility study in female rats, oral administration of dutasieride at doses of 0.05, 2.5, 12.5, and 30
mg/kg/day resulted in reduced litter size, increased embryo resorption and feminization of male fetuses (decreased
anogenital distance) at doses of >2.5 mg/kg/ day (2- to 10-fold the clinical exposure of parent drug in men).
Fetal body weights were also reduced at >0.05 mg/kg/day in rats (<0.02-fold the human exposure).
Pregnancy: Pregnancy Category X. Duagen is contraindicated for use in women. Duagen has not been studied in
women because preclinical data suggest that the suppression of circulating levels of dihydrotestosterone may inhibit
the development of the external genital organs in a male fetus carried by a woman exposed to dutasteride.
In an intravenous embryo-fetal development study in the rhesus monkey (12/group), administration of dutasteride at
400, 780, 1325, or 2010 mg/day on gestation days 20 to 100 did not adversely affect development of male external
genitalia. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian
and testis weights were observed in monkeys treated with the highest dose. Based on the highest measured semen
concentration of dutasteride in treated men (14 ng/mL these doses represent 0.8 to 16 times (based on blood levels of
parent drug) the potential maximum exposure of a 50-kg human female to 5 mL semen daily from a dutasteride-treated
man, assuming 100% absorption. Duiasteride is highly boui.d to proteins in human semen (>96%), potentially
reducing the amount of dutasteride available for vaginal absorption.
In an embryo-fetal development study in female rats, oral administration of dutasteride at doses of 0.05, 2.5,
12.5, and 30 mg/kg/day resulted in feminization of male fetuses (decreased anogenital distance) and male offspring
(nipple development, hypospadias, and distended preputial glands) at all doses (0.07- to 111-fold the expected male
clinical exposure). An increase in stillborn pups was observed at 30 mg/kg/day, and reduced fetal body weight was
observed at doses >2.5 mg/kg/day (15- to 111-fold the expected clinical exposure). Increased incidences of
skeletal variations considered to be delays in ossification associated with reduced body weight were observed at
doses of 12.5 and 30 mg/kg/day (56- to 111-fold the expected clinical exposure).
In an oral pre- and post natal development study in rats, dutasteride doses of 0.05, 2.5, 12.5, or 30 mg/kg/day
were administered. Unequivocal evidence of feminization of the genitalia (i.e., decreased anogenital distance,
increased incidence of hypospadias, nipple development) of Fl generation male offspring occurred at doses >2.5
mg/kg/day (14- to 90-fold the expected clinical exposure in men). At a daily dose of 0.05 mg/kg/day (0.05-fold the
expected clinical exposure), evidence of feminization was limited to a small, but statistically significant, decrease
in anogenital distance. Doses of 2.5 to 30 mg/kg/day resulted in prolonged gestation in the parental females and a
decrease in time to vaginal patency for female offspring and decrease prostate and seminal vesicle weights in male
offspring. Effects on newborn startle response were noted at doses greater than or equal to 12.5 mg/kg/day. Increased
stillbirths were noted at 30 mg/kg/day.
Feminization of male fetuses is an expected physiological consequence of inhibition of the conversion of
testosterone to DHT by 5α-reductase inhibitors. These results are similar to observations in male infants with
genetic 5α-reductase deficiency.
In the rabbit, embryo-fetal study doses of 30, 100, and 200 mg/kg (28- to 93-fold the expected clinical exposure
in men) were administered orally on days 7 to 29 of pregnancy to encompass the late period of external genitalia
development, Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male
fetus at all doses. A second embryo-fetal study in rabbits at doses of 0.05, 0.4, 3.0, and 30 mg/kg/day (0.3- to
53-fold the expected clinical exposure) also produced evidence of feminization of the genitalia in male fetuses at
all doses. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.
Nursing Mothers: Duagen is not indicated for use in women. It is not known whether dutasteride is excreted
in human milk.
Pediatric Use: Duagen is not indicated for use in the pediatric population. Safety and effectiveness in the
pediatric population have not been established.
Geriatric Use: Of 2166 male subjects treated with Duagen in three clinical studies, 60% were 65 and over
and 15% were 75 and over. No overall differences in safety or efficacy were observed between these subjects and
younger subjects. Other reported clinical experience has not identified differences in responses between the elderly
and younger patients.