SIDE EFFECTS

Adverse reactions were generally mild and transient. The most common adverse events leading to withdrawal in both treatment groups were associated with the reproductive system.

The data described below reflect exposure to Duagen in 2166 male subjects, including 1772 exposed for one year. Over 4300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of Duagen in three identical, placebo-controlled Phase in treatment studies. The population was aged 47 to 94 years (mean age 66 years) and greater than 90% Caucasian. A total of 267 subjects (6% of each treatment group) were withdrawn from the studies due to adverse experiences, usually associated with the reproductive system. Withdrawals due to adverse events considered by the investigator to have a reasonable possibility of being caused by the study medication occurred in 3% of the subjects receiving Duagen and in 2% of the subjects receiving placebo. Table 1 summarizes clinical adverse reactions that were reported by the investigator as drug-related in at least 1% of subjects receiving Duagen and at a higher incidence than subjects receiving placebo.

Table 1: Drug-related Adverse Events* Reported in >1% Subjects and More Frequently in the

Duagen Group than the Placebo Group Pivotal Studies Pooled

* A drug-related adverse event is one considered by the investigator to have a reasonable possibility of being caused by the study medication. In assessing causality, investigators were asked to select from one of two options: reasonably related to study medication or unrelated to study medication.

Includes breast tenderness and breast enlargement

Long-Term Treatment: The incidence of sexual adverse events considered by the investigator to have a reasonable possibility of being drug-related decreased with duration of treatment; after the first 6 months of treatment the incidence of onset of impotence, decreased libido, ejaculation disorders or gynecomastia was <1% for subjects receiving either Duagen or placebo.

The adverse event profile for 677 subjects who were maintained on Duagen 0.5 mg/day for 24 months in one pivotal study was consistent with that observed after 12 months of treatment in the three studies combined. The incidence of onset of drug-related events was lower during the second year of treatment compared with the first year of treatment, with the exception of gynecomastia (onset in 1 % during first year and 2% during second year).

DRUG INTERACTIONS

Caution should be used in administering dutasteride to patients taking potent, chronic CYP3A4 inhibitors (see PRECAUTIONS: Use with Potent CYP3A4 Inhibitors).

Dutasteride 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 dutasteride.

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 antibiotics.

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 (see PRECAUTIONS: Effects on PSA and Prostate Cancer Detection).

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: Dutasteride 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 (see CONTRAINDICATIONS). 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.