Included as part of the PRECAUTIONS section.

Exposure of Women—Risk to Male Fetus

AVODART Capsules should not be handled by a woman who is pregnant or who may become pregnant. Dutasteride is absorbed through the skin and could result in unintended fetal exposure. If a woman who is pregnant or who may become pregnant comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water [see Use in Specific Populations].

Evaluation for Other Urological Diseases

Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out prostate cancer and other urological diseases prior to treatment with AVODART and periodically thereafter. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5α-reductase inhibitor therapy and should be carefully monitored for obstructive uropathy.

Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

Dutasteride reduces total serum PSA concentration by approximately 40% following 3 months of treatment and by approximately 50% following 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, although it may vary in individual patients. Therefore, for interpretation of serial PSAs in a man taking AVODART, a new baseline PSA concentration should be established after 3 to 6 months of treatment, and this new value should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with AVODART for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men.

The free-to-total PSA ratio (percent free PSA) remains constant at Month 12, even under the influence of AVODART. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving AVODART, no adjustment to its value appears necessary.

Coadministration of tamsulosin with dutasteride resulted in similar changes to total PSA as dutasteride monotherapy.

Blood Donation

Men being treated with dutasteride should not donate blood until at least 6 months have passed following their last dose. The purpose of this deferred period is to prevent administration of dutasteride to a pregnant female transfusion recipient.

Effect on Semen Characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n = 27 dutasteride, n = 23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all semen parameters at all time-points remained within the normal ranges and did not meet predefined criteria for a clinically significant change (30%), 2 subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24-week follow-up. The clinical significance of dutasteride's effect on semen characteristics for an individual patient's fertility is not known.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 2-year carcinogenicity study was conducted 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 3 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 5α-reductase inhibitors and is consistent with an effect on the hypothalamic-pituitary-testicular axis following 5α-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 (absolute) sperm counts but not sperm concentration (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 dutasteride 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).

Use In Specific Populations

Pregnancy

Pregnancy Category X. [see CONTRAINDICATIONS]. AVODART is contraindicated for use in women of childbearing potential and during pregnancy. AVODART is a 5α-reductase inhibitor that prevents conversion of testosterone to dihydrotesterone (DHT), a hormone necessary for normal development of male genitalia. In animal reproduction and developmental toxicity studies, dutasteride inhibited normal development of external genitalia in male fetuses. Therefore, AVODART may cause fetal harm when administered to a pregnant woman. If AVODART is used during pregnancy or if the patient becomes pregnant while taking AVODART, the patient should be apprised of the potential hazard to the fetus.

Abnormalities in the genitalia of male fetuses is an expected physiological consequence of inhibition of the conversion of testosterone to 5α-dihydrotestosterone (DHT) by 5α-reductase inhibitors. These results are similar to observations in male infants with genetic 5α-reductase deficiency. Dutasteride is absorbed through the skin. To avoid potential fetal exposure, women who are pregnant or may become pregnant should not handle AVODART Soft Gelatin Capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water. Dutasteride is secreted into male semen. The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman's dutasteride concentration would be about 0.175 ng/mL. This concentration is more than 100 times less than concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen ( > 96%), which may reduce the amount of dutasteride available for vaginal absorption [see WARNINGS AND PRECAUTIONS].

In an embryo-fetal development study in female rats, oral administration of dutasteride at doses 10 times less than the maximum recommended human dose (MRHD) resulted in abnormalities of male genitalia in the fetus, and nipple development, hypospadias, and distended preputial glands in male offspring. An increase in stillborn pups was observed at 111 times the MRHD, and reduced fetal body weight was observed at doses 15 times the MRHD. Increased incidences of skeletal variations considered to be delays in ossification associated with reduced body weight were observed at doses 56 times the MRHD. Abnormalities of male genitalia were also observed in an oral pre- and post-natal development study in rats and in 2 embryo-fetal studies in rabbits at one-third the MRHD.

In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously to a dutasteride blood level comparable to the dutasteride concentration found in human semen. The development of male external genitalia of monkey offspring was not adversely affected. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed in monkeys [see Nonclinical Toxicology].

Nursing Mothers

AVODART should not be used by nursing women. It is not known whether dutasteride is excreted in human milk.

Pediatric Use

AVODART is contraindicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of 2,167 male subjects treated with AVODART in 3 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 [see CLINICAL PHARMACOLOGY].

Renal Impairment

No dose adjustment is necessary for AVODART in patients with renal impairment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients. However, in a clinical study where 60 subjects received 5 mg (10 times the therapeutic dose) daily for 24 weeks, no additional adverse events were observed compared with those observed at the therapeutic dose of 0.5 mg [see CLINICAL PHARMACOLOGY].

Bookmark this page: