dutasteride (Rx)

Adverse reactions decrease with duration of treatment, except for gynecomastia

1-10%

Impotence

Decreased libido

Ejaculation disorder

Breast disorders

<1%

Dizziness

Frequency Not Defined

Cardiac failure

Prostate cancer (high grade)

Postmarketing Reports

Immune system disorders: Hypersensitivity reactions, including rash, pruritus, urticaria, localized edema, serious skin reactions, and angioedema

Neoplasms: Male breast cancer

Psychiatric disorders: Depressed mood

Reproductive system and breast disorders: Testicular pain and testicular swelling

Contraindications

Hypersensitivity

Women

Children

Cautions

Prior to initiating treatment, rule out other urologic conditions

Obstructive uropathy, liver disease

Patient should not donate blood until 6 months after last dose of dutasteride

Dutasteride lowers serum PSA 40-50%; establish new baseline PSA after 3-6 months of treatment

Monitor for cardiac changes or cardiac failure

Capsules should not be handled by women who are pregnant or may be pregnant; drug can be absorbed through skin and could result in unintended fetal exposure and potential risk to a male fetus; if a pregnant woman comes in contact with leaking dutasteride capsules, the contact area should be washed immediately with soap and water; drug can be absorbed through skin based on animal studies

5-ARIs and prostate cancer risk

• June 9, 2011: Recent data from 2 large, randomized, controlled trials observed an increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer) in trial participants taking 5-alpha reductase inhibitors (5-ARIs)
• The 2 trials are the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial
• The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, appropriate evaluation should be performed to rule out other urologic conditions, including prostate cancer, that might mimic benign prostatic hyperplasia

Pregnancy

Contraindicated for use in pregnancy because it may cause harm to male fetus; not indicated for use in women

Drug is a 5 alpha-reductase inhibitor that prevents conversion of testosterone to dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia; abnormalities in genitalia of male fetuses is an expected physiological consequence of inhibition of this conversion; these results are similar to observations in male infants with genetic 5 alpha-reductase deficiency

In animal reproduction studies, drug inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than maximum recommended human dose (MRHD) of 0.5 mg daily, in absence of maternal toxicity; at 15 times the MRHD, prolonged pregnancy, decreased reproductive organ weights, and delayed puberty in male offspring were observed in rats, with no-effect levels less than the MRHD of 0.5 mg daily; increased placental weights in rabbits were also observed, with no-effect levels < MRHD of 0.5 mg daily

Although dutasteride is secreted into human semen, drug concentration in human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies; in monkeys dosed during organogenesis at blood concentrations comparable to or above levels to which a human female partner is estimated to be exposed, male offspring external genitalia was not adversely affected; no feminization occurred in male offspring of untreated female rats mated to treated male rats even though detectable blood levels of dutasteride were observed in the female rats

Reproductive Potential

• The effects of 0.5 mg/day on semen characteristics were evaluated in normal volunteers at 52 weeks, the mean percent reductions 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 placebo group; sperm concentration and sperm morphology were unaffected; after 24 weeks of follow-up, the mean percent change in total sperm count in dutasteride group remained 23% lower than baseline
• While mean values for all semen parameters at all timepoints remained within 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 24-week follow-up; clinical significance of dutasteride’s effect on semen characteristics for an individual patient’s fertility not known

Lactation

Not indicated for use in women; there is no information available on presence of drug in human milk, effects on breastfed child, or on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selective inhibitor of type 1 and type 2 isoforms of 5-alpha-reductase; suppresses serum dihydrotestosterone levels by inhibiting the conversion of testosterone to dihydrotestosterone

Absorption

Bioavailability: 60%

Onset: 1-2 weeks

Peak plasma time: 2-3 hours

Distribution

Protein bound: 99%

Vd: 300-500 L

Metabolism

Hepatic P450 enzyme CYP3A4 & CYP3A5

Metabolites, major: 4'-hydroxydutasteride, 6-hydroxydutasteride (as active as parent), 1,2'-dihydrodutasteride

Elimination

Half-life: 5 weeks (at steady state)

Excretion: Feces (40%), urine (<1%)