Dutasteride

Dutasteride capsules is a 5 alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to: (

• improve symptoms,
• reduce the risk of acute urinary retention, and
• reduce the risk of the need for BPH-related surgery.

Dutasteride capsules in combination with the alpha-adrenergic antagonist, tamsulosin, is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. (1.2)

Limitations of Use: Dutasteride capsules is not approved for the prevention of prostate cancer. (1.3)

The capsules should be swallowed whole and not chewed or opened, as contact with the capsule contents may result in irritation of the oropharyngeal mucosa. Dutasteride capsules may be administered with or without food.

0.5-mg, opaque, yellow, oblong shape capsules imprinted with “PC23” in red ink.

Dutasteride is contraindicated for use in pregnancy because it may cause harm to the male fetus [see

Dutasteridem 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 the 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 the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the 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 less than the MRHD of 0.5 mg daily

Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). 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 [see

In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days 6 to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity.

In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50-kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption. The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

In an oral pre-and post-natal development study in rats, feminization of the male genitalia was observed. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with a lack of a no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with a no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, a decrease in time to vaginal patency for female offspring, and a decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]).

• Dutasteride capsules reduce serum prostate-specific antigen (PSA) concentration by approximately 50%. However, any confirmed increase in PSA while on dutasteride capsules may signal the presence of prostate cancer and should be evaluated, even if those values are still within the normal range for untreated men. (
  
  
  5.1 Effects on Prostate-specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection

  In clinical trials, dutasteride reduced serum PSA concentration by approximately 50% within 3 to 6 months of treatment. This decrease was predictable over the entire range of PSA values in subjects with symptomatic BPH, although it may vary in individuals. dutasteride may also cause decreases in serum PSA in the presence of prostate cancer. To interpret serial PSAs in men taking dutasteride, a new PSA baseline should be established at least 3 months after starting treatment and PSA monitored periodically thereafter. Any confirmed increase from the lowest PSA value while on dutasteride may signal the presence of prostate cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a 5 alpha-reductase inhibitor. Noncompliance with dutasteride may also affect PSA test results.

  To interpret an isolated PSA value in a man treated with dutasteride for 3 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, even under the influence of dutasteride. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men receiving dutasteride, no adjustment to its value appears necessary.

  Coadministration of dutasteride and tamsulosin resulted in similar changes to serum PSA as dutasteride monotherapy.
  )
  
• Dutasteride capsules may increase the risk of high-grade prostate cancer. (
  
  
  5.2 Increased Risk of High-grade Prostate Cancer

  In men aged 50 to 75 years with a prior negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL taking dutasteride in the 4-year Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, there was an increased incidence of Gleason score 8-10 prostate cancer compared with men taking placebo (dutasteride 1.0% versus placebo 0.5%) [see Indications and Usage (1.3), Adverse Reactions (6.1)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR^®), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

  5 alpha-reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the effect of 5 alpha-reductase inhibitors to reduce prostate volume or trial-related factors impacted the results of these trials has not been established.
  ,
  
  
  6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trial of another drug and may not reflect the rates observed in practice.

  From clinical trials with Dutasteride as monotherapy or in combination with tamsulosin:

  • The most common adverse reactions reported in subjects receiving dutasteride were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), and ejaculation disorders. The most common adverse reactions reported in subjects receiving combination therapy (dutasteride plus tamsulosin) were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. Ejaculation disorders occurred significantly more in subjects receiving combination therapy (11%) compared with those receiving dutasteride (2%) or tamsulosin (4%) as monotherapy.
  • Trial withdrawal due to adverse reactions occurred in 4% of subjects receiving dutasteride, and 3% of subjects receiving placebo in placebo-controlled trials with dutasteride. The most common adverse reaction leading to trial withdrawal was impotence (1%).
  • In the clinical trial evaluating the combination therapy, trial withdrawal due to adverse reactions occurred in 6% of subjects receiving combination therapy (dutasteride plus tamsulosin) and 4% of subjects receiving dutasteride or tamsulosin as monotherapy. The most common adverse reaction in all treatment arms leading to trial withdrawal was erectile dysfunction (1% to 1.5%).

  Monotherapy

  Over 4,300 male subjects with BPH were randomly assigned to receive placebo or 0.5-mg daily doses of dutasteride in 3 identical 2-year, placebo-controlled, double-blind, Phase 3 treatment trials, each followed by a 2-year open-label extension. During the double-blind treatment period, 2,167 male subjects were exposed to dutasteride, including 1,772 exposed for 1 year and 1,510 exposed for 2 years. When including the open-label extensions, 1,009 male subjects were exposed to dutasteride for 3 years and 812 were exposed for 4 years. The population was aged 47 to 94 years (mean age: 66 years) and greater than 90% were white. Table 1 summarizes clinical adverse reactions reported in at least 1% of subjects receiving dutasteride and at a higher incidence than subjects receiving placebo.

  Table 1. Adverse Reactions Reported in ≥1% of Subjects over a 24-Month Period and More Frequently in the Group Receiving Dutasteride Capsules than the Placebo Group (Randomized, Double-blind, Placebo-Controlled Trials Pooled) by Time of Onset
  Adverse Reaction	Adverse Reaction Time of Onset
  	Months 0-6	Months 7-12	Months 13-18	Months 19-24
  Dutasteride capsules (n)	(n = 2,167)	(n = 1,901)	(n = 1,725)	(n = 1,605)
  Placebo (n)	(n = 2,158)	(n = 1,922)	(n = 1,714)	(n = 1,555)
  Impotencea
  Dutasteride capsules	4.7%	1.4%	1.0%	0.8%
  Placebo	1.7%	1.5%	0.5%	0.9%
  Decreased libidoa
  Dutasteride capsules	3.0%	0.7%	0.3%	0.3%
  Placebo	1.4%	0.6%	0.2%	0.1%
  Ejaculation disordersa
  Dutasteride capsules	1.4%	0.5%	0.5%	0.1%
  Placebo	0.5%	0.3%	0.1%	0.0%
  Breast disordersb
  Dutasteride capsules	0.5%	0.8%	1.1%	0.6%
  Placebo	0.2%	0.3%	0.3%	0.1%
  aThese sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. bIncludes breast tenderness and breast enlargement.

  Long-Term Treatment (Up to 4 Years)

  High-grade Prostate Cancer:

  The REDUCE trial was a randomized, double-blind, placebo-controlled trial that enrolled 8,231 men aged 50 to 75 years with a serum PSA of 2.5 ng/mL to 10 ng/mL and a negative prostate biopsy within the previous 6 months. Subjects were randomized to receive placebo (n = 4,126) or 0.5-mg daily doses of dutasteride capsules (n = 4,105) for up to 4 years. The mean age was 63 years and 91% were white. Subjects underwent protocol-mandated scheduled prostate biopsies at 2 and 4 years of treatment or had “for-cause biopsies” at non-scheduled times if clinically indicated. There was a higher incidence of Gleason score 8-10 prostate cancer in men receiving dutasteride capsules (1.0%) compared with men on placebo (0.5%) [see Indications and Usage (1.3), Warnings and Precautions (5.2)]. In a 7-year placebo-controlled clinical trial with another 5 alpha-reductase inhibitor (finasteride 5 mg, PROSCAR^®), similar results for Gleason score 8-10 prostate cancer were observed (finasteride 1.8% versus placebo 1.1%).

  No clinical benefit has been demonstrated in patients with prostate cancer treated with dutasteride capsules.

  Reproductive and Breast Disorders

  In the 3 pivotal placebo-controlled BPH trials with dutasteride capsules, each 4 years in duration, there was no evidence of increased sexual adverse reactions (impotence, decreased libido, and ejaculation disorder) or breast disorders with increased duration of treatment. Among these 3 trials, there was 1 case of breast cancer in the dutasteride group and 1 case in the placebo group. No cases of breast cancer were reported in any treatment group in the 4-year CombAT trial or the 4-year REDUCE trial.

  The relationship between long-term use of dutasteride and male breast neoplasia is currently unknown.

  Combination with Alpha-blocker Therapy (CombAT)

  Over 4,800 male subjects with BPH were randomly assigned to receive 0.5-mg dutasteride capsules, 0.4-mg tamsulosin, or combination therapy (0.5-mg dutasteride capsules plus 0.4-mg tamsulosin) administered once daily in a 4-year double-blind trial. Overall, 1,623 subjects received monotherapy with dutasteride capsules; 1,611 subjects received monotherapy with tamsulosin; and 1,610 subjects received combination therapy. The population was aged 49 to 88 years (mean age: 66 years) and 88% were white. Table 2 summarizes adverse reactions reported in at least 1% of subjects in the combination group and at a higher incidence than subjects receiving monotherapy with dutasteride capsules or tamsulosin.

  Table 2. Adverse Reactions Reported over a 48-Month Period in ≥1% of Subjects and More Frequently in the Coadministration Therapy Group than the Groups Receiving Monotherapy with Dustateride Capsules or Tamsulosin (CombAT) by Time of Onset
  Adverse Reaction	Adverse Reaction Time of Onset
  	Year 1
  	Months 0-6	Months 7-12	Year 2	Years 3	Year 4
  Combinationa	(n = 1,610)	(n = 1,527)	(n = 1,428)	(n = 1,283)	(n = 1,200)
  Dutasteride capsules	(n = 1,623)	(n = 1,548)	(n = 1,464)	(n = 1,325)	(n = 1,200)
  Tamsulosin	(n = 1,611)	(n = 1,545)	(n = 1,468)	(n = 1,281)	(n = 1,112)
  Ejaculation disordersb,c
  Combination	7.8%	1.6%	1.0%	0.5%	<0.1%
  Dutasteride capsules	1.0%	0.5%	0.5%	0.2%	0.3%
  Tamsulosin	2.2%	0.5%	0.5%	0.2%	0.3%
  Impotencec,d
  Combination	5.4%	1.1%	1.8%	0.9%	0.4%
  Dutasteride capsules	4.0%	1.1%	1.6%	0.6%	0.3%
  Tamsulosin	2.6%	0.8%	1.0%	0.6%	1.1%
  Decreased libidoc,e
  Combination	4.5%	0.9%	0.8%	0.2%	0.0%
  Dutasteride capsules	3.1%	0.7%	1.0%	0.2%	0.0%
  Tamsulosin	2.0%	0.6%	0.7%	0.2%	<0.1%
  Breast disordersf
  Combination	1.1%	1.1%	0.8%	0.9%	0.6%
  Dutasteride capsules	0.9%	0.9%	1.2%	0.5%	0.7%
  Tamsulosin	0.4%	0.4%	0.4%	0.2%	0.0%
  Dizziness
  Combination	1.1%	0.4%	0.1%	<0.1%	0.2%
  Dutasteride capsules	0.5%	0.3%	0.1%	<0.1%	<0.1%
  Tamsulosin	0.9%	0.5%	0.4%	<0.1%	0.0%
  aCombination = Dutasteride capsules 0.5 mg once daily plus tamsulosin 0.4 mg once daily. bIncludes anorgasmia, retrograde ejaculation, semen volume decreased, orgasmic sensation decreased, orgasm abnormal, ejaculation delayed, ejaculation disorder, ejaculation failure, and premature ejaculation. cThese sexual adverse reactions are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after treatment discontinuation. The role of dutasteride in this persistence is unknown. dIncludes erectile dysfunction and disturbance in sexual arousal. eIncludes libido decreased, libido disorder, loss of libido, sexual dysfunction, and male sexual dysfunction. fIncludes breast enlargement, gynecomastia, breast swelling, breast pain, breast tenderness, nipple pain, and nipple swelling.

  Cardiac Failure:

  In CombAT, after 4 years of treatment, the incidence of the composite term cardiac failure in the combination therapy group (12/1,610; 0.7%) was higher than in either monotherapy group: dutasteride capsules, 2/1,623 (0.1%) and tamsulosin, 9/1,611 (0.6%).Composite cardiac failure was also examined in a separate 4-year placebo-controlled trial evaluating dutasteride capsules in men at risk for development of prostate cancer. The incidence of cardiac failure in subjects taking dutasteride capsules was 0.6% (26/4,105) compared with 0.4% (15/4,126) in subjects on placebo. A majority of subjects with cardiac failure in both trials had co-morbidities associated with an increased risk of cardiac failure. Therefore, the clinical significance of the numerical imbalances in cardiac failure is unknown. No causal relationship between dutasteride capsules, alone or in combination with tamsulosin, and cardiac failure has been established. No imbalance was observed in the incidence of overall cardiovascular adverse events in either trial
  )
  
• Prior to initiating treatment with dutasteride capsules, consideration should be given to other urological conditions that may cause similar symptoms. (
  
  
  5.3 Evaluation for Other Urological Diseases

  Prior to initiating treatment with dutasteride, consideration should be given to other urological conditions that may cause similar symptoms. In addition, BPH and prostate cancer may coexist.
  )
  
• Women who are pregnant or may be pregnant should not handle dutasteride capsules due to potential risk to a male fetus. (
  
  
  5.4 Transdermal Exposure of Dutasteride in Pregnant Women—Risk to Male Fetus

  Dutasteride capsules should not be handled by women who are pregnant or may be pregnant. Dutasteride can be absorbed through the 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 [see Use in Specific Populations (8.1)]. Dutasteride can be absorbed through the skin based on animal studies [see Nonclinical Toxicology (13.2)].
  ,
  
  
  8.1 Pregnancy

  Risk Summary

  Dutasteride is contraindicated for use in pregnancy because it may cause harm to the male fetus [see Contraindications (4)]. Dutasteride is not indicated for use in women.

  Dutasteridem 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 the 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 the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  In animal reproduction studies, dutasteride inhibited normal development of external genitalia in male offspring when given to rats or rabbits during organogenesis at less than the maximum recommended human dose (MRHD) of 0.5 mg daily, in the 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 less than the MRHD of 0.5 mg daily

  (see Data).

  Although dutasteride is secreted into human semen, the drug concentration in the human female partner is approximately 100 times less than concentrations producing abnormalities of male genitalia in animal studies (see Data). 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 [see Nonclinical Toxicology (13.1)].

  Data

  Human Data:

  The highest measured semen concentration of dutasteride in treated men was 14 ng/mL. Although dutasteride is detected in semen, assuming exposure of a 50-kg woman to 5 mL of semen and 100% absorption, the woman’s expected dutasteride blood concentration through semen would be about 0.0175 ng/mL. This concentration is approximately 100 times less than blood concentrations producing abnormalities of male genitalia in animal studies. Dutasteride is highly protein bound in human semen (greater than 96%), which may reduce the amount of dutasteride available for vaginal absorption.

  Animal Data:

  In an embryo-fetal development study in rats, oral administration of dutasteride at 10 times less than the MRHD of 0.5 mg daily (based on average blood levels in men) resulted in feminization of male genitalia in the fetus (decreased anogenital distance at 0.05 mg/kg/day, with a lack of a no-effect level) in the absence of maternal toxicity. In addition, nipple development, hypospadias, and distended preputial glands occurred in fetuses of dams treated at doses of 2.5 mg/kg/day or greater (approximately 15 times the MRHD). Reduced fetal body weight and associated delayed ossification in the presence of maternal toxicity (decreased body weight gain) were observed at maternal exposure approximately 15 times the MRHD (dose of 2.5 mg/kg/day or greater). An increase in stillborn pups was observed in dams treated at 30 mg/kg/day (approximately 111 times the MRHD), with a no-effect level of 12.5 mg/kg/day.

  In a rabbit embryo-fetal development study, doses 28 times the MRHD (doses of 30 mg/kg/day or greater), based on average blood levels in men, were administered orally on Gestation Days 7 to 29 (during organogenesis and the late period of external genitalia development). Histological evaluation of the genital papilla of fetuses revealed evidence of feminization of the male fetus as well as fused skull bones and increased placental weights at all doses in the absence of maternal toxicity. A second embryo-fetal development study in rabbits dosed throughout pregnancy (organogenesis and later period of external genitalia development [Gestation Days 6 to 29]) at 0.3 times the MRHD (doses of 0.05 mg/kg/day or greater, with no no-effect level), also produced evidence of feminization of the genitalia in male fetuses and increased placental weights at all doses in the absence of maternal toxicity.

  In an embryo-fetal development study, pregnant rhesus monkeys were exposed intravenously during organogenesis (Gestation Days 20 to 100) to a dutasteride blood level comparable to or above the estimated dutasteride exposure of a human female partner. Dutasteride was administered on Gestation Days 20 to 100 (during organogenesis) at doses of 400, 780, 1,325, or 2,010 ng/day (12 monkeys/group). No feminization of male external genitalia of monkey offspring was observed. Reduction of fetal adrenal weights, reduction in fetal prostate weights, and increases in fetal ovarian and testis weights were observed at the highest dose tested. Based on the highest measured semen concentration of dutasteride in treated men (14 ng/mL), these doses in the monkey represent up to 16 times the potential maximum exposure of a 50-kg human female to 5 mL of semen daily from a dutasteride-treated male, assuming 100% absorption. The dose levels (on a ng/kg basis) administered to monkeys in this study are 32 to 186 times the nominal (ng/kg) dose to which a female would potentially be exposed via the semen. It is not known whether rabbits or rhesus monkeys produce any of the major human metabolites.

  In an oral pre-and post-natal development study in rats, feminization of the male genitalia was observed. Decreased anogenital distance was observed at 0.05 times the MRHD and greater (0.05 mg/kg/day and greater), with a lack of a no-effect level, based on average blood levels in men as an estimation of AUC. Hypospadias and nipple development were observed at 2.5 mg/kg/day or greater (14 times the MRHD or greater, with a no-effect level at 0.05 mg/kg/day). Doses of 2.5 mg/kg/day and greater also resulted in prolonged gestation in the parental females, an increase in time to balano-preputial separation in male offspring, a decrease in time to vaginal patency for female offspring, and a decrease in prostate and seminal vesicle weights in male offspring. Increased stillbirths and decreased neonatal viability in offspring were noted at 30 mg/kg/day (102 times the MRHD in the presence of maternal toxicity [decreased body weights]).
  )
  
• Patients should not donate blood until 6 months after their last dose of dutasteride capsules. (5.5)