Dutasteride Capsules

Dutasteride is an oral 5-alpha-reductase inhibitor (5-ARI) indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) as monotherapy or in combination with tamsulosin. Dutasteride is used off-label for male-pattern baldness (androgenetic alopecia). According to the American Urological Association (AUA) guidelines, 5-ARIs (e.g., dutasteride, finasteride) may be used to prevent the progression of lower urinary tract symptoms (LUTS) secondary to BPH and to reduce the risk of urinary retention and future prostate-related surgery. The guidelines further state that 5-ARIs are appropriate and effective alternatives for men with LUTS secondary to BPH who have demonstrable prostate enlargement. 5-ARIs should not be used in the absence of prostatic enlargement. Compared to finasteride, the long half-life of dutasteride (5 weeks) may affect the duration of adverse effects upon discontinuation of the drug. In addition, dutasteride must be swallowed whole to avoid irritation of the oropharyngeal mucosa. Results from two large, randomized controlled trials indicate that there may be a decreased risk of low-grade prostate cancer but an increased risk of high-grade prostate cancer in patients receiving 5-ARIs. Therefore, the known treatment benefits of 5-ARIs should be weighed against the potential increased risk of prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with dutasteride and periodically thereafter. Because 5-ARIs inhibit the conversion of testosterone to dihydrotestosterone which can cause abnormalities in the external genitalia of the male fetus, pregnant women or women trying to conceive should not handle 5-ARIs since absorption through the skin may result in fetal exposure and severe adverse outcomes.

Dutasteride inhibits the conversion of testosterone to 5-alpha-dihydrotestosterone (DHT), the primary androgen that stimulates the development of prostate tissue. The intracellular enzyme 5-alpha-reductase is responsible for this conversion and exists in two isoforms, type I and II. The type II isoenzyme is primarily active in reproductive tissues (i.e., prostate, seminal vesicles, epididymides) and is responsible for two-thirds of circulating DHT. The type I isoenzyme is mostly active in the skin and liver. In the treatment of benign prostatic hyperplasia, dutasteride reduces circulating DHT which leads to a reduction in prostate hypertrophy and improvement in urine flow. In male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Dutasteride decreases scalp and serum DHT concentrations, thus interrupting a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Dutasteride does not bind to androgen receptors in humans.

The pharmcodynamic effects of dutasteride include decrease in serum DHT, increase in total testosterone, increase in thyroid-stimulating hormone (TSH), and a decrease in total serum prostate specific antigen (PSA). The reduction of serum DHT is dose dependent and is observed within 1 to 2 weeks. Dutasteride does not appear to alter circulating concentrations of sex hormone binding globulin, estradiol, luteinizing hormone, follicle-stimulating hormone, thyroxine (free T4), and dehydroepiandrosterone in healthy volunteers. Dutasteride does not affect the hypothalamic-pituitary-testicular-axis.

Dutasteride is administered orally. Once in the systemic circulation, approximately 99% is highly bound to albumin and alpha1-acid glycoprotein. It is distributed widely throughout the body. Dutasteride is metabolized in the liver via CYP3A4 enzyme. Two minor mono-hydroxylated metabolites and 3 major metabolites have been identified. Of these metabolites, the 6-beta-hydroxydutasteride is the only one to have activity comparable to that of dutasteride. Dutasteride and its metabolites are primarily excreted in feces (5% unchanged drug and 40% as metabolites). Only trace amounts of unchanged drug were found in urine (< 1%). The dose unaccounted for was approximately 55%. The terminal elimination half-life is about 5 weeks at steady state (average 40 ng/ml). Following daily dosing of 0.5 mg, 65% of steady-state concentration is achieved after 1 month and approximately 90% after 3 months. Steady-state serum and semen concentrations are achieved at about 6 months. On average, semen concentrations are 11.5% of serum concentrations in healthy patients at 1 year. Because of the long half-life, serum concentrations remain detectable (> 0.1 ng/ml) for up to 4 to 6 months after stopping therapy.

Route-Specific Pharmacokinetics

Oral Route: After oral administration, dutasteride is absorbed rapidly with a short distribution phase. It’s bioavailability is estimated to be about 60% (range 40% to 94%). Peak serum concentrations occur within 2—3 hours. When administered with food, the Cmax was reduced by 10—15%, however, this is of no clinical significance.

Special Populations

Hepatic Impairment: The effects of hepatic impairment on dutasteride pharmacokinetics have not been studied. However, dutasteride is extensively metabolized by the liver and systemic exposure could be higher in patients with hepatic impairment. Since the half-life of dutasteride is about 5 weeks at steady state, caution is advised when administering the drug to patients with hepatic impairment.

Renal Impairment: The effects of renal impairment on dutasteride pharmacokinetics have not been studied. Less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, therefore, no dosage adjustment is anticipated for patients with renal impairment.

Pediatrics: Dutasteride pharmacokinetics have not been evaluated in patients under 18 years of age.

Geriatric: Dutasteride dosage adjustments are not necessary in elderly patients. No overall differences in safety or efficacy were observed between elderly and younger patients.

Gender Differences: Dutasteride is not indicated for use in women; its pharmacokinetic parameters have not been studied in women.

Ethnic Differences: The effect of race on dutasteride pharmacokinetics has not been studied.

For the treatment of benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve urinary symptoms, reduce risk of acute urinary retention, and reduce the risk of the need for BPH-related surgery

For the treatment of mild to moderate male pattern hair loss† (i.e., androgenetic alopecia†)

Dutasteride is contraindicated in patients with a known hypersensitivity to dutasteride (e.g., angioedema) or any ingredient in the preparation. Cross-sensitivity with other 5-alpha-reductase inhibitors is possible.

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in urine, so no adjustment in dosage is expected for patients with renal impairment.

No overall differences in safety or effectiveness have been observed between elderly (> 65 years of age) and other younger adult patients.

Dutasteride is contraindicated for use in females of childbearing potential and is therefore contraindicated during pregnancy. Dutasteride and other 5-alpha-reductase inhibitors inhibit the conversion of testosterone to DHT that can cause abnormalities in the external genitalia of the male fetus. Pregnant women or women trying to conceive should not handle dutasteride capsules because dutasteride is absorbed through the skin and may result in fetal exposure. If skin contact with a leaking capsule occurs, the affected area should be washed with soap and water immediately. Dutasteride is secreted into male semen. The amount of dutasteride in semen that is available for vaginal absorption is estimated to be less than 100 times the concentrations that produces abnormalities in the genitalia of male offspring in animal studies. In addition, dutasteride is more than 96% protein bound in human semen, which may decrease vaginal absorption of the drug.

Dutasteride is not indicated for use in women of childbearing potential and thus is contraindicated for use during breast-feeding. It is not known whether dutasteride is excreted in human milk. Therefore, the effects of dutasteride on infants during breast-feeding cannot be determined.

Dutasteride should be used with caution in patients with hepatic disease; data are limited regarding the incidence of adverse effects or drug accumulation in these patients. The drug is extensively metabolized by the liver and has a half-life of about 5 weeks at steady state. The effect of potent hepatic CYP3A4 isoenzyme inhibitors on the metabolism of dutasteride has not been studied. Care should be taken when administering dutasteride to patients taking potent CYP3A4 inhibitors chronically.

Dutasteride is contraindicated for use in neonates, infants, children, and adolescents. Safety and effectiveness have not been established in these age groups.

Dutasteride reduces total serum prostate specific antigen (PSA) by about 40% after 3 months of treatment and 50% after 6, 12, and 24 months of treatment. This decrease is predictable over the entire range of PSA values, but may vary in individual patients. It is recommended that a new baseline PSA concentration be established after 3—6 months for interpretation of serial PSAs in men taking dutasteride. This new baseline PSA should be used to assess potentially cancer-related changes in PSA. To interpret an isolated PSA value in a man treated with dutasteride for 6 months or more, the PSA value should be doubled for comparison with normal values in untreated men. Increased PSA levels from nadir during dutasteride treatment may indicate possible prostate cancer and should be carefully evaluated regardless of whether or not the levels fall within the normal range for men not taking a 5-alpha reductase inhibitor. The free-to-total PSA ratio (percent free PSA) remains constant at month 12, 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. In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the REDUCE trial showed that men receiving dutasteride had a 23% decreased risk of being diagnosed with prostate cancer when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with dutasteride compared to placebo (1% vs. 0.5%, respectively). Therefore, in initiating or continuing treatment with dutasteride, clinicians should weigh the known benefits of treatment against the potential risk and be aware that dutasteride may increase the risk of high-grade prostate cancer. Lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with dutasteride and periodically thereafter. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5-alpha-reductase inhibitor therapy and should be carefully monitored for urinary tract obstruction.

Males treated with dutasteride should not undergo blood donation 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 receiving a blood transfusion. Serum levels of dutasteride are detectable for 4—6 months following termination of therapy.

Dutasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. The clinical significance of dutasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal male 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 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 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.

Dutasteride is contraindicated for use in females of childbearing potential and is therefore contraindicated during pregnancy. Dutasteride and other 5-alpha-reductase inhibitors inhibit the conversion of testosterone to DHT that can cause abnormalities in the external genitalia of the male fetus. Pregnant women or women trying to conceive should not handle dutasteride capsules because dutasteride is absorbed through the skin and may result in fetal exposure. If skin contact with a leaking capsule occurs, the affected area should be washed with soap and water immediately. Dutasteride is secreted into male semen. The amount of dutasteride in semen that is available for vaginal absorption is estimated to be less than 100 times the concentrations that produces abnormalities in the genitalia of male offspring in animal studies. In addition, dutasteride is more than 96% protein bound in human semen, which may decrease vaginal absorption of the drug.

Dutasteride is not indicated for use in women of childbearing potential and thus is contraindicated for use during breast-feeding. It is not known whether dutasteride is excreted in human milk. Therefore, the effects of dutasteride on infants during breastfeeding cannot be determined.

During three identical, placebo-controlled Phase III studies of dutasteride for the treatment of BPH, the most common adverse reactions reported in the first 6 months of the 24-month treatment period, compared to placebo, were ejaculation dysfunction (1.4% vs. 0.5%), impotence (erectile dysfunction) (4.7% vs. 1.7%), libido decrease (3% vs. 1.4%), and mastalgia or breast enlargement (0.5% vs. 0.2%). After 6 months of treatment, the incidence of these adverse reactions decreased to < 1% for those receiving either dutasteride or placebo. Twelve-month and 24-month data were similar. The incidence of onset of drug-related events was lower in the second year of treatment compared with the first year, with the exception of gynecomastia (onset in 1% of subjects during first year and 2% in second year). During 24 months of a multi-center, parallel clinical trial, commonly report adverse effects in the dutasteride plus tamsulosin treatment arm included ejaculation disorders (7.8%), impotence (5.4%), decreased libido (4.5%), breast disorders (e.g., breast enlargement and tenderness) (1.1%), and dizziness (1.1%).1 In the same study, ejaculation disorders were reported in 1% and 2.2% of subjects receiving monotherapy with dutasteride or tamsulosin, respectively. Impotence was reported in 4% and 2.6% of subjects receiving monotherapy with dutasteride or tamsulosin, respectively. Impotence was the most common adverse effect leading to withdrawal from the study (1%). In general, adverse effects were reported more frequently during the first 6 months compared to the remaining 18 months of treatment. No cases of floppy iris syndrome or breast neoplasms were reported.

Reported post-marketing adverse effects of dutasteride include allergic reactions such as rash (unspecified), pruritus, urticaria, localized edema, serious skin reactions (unspecified), and angioedema.

Decreased ejaculate volume (26% decrease), decreased sperm count (23% decrease), and decreased sperm motility (18% decrease) were reported in a study involving normal volunteers, however, there was no clinically relevant changes in sperm concentration or morphology.

By inhibiting the conversion of testosterone to DHT, dutasteride and other 5-alpha-reductase inhibitors have the ability to cause teratogenesis, specifically abnormalities in the external genitalia of the male fetus (e.g., hypospadias).
Dutasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. The clinical significance of dutasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal male 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 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 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.

Increased incidences of heart failure have been observed in dutasteride clinical trials. In one study, composite cardiac failure was observed after 4 years of treatment in patients receiving dutasteride-tamsulosin combination therapy (0.7%), tamsulosin monotherapy (0.6%), and dutasteride monotherapy (0.1%). In a separate placebo-controlled study, the incidence of composite cardiac failure after 4 years of treatment was 0.6% and 0.4% for dutasteride and placebo treated patients, respectively. The clinical significance of these findings is uncertain since most cases of cardiac failure reported during clinical studies have occurred in patients with pre-existing co-morbidities associated with an increased risk of cardiac failure. At this time, no causal relationship between dutasteride, alone or in combination with tamsulosin, and heart failure has been established.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1.Roehrborn C, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Uro
2.FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs) may increase the risk of a more serious form of prostate cancer. Retrieved June 9, 2011. Available on the World Wide Web at: http://www.fda.gov/Drugs/DrugSafety/ucm258314.htm
3.McVary KT, Roehrborn CG, Avins AL, et al. American Urological Association guideline: management of benign prostatic hyperplasia (BPH). Linthicum, MD: American Urological Association; 2010. 1-62; Appendix 278-85. Retrieved on February 4, 2020. Available on the Worldwide Web at https://www.auanet.org/guidelines/benign-prostatic-hyperplasia-(bph)-guideline/benign-prostatic-hyperplasia-(2010-reviewed-and-validity-confirmed-2014).
4.Dimitropoulos K, Gravas S. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia. Ther Adv Urol 2016;8:19-28.
5.Harcha WG, Martinez JB, Tsai TF, et al. A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. J Am Acad Dermatol 2014;70:489-98.
6.Avodart (dutasteride soft gelatin capsules) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2020 Jan.
7.Amory JK, Wang C, Swerdloff RS, et al. The effect of 5-alpha-reductaxe inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men. J Clin Endocrin Metab 2007;92(5):1659-65