Dutasteride

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Dutasteride
Clinical data
Trade namesAvodart, others
Other namesGG-745; GI-198745; GI-198745X; N-[2,5-Bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide
AHFS/Drugs.comMonograph
MedlinePlusa603001
License data
Pregnancy
category
  • Not to be used during pregnancy
Routes of
administration		By mouth
Drug class5α-Reductase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60%[1]
Protein binding99%[1]
MetabolismLiver (CYP3A4)[1]
Metabolites• 4'-Hydroxydutasteride[1]
• 6'-Hydroxydutasteride[1]
• 1,2-Dihydrodutasteride[1]
(All three active)[1]
Elimination half-life4–5 weeks[2][3]
ExcretionFeces: 40% (metabolites)[1]
Urine: 5% (unchanged)[1]
Identifiers
  • (1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-[2,5-bis(trifluoromethyl)phenyl]-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide
JSmol)
  • FC(F)(F)c1cc(c(cc1)C(F)(F)F)NC(=O)[C@@H]3[C@]2(CC[C@H]4[C@H]([C@@H]2CC3)CC[C@H]5NC(=O)\C=C/[C@]45C)C
  • InChI=1S/C27H30F6N2O2/c1-24-11-9-17-15(4-8-21-25(17,2)12-10-22(36)35-21)16(24)6-7-19(24)23(37)34-20-13-14(26(28,29)30)3-5-18(20)27(31,32)33/h3,5,10,12-13,15-17,19,21H,4,6-9,11H2,1-2H3,(H,34,37)(H,35,36)/t15-,16-,17-,19+,21+,24-,25+/m0/s1 checkY
  • Key:JWJOTENAMICLJG-QWBYCMEYSA-N checkY
  (verify)

Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a

transgender women.[5][6] It is usually taken by mouth.[7][8][4]

The most commonly reported side effects of dutasteride, although rare, include sexual dysfunction and depression.[7] In the largest available study of 6,729 men with BPH, 9% experienced erectile dysfunction (compared to 5.7% treated with a placebo), 3.3% experienced decreased sex drive (vs 1.6% of placebo), and 1.9% had enlarged breasts (vs 1% of placebo).[9][10] Exposure during pregnancy is specifically contraindicated because antiandrogens such as dutasteride have been shown to interfere with the sexual development of male fetuses.[3][7]

Dutasteride was patented in 1993 by

generic medication.[4] In 2018, it was the 291st-most commonly prescribed medication in the US with more than 1 million prescriptions.[12]

Medical uses

Benign prostatic hyperplasia and prostate cancer

Dutasteride is used for treating BPH, colloquially known as an "enlarged prostate".

Cochrane review found a 25–26% reduction in the risk of developing prostate cancer with 5α-reductase inhibitor chemoprevention.[15]

Scalp hair loss and excessive hair growth

Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea and Japan at a dosage of 0.5 mg per day.[5][16] Several studies have found it to induce hair regrowth in men more rapidly and to a greater extent than even the highest approved dosage of finasteride.[5][17][18][19] The superior effectiveness of dutasteride relative to finasteride for this indication is because the inhibition of 5α-reductase and consequent reduction of dihydrotestosterone (DHT) production within the hair follicles is more complete with dutasteride. Dutasteride is also used off-label in the treatment of female pattern hair loss.[20][21]

Other 5α-reductase inhibitors such as finasteride (a type 2 inhibitor) have been used off-label to treat excessive hair growth in women with hirsutism.[3][22] Since dutasteride is an inhibitor of both type 1 and 2 5α-reductases, it could theoretically be a more effective therapy for hirsutism. However, dutasteride is not recommended for this indication due to a lack of supportive clinical evidence and a substantial risk of birth defects in female patients who inadvertently become pregnant.[22][23]

Transgender hormone therapy

Dutasteride is sometimes used as a component of

hormone therapy for transgender women in combination with an estrogen and/or another antiandrogen such as spironolactone.[6] It may be useful for treating scalp hair loss or in those who have issues tolerating spironolactone.[6]

Available forms

Dutasteride is provided in the form of soft, oil-filled gelatin capsules containing 0.5 mg dutasteride each.[24]

Contraindications

Women who are or who may become

elimination half-life.[24]

Children and people with known significant

skin reactions, angioedema) to dutasteride should not take it.[24]

Adverse effects

Dutasteride has overall been found to be

gastrointestinal discomfort.[26] Isolated reports of menstrual changes, acne, and dizziness also exist.[26] A small risk of sexual side effects has been documented in men taking the drug during the first few months of therapy.[26][27]

The FDA added a black-box warning to dutasteride in 2011 describing an increased risk of high-grade prostate cancer in those who take the drug.[28] No direct mechanistic link between 5α-reductase inhibitors and prostate cancer has been established.[29] This is not due to a direct link between dutasteride or other 5α-reductase inhibitors and cancer per se, but rather that those who take 5α-reductase inhibitors may have a decrease in prostate-specific antigen (PSA) levels, and therefore increases in PSA (which are an indicator of possible cancer) may be masked in those who take the drug.[30] This is thought to delay cancer diagnosis so that patients taking 5α-reductase inhibitors present with a higher-grade tumor at the time of diagnosis. The American Urological Association advises that increased risk for patients taking these drugs leads to higher prostate cancer-specific and all-cause mortality.[29] The AUA also advises that this affect can be alleviated with more frequent screening and lower PSA cutoffs for diagnostic biopsies in men taking dutasteride or other 5α-reductase inhibitors.[29] Dutasteride is known to reduce the growth and prevalence of benign prostate tumors.[31] A 2018 meta-analysis found no higher risk of breast cancer with 5α-reductase inhibitors.[32]

loss of libido,[34] depression,[35] and reduced semen volume occur in as many as 4.8% of patients taking 5α-reductase inhibitors including dutasteride.[36][34] In affected men, semen volume is decreased an average of 30%,[37] with a smaller subgroup of patients also experiencing a decrease of sperm motility of 6-12%.[38][39] Sperm shape and function are unaffected and the impact on male fertility is unknown.[40] These negative effects reverse by 3–4 months after discontinuation of the drug.[40][39][29]

In a study of 6,729 men with benign prostatic hyperplasia (BPH, a condition where the prostate grows unnassociated with cancer), 9% had erectile dysfunction (compared to 5.7% treated with a placebo), 3.3% experienced decreased sex drive (vs 1.6% of placebo), and 1.9% had enlarged breasts (vs 1% of placebo).[33][10] These effects were noted to resolve over time, with many fewer men reporting any adverse effects by the end of the 4-year study.[10][33] The rate of discontinuation of the drug due to adverse effects was less than 5%.[10]

A subset of men affected by sexual and mood side effects report persistent loss of libido,[33] depression,[26] and erectile dysfunction for several years after discontinuing treatment.[34] This remains a highly contested topic in the academic literature due to disagreements about whether the nocebo effect may play a role,[41][42][43] whether self-report questionnaires are reliable for this data,[29] and whether enough objective evidence exists to conclude these effects are persistent after discontinuation of the drug.[29][44][45] The Post-Finasteride Syndrome Foundation (PFSF) was created with a medical advisory board to study the topic (finasteride is a similar 5α-reductase inhibitor)[46] and lawsuits alleging harm from the drug are ongoing.[47] Concerns from the PFSF and other patient advocates led the FDA to add a black-box warning to Finasteride for possible risks of suicide in June 2022.[29][48] Some experts have questioned the basis of the black-box warning, given that it relies on anecdotal patient-reported outcomes rather than prospective trials.[29]

Overdose

No specific

safety concerns or additional side effects.[49]

Current investigations

Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer.[50][51][52]

Ongoing clinical trials are investigating whether dutasteride may be an effective treatment for premenstrual dysphoric disorder (PMDD), because dutasteride may inhibit the conversion of progesterone to allopregnanolone, a neurosteroid metabolite, which may be responsible for some of the debilitating symptoms of PMDD.[53][54]

Pharmacology

Pharmacodynamics

Dutasteride belongs to a class of drugs called 5α-reductase inhibitors, which block the action of the 5α-reductase enzymes that convert testosterone into DHT.

prostate gland,[61] where the type II isoform predominates.[58]

Since 5α-reductases degrade testosterone to DHT, the inhibition of these enzymes could theoretically cause an increase in testosterone. A 2018 review found that initiation of 5α-reductase inhibitors did not result in a consistent increase in testosterone levels.[62] Among the studies analyzed, there was no statistically significant change in testosterone levels from 5α-reductase inhibitors overall, though men with lower baseline testosterone levels did show an increase.[62]

In addition to inhibition of DHT production, 5α-reductase inhibitors such as dutasteride are also

animal research.[36][63][64] For this reason, decreased neurosteroid production is one hypothesized mechanism for sexual dysfunction and depression associated with 5α-reductase inhibitors such as dutasteride.[36]

Pharmacokinetics

The oral

steady-state concentrations.[58] It also remains in the body for a long time after discontinuation and can be detected up to 4 to 6 months.[1][2] In contrast to dutasteride, finasteride has a short terminal half-life of only 5 to 8 hours.[3][1] Dutasteride is eliminated mainly in the feces (40%) as metabolites.[1] A smaller portion (5%) is eliminated unchanged in the urine.[1]

Chemistry

See also: List of 5α-reductase inhibitors

Dutasteride, also known as N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is a

4-azasteroid.[65][66] It is an analogue of finasteride in which the tert-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group.[66]

History

Dutasteride was

patent protection of dutasteride expired in November 2015, so the drug has since become available in the United States in a variety of low-cost generic formulations.[67]

It was approved for the treatment of scalp hair loss in South Korea in 2009 and in Japan in 2015.

off-label.[20]

Society and culture

Avodart (dutasteride) 500 µg soft capsules

Generic names

Dutasteride is the

generic name of the drug Avodart and its international nonproprietary name, United States Adopted Name, British Approved Name, and Japanese Accepted Name.[70]

Brand names

Dutasteride is sold primarily under the brand name Avodart, but also in combination with tamsulosin under the brand names Combodart, Duodart, and Jalyn.[70] Dutasteride is also available in India in combination with alfuzosin under the brand names Alfusin-D and Dutalfa.[70]

Availability

Dutasteride is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, Europe, Australia, South Africa, Latin America, Asia, and elsewhere.[70] It is available as a generic medication in many countries, including the United States.[67]

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Further reading

  • Frye SV (2006). "Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor". Current Topics in Medicinal Chemistry. 6 (5): 405–421.
    PMID 16719800
    .
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