Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before benefits occur.[5] It is also used for scalp hair loss in men and as a part of hormone therapy in transgender women.[6][7] It is usually taken by mouth.[8][9][5]
The most commonly reported side effects of dutasteride, although rare, include sexual dysfunction and depression.[8] 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).[10][11] Exposure during pregnancy is specifically contraindicated because antiandrogens such as dutasteride have been shown to interfere with the sexual development of male fetuses.[3][8]
Dutasteride was patented in 1993 by GlaxoSmithKline and was approved for medical use in 2001.[12][8] In the United States and elsewhere, it is available as a generic medication.[5] In 2018, it was the 291st-most commonly prescribed medication in the US with more than 1million prescriptions.[13]
Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea and Japan at a dosage of 0.5 mg per day.[6][17] 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.[6][18][19][20] 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.[21][22]
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][23] 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.[23][24]
Dutasteride is provided in the form of soft, oil-filled gelatincapsules containing 0.5 mg dutasteride each.[25]
Contraindications
Women who are or who may become pregnant should not handle the drug. Dutasteride can cause birth defects in male fetuses, specifically ambiguous genitalia and undermasculinization.[25][26] This is due to its antiandrogenic effects similar to what is seen in 5α-reductase deficiency.[26] For the same reason, women who are currently pregnant should never take dutasteride.[25] People taking dutasteride should not donate blood to prevent birth defects if a pregnant woman receives blood and should also not donate blood for at least 6 months after the cessation of treatment due to the drug's long elimination half-life.[25]
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.[29] No direct mechanistic link between 5α-reductase inhibitors and prostate cancer has been established.[30] 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.[31] 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.[30] 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.[30] Dutasteride is known to reduce the growth and prevalence of benign prostate tumors.[32] A 2018 meta-analysis found no higher risk of breast cancer with 5α-reductase inhibitors.[33]
Sexual and mood side effects, such as erectile dysfunction,[34]loss of libido,[35]depression,[36] and reduced semen volume occur in as many as 4.8% of patients taking 5α-reductase inhibitors including dutasteride.[37][35] In affected men, semen volume is decreased an average of 30%,[38] with a smaller subgroup of patients also experiencing a decrease of sperm motility of 6 to 12%.[39][40] Sperm shape and function are unaffected and the impact on male fertility is unknown.[41] These negative effects reverse by 3–4 months after discontinuation of the drug.[41][40][30]
In a study of 6,729 men with benign prostatic hyperplasia (BPH, a condition where the prostate grows unassociated 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).[34][11] These effects were noted to resolve over time, with many fewer men reporting any adverse effects by the end of the 4-year study.[11][34] The rate of discontinuation of the drug due to adverse effects was less than 5%.[11]
A subset of men affected by sexual and mood side effects report persistent loss of libido,[34] depression,[27] and erectile dysfunction for several years after discontinuing treatment.[35] This remains a highly contested topic in the academic literature due to disagreements about whether the nocebo effect may play a role,[42][43][44] whether self-report questionnaires are reliable for this data,[30] and whether enough objective evidence exists to conclude these effects are persistent after discontinuation of the drug.[30][45][46] The Post-Finasteride Syndrome Foundation (PFSF) was created with a medical advisory board to study the topic (finasteride is a similar 5α-reductase inhibitor)[47] and lawsuits alleging harm from the drug are ongoing.[48] 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.[30][49] Some experts have questioned the basis of the black-box warning, given that it relies on anecdotal patient-reported outcomes rather than prospective trials.[30]
Overdose
No specific antidote for overdose of dutasteride is known, since the drug is extremely safe and well tolerated. Research studies show that even at 100 times the normal dose, dutasteride is not lethal.[50] Treatment of dutasteride overdose should be based on symptoms and should be with supportive therapies.[50] The long elimination half-life of dutasteride should be taken into consideration in the event of an overdose of the medication.[50] Dutasteride has been used in clinical studies at doses of up to 40 mg/day for a week (80 times the therapeutic dosage) and 5 mg/day for 6 months (10 times the therapeutic dosage) with no significant safety concerns or additional side effects.[50]
Current investigations
Dutasteride has been studied in combination with bicalutamide in the treatment of prostate cancer.[51][52][53]
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.[56] It inhibits all three forms of 5α-reductase, and can decrease DHT levels in the blood by up to 98%.[1][57][58] Specifically it is a competitive, mechanism-based (irreversible) inhibitor of all three isoforms of 5α-reductase, types I, II, and III (IC50Tooltip Half-maximal inhibitory concentration values are 3.9 nM for type I and 1.8 nM for type II).[1][57][59][60] This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase but only inhibits the type II and III isoenzymes.[60][61][57] As a result of this difference, dutasteride is able to achieve a reduction in circulating DHT levels of up to 98%, whereas finasteride is able to achieve a reduction of only 65 to 70%.[58][2][56][62] In spite of the differential reduction in circulating DHT levels, the two drugs decrease levels of DHT to a similar extent of approximately 85 to 90% in the prostate gland,[62] where the type II isoform predominates.[59]
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.[63] 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.[63]
The oral bioavailability of dutasteride is about 60%.[1] Consumption with food does not adversely affect its absorption.[1]Peak plasma levels occur 2 to 3 hours after administration.[1] Dutasteride is present in semen at levels up to 3 ng/ml, with no significant effects on DHT levels of sexual partners.[1] The drug is extensively metabolized in the liver by CYP3A4.[1] It has three major metabolites: 6'-hydroxydutasteride, 4'-hydroxydutasteride, and 1,2-dihydrodutasteride. The former two are formed by CYP3A4, while the latter is not.[1] All three metabolites are active; 6'-hydroxydutasteride has similar 5α-reductase inhibitor potency as dutasteride, while the other two are less potent.[1] Dutasteride has an extremely long terminal or elimination half-life of about 4 to 5 weeks.[2][3] Its elimination half-life is increased in the elderly (170 hours for men aged 20–49 years, 300 hours for men aged >70 years).[1] No dosage adjustment is necessary in the elderly nor in patients with renal impairment.[1] Because of its long elimination half-life, dutasteride requires 5 to 6 months to reach steady-state concentrations.[59] 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]
Dutasteride, also known as N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is a syntheticandrostanesteroid and a 4-azasteroid.[66][67] It is an analogue of finasteride in which the tert-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group.[67]
History
Dutasteride was patented in 1996 and was first described in the scientific literature in 1997.[68][69] It was approved by the FDA for the treatment of BPH in November 2001, and was introduced on the United States market the following year under the brand name Avodart.[69] Dutasteride has subsequently been introduced in many other countries, including throughout Europe and South America.[69] The 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.[68]
It was approved for the treatment of scalp hair loss in South Korea in 2009 and in Japan in 2015.[70] It has not been approved for this indication in the United States,[6][17] though it is often used off-label.[21]
Dutasteride is sold primarily under the brand name Avodart, but also in combination with tamsulosin under the brand names Combodart, Duodart, and Jalyn.[71] Dutasteride is also available in India in combination with alfuzosin under the brand names Alfusin-D and Dutalfa.[71]
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.[71] It is available as a generic medication in many countries, including the United States.[68]
^ abcWesp LM, Deutsch MB (March 2017). "Hormonal and Surgical Treatment Options for Transgender Women and Transfeminine Spectrum Persons". The Psychiatric Clinics of North America. 40 (1): 99–111. doi:10.1016/j.psc.2016.10.006. PMID28159148.
^Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, et al. (December 2006). "The importance of dual 5alpha-reductase inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride". Journal of the American Academy of Dermatology. 55 (6): 1014–1023. doi:10.1016/j.jaad.2006.05.007. PMID17110217.
^ abNusbaum AG, Rose PT, Nusbaum BP (August 2013). "Nonsurgical therapy for hair loss". Facial Plastic Surgery Clinics of North America. 21 (3): 335–342. doi:10.1016/j.fsc.2013.04.003. PMID24017975.
^ abcdefghLerner LB, McVary KT, Barry MJ, Bixler BR, Dahm P, Das AK, et al. (October 2021). "Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA GUIDELINE PART I-Initial Work-up and Medical Management". The Journal of Urology. 206 (4): 806–817. doi:10.1097/JU.0000000000002183. PMID34384237. S2CID236999299.
^Walsh PC (April 2010). "Chemoprevention of prostate cancer". The New England Journal of Medicine. 362 (13): 1237–1238. doi:10.1056/NEJMe1001045. PMID20357287.
^ abcTraish AM, Melcangi RC, Bortolato M, Garcia-Segura LM, Zitzmann M (September 2015). "Adverse effects of 5α-reductase inhibitors: What do we know, don't know, and need to know?". Reviews in Endocrine & Metabolic Disorders. 16 (3): 177–198. doi:10.1007/s11154-015-9319-y. PMID26296373. S2CID25002351.
^Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML (March 2011). "Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients". The Journal of Sexual Medicine. 8 (3): 872–884. doi:10.1111/j.1743-6109.2010.02157.x. PMID21176115.
^Amory JK, Wang C, Swerdloff RS, Anawalt BD, Matsumoto AM, Bremner WJ, et al. (May 2007). "The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men". The Journal of Clinical Endocrinology and Metabolism. 92 (5): 1659–1665. doi:10.1210/jc.2006-2203. PMID17299062.
^Coskuner ER, Ozkan B, Culha MG (April 2019). "Sexual Problems of Men With Androgenic Alopecia Treated With 5-Alpha Reductase Inhibitors". Sexual Medicine Reviews. 7 (2): 277–282. doi:10.1016/j.sxmr.2018.07.003. PMID30301703. S2CID52946784.
^Liu L, Zhao S, Li F, Li E, Kang R, Luo L, et al. (September 2016). "Effect of 5α-Reductase Inhibitors on Sexual Function: A Meta-Analysis and Systematic Review of Randomized Controlled Trials". The Journal of Sexual Medicine. 13 (9): 1297–1310. doi:10.1016/j.jsxm.2016.07.006. PMID27475241.
^Chu FM, Sartor O, Gomella L, Rudo T, Somerville MC, Hereghty B, et al. (August 2015). "A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer". European Journal of Cancer. 51 (12): 1555–1569. doi:10.1016/j.ejca.2015.04.028. PMID26048455.
^Gaudet M, Vigneault É, Foster W, Meyer F, Martin AG (January 2016). "Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer". Radiotherapy and Oncology. 118 (1): 141–147. doi:10.1016/j.radonc.2015.11.022. PMID26702991.
^Naguy A, El-Sheshai A, Thiguti SH, Alamiri B (June 2022). "Psychopharmacotherapy of Premenstrual Dysphoric Disorder-New Vistas". Psychopharmacology Bulletin. 52 (3): 81–83. PMC9235312. PMID35815174. Capitalizing on this premise, agents in the pipeline for PMDD including dutasteride, ulipristal acetate, and sepranolone are promising. Dutasteride, FDA-approved for benign prostatic hyperplasia, is a 5-α reductase inhibitor; the latter catalyzes the rate-limiting step in metabolism of progesterone to allopregnanolone...Two double-blind RCTs, cross-over trials, support use of dutasteride where high-dose (2.5 mg/d) outperforms placebo.
^ abcYamana K, Labrie F, Luu-The V (August 2010). "Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride". Hormone Molecular Biology and Clinical Investigation. 2 (3): 293–299. doi:10.1515/hmbci.2010.035. PMID25961201. S2CID28841145.
^ abGisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO (December 1998). "A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride". Clinical Pharmacology and Therapeutics. 64 (6): 636–647. doi:10.1016/S0009-9236(98)90054-6. PMID9871428. S2CID42901328.
^Tvrdeić A, Poljak L (2016). "Neurosteroids, GABAA receptors and neurosteroid based drugs: are we witnessing the dawn of the new psychiatric drugs?". Endocrine Oncology and Metabolism. 2 (1): 60–71. doi:10.21040/eom/2016.2.7 (inactive 1 November 2024).{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^ abcLlewellyn W (2011). Anabolics. Molecular Nutrition Llc. pp. 968–, 971–. ISBN978-0-9828280-1-4. Archived from the original on 12 January 2023. Retrieved 11 December 2017.
^ abcd"Dutasteride". Drugs.com. Archived from the original on 11 December 2017. Retrieved 11 December 2017.
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. doi:10.2174/156802606776743101. PMID16719800.
