View source for Flutamide

{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 461102563
| IUPAC_name = 2-Methyl-''N''-[4-nitro-3-(trifluoromethyl)phenyl]propanamide
| image = Flutamide.svg
| width = 225px
| image2 = Flutamide molecule ball.png
| width2 = 225px

<!--Clinical data-->
| tradename = Eulexin, others
| Drugs.com = {{drugs.com|monograph|flutamide}}
| MedlinePlus = a697045
| pregnancy_category = D
| legal_status = Rx-only
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Nonsteroidal antiandrogen]]

<!--Pharmacokinetic data-->
| bioavailability = Complete (>90%)<ref name="Flutamide-Label">{{Cite web|url=https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d037fb0c-881f-43d2-8693-aa1342d0130a&type=display|title = Flutamide Capsules USP}}</ref>
| protein_bound = Flutamide: 94–96%<ref name="Flutamide-Label" /><br />Hydroxyflutamide: 92–94%<ref name="Flutamide-Label" />
| metabolism = [[Liver]] ([[CYP1A2]])<ref name="Lehne2013" /><ref name="ChabnerLongo2010" />
| metabolites = [[Hydroxyflutamide]]<ref name="pmid10495361" /><ref name="ChabnerLongo2010" />
| elimination_half-life = Flutamide: 5–6 hours<ref name="Gulley2011"/><ref name="ChabnerLongo2010" /><br />Hydroxyflutamide: 8–10 hours<ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1373|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=1373–}}</ref><ref name="DenisGriffiths1999" /><ref name="ChabnerLongo2010" /><ref name="Flutamide-Label" />
| excretion = [[Urine]] (mainly)<ref name="Flutamide-Label" /><br />[[Feces]] (4.2%)<ref name="Flutamide-Label" />

<!--Identifiers-->
| IUPHAR_ligand = 6943
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 13311-84-7
| ATC_prefix = L02
| ATC_suffix = BB01
| ATC_supplemental =
| PubChem = 3397
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00499
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3280
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 76W6J0943E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00586
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5132
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 806
| synonyms = Niftolide; SCH-13521; 4'-Nitro-3'-trifluoromethyl-isobutyranilide

<!--Chemical data-->
| C=11 | H=11 | F=3 | N=2 | O=3
| SMILES = CC(C)C(=O)NC1=CC(=C(C=C1)[N+](=O)[O-])C(F)(F)F
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C11H11F3N2O3/c1-6(2)10(17)15-7-3-4-9(16(18)19)8(5-7)11(12,13)14/h3-6H,1-2H3,(H,15,17)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MKXKFYHWDHIYRV-UHFFFAOYSA-N

<!--Physical data-->
| melting_point = 111.5
| melting_high = 112.5
}}
<!-- Definition and medical uses -->
'''Flutamide''', sold under the brand name '''Eulexin''' among others, is a [[nonsteroidal antiandrogen]] (NSAA) which is used primarily to treat [[prostate cancer]].<ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA466|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=466–}}</ref><ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA573|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=573–}}</ref> It is also used in the treatment of [[androgen-dependent condition]]s like [[acne]], [[hirsutism|excessive hair growth]], and [[hyperandrogenism|high androgen level]]s in women.<ref>{{cite web |url=http://www.nhs.uk/Conditions/Polycystic-ovarian-syndrome/Pages/Treatment.aspx |title=Polycystic Ovary Syndrome - Treatment - NHS Choices |publisher=Nhs.uk |date=2011-10-17 |access-date=2013-01-04 |archive-date=2011-11-06 |archive-url=https://web.archive.org/web/20111106005039/http://www.nhs.uk/Conditions/Polycystic-ovarian-syndrome/Pages/Treatment.aspx |url-status=dead }}</ref> It is taken [[oral administration|by mouth]], usually three times per day.<ref name="MungadiMbibu2013">{{cite book | vauthors = Mungadi IA, Shittu OB, Abdulwahab-Ahmed A | chapter = Prostate Cancer | veditors = Mungadi IA, Mbibu HN, Eltahawy E, Abdulwahab-Ahmed A |title=Manual of Medical Treatment in Urology| chapter-url = https://books.google.com/books?id=i9-LAgAAQBAJ&pg=PA120|date=30 November 2013|publisher=JP Medical Ltd|isbn=978-93-5090-844-0|pages=120–}}</ref>

<!-- Side effects -->
[[Side effect]]s in men include [[breast tenderness]] and [[gynecomastia|enlargement]], [[feminization (biology)|feminization]], [[sexual dysfunction]], and [[hot flash]]es. Conversely, the medication has fewer side effects and is better-tolerated in women with the most common side effect being dry skin. [[Diarrhea]] and [[elevated liver enzymes]] can occur in both sexes. Rarely, flutamide can cause [[hepatotoxicity|liver damage]], [[interstitial pneumonitis|lung disease]], [[photosensitivity|sensitivity to light]], [[methemoglobinemia|elevated methemoglobin]], [[sulfhemoglobinemia|elevated sulfhemoglobin]], and [[neutropenia|deficient neutrophil]]s.<ref name="pmid28379593" /><ref name="pmid12353966" /><ref name="Aronson2010" /><ref name="pmid10388026">{{cite journal | vauthors = McLeod DG | title = Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer | journal = The Oncologist | volume = 2 | issue = 1 | pages = 18–27 | year = 1997 | pmid = 10388026 | doi = 10.1634/theoncologist.2-1-18 | doi-access = free }}</ref> Numerous cases of [[liver failure]] and death have been reported, which has limited the use of flutamide.<ref name="pmid28379593" />

<!-- Mechanism of action -->
Flutamide acts as a [[binding selectivity|selective]] [[receptor antagonist|antagonist]] of the [[androgen receptor]] (AR), competing with [[androgen]]s like [[testosterone]] and [[dihydrotestosterone]] (DHT) for binding to ARs in tissues like the [[prostate gland]]. By doing so, it prevents their effects and stops them from stimulating prostate cancer cells to grow. Flutamide is a [[prodrug]] to a more active form. Flutamide and its active form stay in the body for a relatively short time, which makes it necessary to take flutamide multiple times per day.{{citation needed|date=May 2021}}

<!-- History, society, and culture -->
Flutamide was first described in 1967 and was first introduced for medical use in 1983.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=515 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA515 |language=en}}</ref> It became available in the United States in 1989. The medication has largely been replaced by newer and improved NSAAs, namely [[bicalutamide]] and [[enzalutamide]], due to their better [[efficacy]], [[drug tolerability|tolerability]], [[drug safety|safety]], and dosing frequency (once per day), and is now relatively little-used.<ref name="Gulley2011">{{cite book| vauthors = Gulley JL |title=Prostate Cancer|url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81|year=2011|publisher=Demos Medical Publishing|isbn=978-1-935281-91-7|pages=81–}}</ref><ref name="Moser2008">{{cite book| vauthors = Wirth MP, Hakenberg OW, Froehner M | chapter = Adjuvant Hormonal Treatment - The Bicalutamide Early Prostate Cancer Program | veditors = Moser L |title=Controversies in the Treatment of Prostate Cancer| chapter-url=https://books.google.com/books?id=4J4OCRyHWRYC&pg=PA41|date=1 January 2008|publisher=Karger Medical and Scientific Publishers|isbn=978-3-8055-8524-8|pages=41–42|quote=Latest studies suggest that [flutamide] also reduces adrenal and ovarian androgen synthesis [58,59]. [...] No alteration in the hormone levels has been observed in patients treated with flutamide for 6 or 12 months [61,62]. However in other studies flutamide decreased circulating concentrations of DHEAS as well as androstenedione, total testosterone and 3a-androstanediol glucuronide, in young women with PCOS [41,59]. These effects may be due to inhibition of adrenal 17-20 lyase [17,63]. Although there was no effect on gonadotropin response to GnRH, basal levels of FSH showed a rise associated with a small fall of LH [64].}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>
{{TOC limit|3}}

==Medical uses==

===Prostate cancer===
GnRH is released by the [[hypothalamus]] in a [[pulsatile secretion|pulsatile]] fashion; this causes the [[anterior pituitary|anterior]] [[pituitary gland]] to release [[luteinizing hormone]] (LH) and [[follicle-stimulating hormone]] (FSH). LH stimulates the [[testis|testes]] to produce testosterone, which is metabolized to DHT by the enzyme [[5α-reductase]].{{citation needed|date=May 2021}}

DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as [[leuprorelin]] or [[cetrorelix]]. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other NSAAs continue in this use. In contrast to GnRH agonists, GnRH antagonists don't cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.{{Citation needed|date=July 2015}}

There have been studies to investigate the benefit of adding an antiandrogen to surgical [[orchiectomy]] or its continued use with a GnRH analogue ([[combined androgen blockade]] (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.{{Citation needed|date=July 2015}}

Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with [[Antiandrogen|antiandrogens]] exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.<ref name=Harrison>Scher, Howard I. (2005). "Hyperplastic and Malignant Diseases of the Prostate". In Dennis L. Kasper, Anthony S. Fauci, Dan L. Longo, Eugene Braunwald, Stephen L. Hauser, & J. Larry Jameson (Eds.), ''[[Harrison's Principles of Internal Medicine]]'' (16th edition), pp. 548–9. New York: McGraw-Hill.</ref>

Flutamide has been found to be similarly effective in the treatment of prostate cancer to [[bicalutamide]], although indications of inferior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels with bicalutamide, were observed.<ref name="HelsenVan den Broeck2014">{{cite journal | vauthors = Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, Claessens F | title = Androgen receptor antagonists for prostate cancer therapy | journal = Endocrine-Related Cancer | volume = 21 | issue = 4 | pages = T105–T118 | date = August 2014 | pmid = 24639562 | doi = 10.1530/ERC-13-0545 | doi-access = free }}</ref><ref name="pmid26024831" /> The medication, at a dosage of 750&nbsp;mg/day (250&nbsp;mg three times daily), has also been found to be equivalent in effectiveness to 250&nbsp;mg/day oral [[cyproterone acetate]] as a [[monotherapy]] in the treatment of prostate cancer in a large-scale clinical trial of 310&nbsp;patients, though its side effect and toxicity profiles (including gynecomastia, diarrhea, nausea, loss of appetite, and liver disturbances) were regarded as considerably worse than those of cyproterone acetate.<ref name="MydloGodec2015">{{cite book | vauthors = Slovin SF | chapter = Sipuleucel-T - A Model for Immunotherapy Trial Development | veditors = Mydlo JH, Godec CJ |title=Prostate Cancer: Science and Clinical Practice| chapter-url = https://books.google.com/books?id=292cBAAAQBAJ&pg=PA530|date=29 September 2015|publisher=Elsevier Science|isbn=978-0-12-800592-7|pages=516–521, 534–540}}</ref>

A dosage of 750&nbsp;mg/day flutamide (250&nbsp;mg/three times a day) is roughly equivalent in terms of effectiveness to 50&nbsp;mg/day bicalutamide when used as the antiandrogen component in [[combined androgen blockade]] in the treatment of [[advanced prostate cancer]].<ref name="pmid14748655">{{cite journal | vauthors = Fradet Y | title = Bicalutamide (Casodex) in the treatment of prostate cancer | journal = Expert Review of Anticancer Therapy | volume = 4 | issue = 1 | pages = 37–48 | date = February 2004 | pmid = 14748655 | doi = 10.1586/14737140.4.1.37 | s2cid = 34153031 }}</ref>

Flutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.<ref name="pmid16986003">{{cite journal | vauthors = Thompson IM | title = Flare Associated with LHRH-Agonist Therapy | journal = Reviews in Urology | volume = 3 | issue = Suppl 3 | pages = S10–S14 | date = 2001 | pmid = 16986003 | pmc = 1476081 }}</ref><ref name="pmid8481213">{{cite journal | vauthors = Scaletscky R, Smith JA | title = Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it? | journal = Drug Safety | volume = 8 | issue = 4 | pages = 265–270 | date = April 1993 | pmid = 8481213 | doi = 10.2165/00002018-199308040-00001 | s2cid = 36964191 }}</ref><ref name="pmid11706524">{{cite journal | vauthors = Noguchi K, Uemura H, Harada M, Miura T, Moriyama M, Fukuoka H, Kitami K, Hosaka M | title = Inhibition of PSA flare in prostate cancer patients by administration of flutamide for 2 weeks before initiation of treatment with slow-releasing LH-RH agonist | journal = International Journal of Clinical Oncology | volume = 6 | issue = 1 | pages = 29–33 | date = February 2001 | pmid = 11706524 | doi = 10.1007/PL00012076 | s2cid = 23123697 }}</ref><ref name="pmid2144596">{{cite journal | vauthors = Schulze H, Senge T | title = Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate | journal = The Journal of Urology | volume = 144 | issue = 4 | pages = 934–941 | date = October 1990 | pmid = 2144596 | doi = 10.1016/S0022-5347(17)39625-8 }}</ref><ref name="pmid11316974">{{cite journal | vauthors = Tsushima T, Nasu Y, Saika T, Maki Y, Noda M, Suyama B, Yamato T, Kumon H | title = Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist | journal = Urologia Internationalis | volume = 66 | issue = 3 | pages = 135–139 | date = 2001 | pmid = 11316974 | doi = 10.1159/000056592 | s2cid = 38018788 }}</ref><ref name="pmid3309363">{{cite journal | vauthors = Labrie F, Dupont A, Belanger A, Lachance R | title = Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist | journal = The Journal of Urology | volume = 138 | issue = 4 | pages = 804–806 | date = October 1987 | pmid = 3309363 | doi = 10.1016/S0022-5347(17)43380-5 }}</ref><ref name="pmid2503724">{{cite journal | vauthors = Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, Blumenstein BA, Davis MA, Goodman PJ | title = A controlled trial of leuprolide with and without flutamide in prostatic carcinoma | journal = The New England Journal of Medicine | volume = 321 | issue = 7 | pages = 419–424 | date = August 1989 | pmid = 2503724 | doi = 10.1056/NEJM198908173210702 }}</ref><ref name="pmid8252509">{{cite journal | vauthors = Ferrari P, Castagnetti G, Ferrari G, Pollastri CA, Tavoni F, Dotti A | title = Combination treatment in M1 prostate cancer | journal = Cancer | volume = 72 | issue = 12 Suppl | pages = 3880–3885 | date = December 1993 | pmid = 8252509 | doi = 10.1002/1097-0142(19931215)72:12+<3880::AID-CNCR2820721724>3.0.CO;2-4 | s2cid = 21911154 | doi-access = free }}</ref>{{excessive citations inline|date=May 2021}}

The combination of flutamide with an [[estrogen (medication)|estrogen]] such as [[ethinylestradiol sulfonate]] has been used as a form of combined androgen blockade and as an alternative to the combination of flutamide with surgical or medical castration.<ref name="HinkelbeinMiller2013">{{cite book| vauthors = Schnorr D | chapter = Palliativtherapie des hämatogen metastasierten Prostatakarzinoms | veditors = Hinkelbein W, Miller K, Wiegel T |title=Prostatakarzinom — urologische und strahlentherapeutische Aspekte: urologische und strahlentherapeutische Aspekte|trans-title=Prostate carcinoma — urological and radiotherapeutic aspects: urological and radiotherapeutic aspects| chapter-url = https://books.google.com/books?id=wdTLBgAAQBAJ&pg=PA99 |date=7 March 2013|publisher=Springer-Verlag|isbn=978-3-642-60064-7|pages=99–}}</ref>

===Skin and hair conditions===
Flutamide has been researched and used extensively in the treatment of [[androgen-dependent condition|androgen-dependent]] [[skin condition|skin]] and [[hair condition]]s in women including [[acne]], [[seborrhea]], [[hirsutism]], and [[androgenetic alopecia|scalp hair loss]], as well as in [[hyperandrogenism]] (e.g., in [[polycystic ovary syndrome]] or [[congenital adrenal hyperplasia]]), and is effective in improving the symptoms of these conditions. The dosages used are lower than those used in the treatment of prostate cancer. Although flutamide continues to be used for these indications, its use in recent years has been limited due to the risk of potentially fatal hepatotoxicity, and it is no longer recommended as a first- or second-line therapy.<ref name="pmid24889738" /><ref name="Ostrzenski2002">{{cite book| vauthors = Ostrzenski A | chapter = Hyperandrogenism |title=Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy| chapter-url=https://books.google.com/books?id=TYlZsGdwqrQC&pg=PA86|year=2002|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2761-7|pages=86–}}</ref><ref name="Blume-PeytaviWhiting2008">{{cite book| vauthors = Olsen EA | chapter = Female Pattern Hair Loss | veditors = Blume-Peytavi U, Whiting DA, Trüeb RM |title=Hair Growth and Disorders| chapter-url = https://books.google.com/books?id=pHrX2-huQCoC&pg=PA181|date=26 June 2008|publisher=Springer Science & Business Media|isbn=978-3-540-46911-7|pages=181–}}</ref><ref name="Becker2001">{{cite book| vauthors = Matsumoto AM | chapter = Clinical Use and Abuse of Androgens and Antiandrogens | veditors = Becker KL |title=Principles and Practice of Endocrinology and Metabolism| chapter-url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1196, 1208}}</ref> The related NSAA bicalutamide has also been found to be effective in the treatment of hirsutism in women and appears to have comparable effectiveness to that of flutamide,<ref name="Müderri̇sÖner2009" /><ref name="pmid24455796">{{cite journal | vauthors = Erem C | title = Update on idiopathic hirsutism: diagnosis and treatment | journal = Acta Clinica Belgica | volume = 68 | issue = 4 | pages = 268–274 | year = 2013 | pmid = 24455796 | doi = 10.2143/ACB.3267 | s2cid = 39120534 }}</ref><ref name="pmid11915584">{{cite journal | vauthors = Müderris II, Bayram F, Ozçelik B, Güven M | title = New alternative treatment in hirsutism: bicalutamide 25 mg/day | journal = Gynecological Endocrinology | volume = 16 | issue = 1 | pages = 63–66 | date = February 2002 | pmid = 11915584 | doi = 10.1080/gye.16.1.63.66 | s2cid = 6942048 }}</ref> but has a far lower and only small risk of hepatotoxicity in comparison.<ref name="KolvenbagFurr2009">{{cite book | vauthors = Kolvenbag GJ, Furr BJ | chapter = Nonsteroidal Antiandrogens | pages = 347–368 | doi = 10.1007/978-1-59259-152-7_16 | title = Hormone Therapy in Breast and Prostate Cancer | veditors = Jordan VC, Furr VJ | year = 2009 | publisher = Humana Press | isbn = 978-1-60761-471-5}}</ref><ref name="DansetteSnyder2012">{{cite book | vauthors = Dansette P, Snyder RR, Monks TJ, Jollow DJ, Sipes IG, Greim H, Gibson GG, Delaforge M | title = Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases|url=https://books.google.com/books?id=xRflBwAAQBAJ&pg=PA37|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4615-0667-6|pages=37–}}</ref><ref name="RamonDenis2007">{{cite book | vauthors = Ramon J, Denis LJ | title = Prostate Cancer|url=https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA256|date=5 June 2007|publisher=Springer Science & Business Media|isbn=978-3-540-40901-4|pages=256–}}</ref>

Aside from its risk of liver toxicity and besides other nonsteroidal antiandrogens, it has been said that flutamide is likely the best typically used antiandrogen medication for the treatment of androgen-dependent symptoms in women.<ref name="Azziz2007" /> This is related to its high effectiveness and minimal side effects.<ref name="Azziz2007" />

====Acne and seborrhea====
Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies.<ref name="pmid25845307">{{cite journal | vauthors = Husein-ElAhmed H | title = Management of acne vulgaris with hormonal therapies in adult female patients | journal = Dermatologic Therapy | volume = 28 | issue = 3 | pages = 166–172 | year = 2015 | pmid = 25845307 | doi = 10.1111/dth.12231 | s2cid = 2628354 | doi-access = free }}</ref><ref name="pmid25627824">{{cite journal | vauthors = Bettoli V, Zauli S, Virgili A | title = Is hormonal treatment still an option in acne today? | journal = The British Journal of Dermatology | volume = 172 | issue = Suppl 1 | pages = 37–46 | date = July 2015 | pmid = 25627824 | doi = 10.1111/bjd.13681 | s2cid = 35615492 | doi-access =  }}</ref> In a long-term study of 230&nbsp;women with acne, 211 of whom also had seborrhea, very-low-dose flutamide alone or in combination with an [[oral contraceptive]] caused a marked decrease in acne and seborrhea after 6&nbsp;months of treatment, with maximal effect by 1&nbsp;year of treatment and benefits maintained in the years thereafter.<ref name="pmid25845307" /><ref name="pmid21117864">{{cite journal | vauthors = Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S | title = Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period | journal = Gynecological Endocrinology | volume = 27 | issue = 10 | pages = 823–829 | date = October 2011 | pmid = 21117864 | doi = 10.3109/09513590.2010.526664 | s2cid = 20250916 }}</ref> In the study, 97% of the women reported satisfaction with the control of their acne with flutamide.<ref name="pmid28492054">{{cite journal | vauthors = Trivedi MK, Shinkai K, Murase JE | title = A Review of hormone-based therapies to treat adult acne vulgaris in women | journal = International Journal of Women's Dermatology | volume = 3 | issue = 1 | pages = 44–52 | date = March 2017 | pmid = 28492054 | pmc = 5419026 | doi = 10.1016/j.ijwd.2017.02.018 }}</ref> In another study, flutamide decreased acne and seborrhea scores by 80% in only 3&nbsp;months.<ref name="ShelleyShelley2001">{{cite book| vauthors= Shelley WB, Shelley ED |title=Advanced Dermatologic Therapy II|url=https://books.google.com/books?id=vuJsAAAAMAAJ|year=2001|publisher=W. B. Saunders|isbn=978-0-7216-8258-7}}</ref><ref name="pmid10495361">{{cite journal | vauthors = Diamanti-Kandarakis E | title = Current aspects of antiandrogen therapy in women | journal = Current Pharmaceutical Design | volume = 5 | issue = 9 | pages = 707–723 | date = September 1999 | pmid = 10495361 | doi = 10.2174/1381612805666230111201150 }}</ref> In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications.<ref name="ShelleyShelley2001" /><ref name="BalenFranks2010" /> Flutamide has, in general, been found to reduce symptoms of acne by as much as 90% even at low doses, with several studies showing complete acne clearance.<ref name="pmid25627824" /><ref name="pmid28562419">{{cite journal | vauthors = Nguyen HL, Tollefson MM | title = Endocrine disorders and hormonal therapy for adolescent acne | journal = Current Opinion in Pediatrics | volume = 29 | issue = 4 | pages = 455–465 | date = August 2017 | pmid = 28562419 | doi = 10.1097/MOP.0000000000000515 | s2cid = 4640778 }}</ref><ref name="pmid10495361" />

====Excessive hair growth====
[[File:Facial hirsutism in a woman with hyperandrogenism treated with flutamide and a contraceptive.png|thumb|right|185px|Improvement of facial hirsutism in a woman with hyperandrogenism before (top) and after (bottom) treatment with 125&nbsp;mg/day flutamide and an oral contraceptive for 6&nbsp;months (click image to view a larger version).<ref name="Blume-PeytaviWhiting2008"/>{{rp|368}}]]

Flutamide has been found to be effective in the treatment of hirsutism (excessive [[body hair|body]]/[[facial hair]] growth) in numerous studies.<ref name="pmid24889738">{{cite journal | vauthors = Somani N, Turvy D | title = Hirsutism: an evidence-based treatment update | journal = American Journal of Clinical Dermatology | volume = 15 | issue = 3 | pages = 247–266 | date = July 2014 | pmid = 24889738 | doi = 10.1007/s40257-014-0078-4 | s2cid = 45234892 }}</ref><ref name="pmid26138647">{{cite journal | vauthors = Schmidt TH, Shinkai K | title = Evidence-based approach to cutaneous hyperandrogenism in women | journal = Journal of the American Academy of Dermatology | volume = 73 | issue = 4 | pages = 672–690 | date = October 2015 | pmid = 26138647 | doi = 10.1016/j.jaad.2015.05.026 }}</ref><ref name="Müderri̇sÖner2009">Müderri̇s, İ. İ., & Öner, G. (2009). Flutamide and Bicalutamide Treatment in Hirsutism. Turkiye Klinikleri Journal of Endocrinology-Special Topics, 2(2), 110. http://www.turkiyeklinikleri.com/article/en-hirsutizm-tedavisinde-flutamid-ve-bikalutamid-kullanimi-55753.html</ref> It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate.<ref name="pmid26138647" /><ref name="pmid24889738" /> The medication shows equivalent or superior effectiveness to other antiandrogens including spironolactone, cyproterone acetate, and finasteride in the treatment of hirsutism, although its relatively high risk of hepatotoxicity makes it unfavorable compared to these other options.<ref name="pmid10495361" /><ref name="pmid24889738"/> It has been used to treat hirsutism at dosages ranging from 62.5&nbsp;mg/day to 750&nbsp;mg/day.<ref name="Azziz2007">{{cite book | vauthors = Moghetti P | chapter = Ovarian Suppression and Treatment of Hirsutism | veditors = Azziz R |title=Androgen Excess Disorders in Women| chapter-url=https://books.google.com/books?id=Ch-BsGAOtucC&pg=PA384|date=8 November 2007|publisher=Springer Science & Business Media|isbn=978-1-59745-179-6|pages=384–}}</ref> A study found that multiple dosages of flutamide significantly reduced hirsutism in women with polycystic ovary syndrome and that there were no significant differences in the effectiveness for dosages of 125&nbsp;mg/day, 250&nbsp;mg/day, and 375&nbsp;mg/day.<ref name="pmid24889738" /><ref name="BalenFranks2010">{{cite book| vauthors = Layton AM | chapter = Treatment of hyperandrogenism in polycystic ovary syndrome | veditors = Balen A, Franks S, Homburg R, Kehoe S |title=Current Management of Polycystic Ovary Syndrome|chapter-url=https://books.google.com/books?id=0rtUBAAAQBAJ&pg=PA132|date=October 2010|publisher=Cambridge University Press|isbn=978-1-906985-41-7|pages=132–}}</ref><ref name="pmid17566093">{{cite journal | vauthors = Calaf J, López E, Millet A, Alcañiz J, Fortuny A, Vidal O, Callejo J, Escobar-Jiménez F, Torres E, Espinós JJ | title = Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 9 | pages = 3446–3452 | date = September 2007 | pmid = 17566093 | doi = 10.1210/jc.2006-2798 | doi-access = free | hdl = 10668/684 | hdl-access = free }}</ref> In addition, a study found that combination of 125&nbsp;mg/day flutamide with finasteride was no more effective than 125&nbsp;mg/day flutamide alone in the treatment of hirsutism.<ref name="YasaDural2016">{{cite journal | vauthors = Yasa C, Dural Ö, Bastu E, Uğurlucan FG |title=Hirsutism, Acne, and Hair Loss: Management of Hyperandrogenic Cutaneous Manifestations of Polycystic Ovary Syndrome|journal=Gynecology Obstetrics & Reproductive Medicine|year=2016|volume=23|issue=2|pages=110–119|issn=1300-4751|doi=10.21613/GORM.2016.613|doi-access=free}}</ref> These findings support the use of flutamide at lower doses for hirsutism without loss of effectiveness, which may help to lower the risk of hepatotoxicity.<ref name="pmid24889738" /> However, the risk has been found to remain even at very low doses.<ref name="pmid28379593">{{cite journal | vauthors = Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A | title = Flutamide-induced hepatotoxicity: ethical and scientific issues | journal = European Review for Medical and Pharmacological Sciences | volume = 21 | issue = 1 Suppl | pages = 69–77 | date = March 2017 | pmid = 28379593 }}</ref>

====Scalp hair loss====
Flutamide has been found to be effective in the treatment of female [[pattern hair loss]] in a number of studies.<ref name="pmid27554257">{{cite journal | vauthors = Kelly Y, Blanco A, Tosti A | title = Androgenetic Alopecia: An Update of Treatment Options | journal = Drugs | volume = 76 | issue = 14 | pages = 1349–1364 | date = September 2016 | pmid = 27554257 | doi = 10.1007/s40265-016-0629-5 | s2cid = 35875856 }}</ref><ref name="pmid28492055">{{cite journal | vauthors = Brough KR, Torgerson RR | title = Hormonal therapy in female pattern hair loss | journal = International Journal of Women's Dermatology | volume = 3 | issue = 1 | pages = 53–57 | date = March 2017 | pmid = 28492055 | pmc = 5419033 | doi = 10.1016/j.ijwd.2017.01.001 }}</ref><ref name="pmid23039053">{{cite journal | vauthors = van Zuuren EJ, Fedorowicz Z, Carter B | title = Evidence-based treatments for female pattern hair loss: a summary of a Cochrane systematic review | journal = The British Journal of Dermatology | volume = 167 | issue = 5 | pages = 995–1010 | date = November 2012 | pmid = 23039053 | doi = 10.1111/j.1365-2133.2012.11166.x | s2cid = 205263486 }}</ref><ref name="pmid24039457">{{cite journal | vauthors = Levy LL, Emer JJ | title = Female pattern alopecia: current perspectives | journal = International Journal of Women's Health | volume = 5 | pages = 541–556 | date = August 2013 | pmid = 24039457 | pmc = 3769411 | doi = 10.2147/IJWH.S49337 | doi-access = free }}</ref> In one study of 101&nbsp;pre- and postmenopausal women, flutamide alone or in combination with an oral contraceptive produced a marked decrease in hair loss scores after 1&nbsp;year of treatment, with maximum effect after 2&nbsp;years of treatment and benefits maintained for another 2&nbsp;years.<ref name="pmid24039457" /><ref name="pmid21487083">{{cite journal | vauthors = Paradisi R, Porcu E, Fabbri R, Seracchioli R, Battaglia C, Venturoli S | title = Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss | journal = The Annals of Pharmacotherapy | volume = 45 | issue = 4 | pages = 469–475 | date = April 2011 | pmid = 21487083 | doi = 10.1345/aph.1P600 | s2cid = 38456195 }}</ref> In a small study of flutamide with an oral contraceptive, the medication caused an increase in cosmetically acceptance hair density in 6 of 7&nbsp;women with diffuse scalp hair loss.<ref name="Diamanti-Kandarakis_1999">{{cite journal | vauthors = Diamanti-Kandarakis E | title = Current aspects of antiandrogen therapy in women | journal = Current Pharmaceutical Design | volume = 5 | issue = 9 | pages = 707–723 | date = September 1999 | pmid = 10495361 | doi = 10.2174/1381612805666230111201150 | quote = Several trials demonstrated complete clearing of acne with flutamide [62,77]. Flutamide used in combination with an [oral contraceptive], at a dose of 500mg/d, flutamide caused a dramatic decrease (80%) in total acne, seborrhea and hair loss score after only 3 months of therapy [53]. When used as a monotherapy in lean and obese PCOS, it significantly improves the signs of hyperandrogenism, hirsutism and particularly acne [48]. [...] flutamide 500mg/d combined with an [oral contraceptive] caused an increase in cosmetically acceptable hair density, in sex of seven women suffering from diffuse androgenetic alopecia [53]. }}</ref> In a comparative study, flutamide significantly improved scalp hair growth (21% reduction in [[Ludwig scale|Ludwig]] scores) in hyperandrogenic women after 1&nbsp;year of treatment, whereas [[cyproterone acetate]] and [[finasteride]] were ineffective.<ref name="pmid24039457" /><ref name="pmid12524069">{{cite journal | vauthors = Carmina E, Lobo RA | title = Treatment of hyperandrogenic alopecia in women | journal = Fertility and Sterility | volume = 79 | issue = 1 | pages = 91–95 | date = January 2003 | pmid = 12524069 | doi = 10.1016/s0015-0282(02)04551-x | doi-access = free }}</ref>

===Other uses===
Flutamide has been used in [[case report]]s to decrease the frequency of [[spontaneous orgasm]]s, for instance in men with [[post-orgasmic illness syndrome]].<ref name="pmid11995603">{{cite journal | vauthors = Waldinger MD, Schweitzer DH | title = Postorgasmic illness syndrome: two cases | journal = Journal of Sex & Marital Therapy | volume = 28 | issue = 3 | pages = 251–255 | date = 2002 | pmid = 11995603 | doi = 10.1080/009262302760328280 | s2cid = 27162173 }}</ref><ref name="pmid28454896">{{cite journal | vauthors = Reinert AE, Simon JA | title = "Did You Climax or Are You Just Laughing at Me?" Rare Phenomena Associated With Orgasm | journal = Sexual Medicine Reviews | volume = 5 | issue = 3 | pages = 275–281 | date = July 2017 | pmid = 28454896 | doi = 10.1016/j.sxmr.2017.03.004 }}</ref><ref name="pmid32033716">{{cite journal | vauthors = Paulos MR, Avelliino GJ | title = Post-orgasmic illness syndrome: history and current perspectives | journal = Fertility and Sterility | volume = 113 | issue = 1 | pages = 13–15 | date = January 2020 | pmid = 32033716 | doi = 10.1016/j.fertnstert.2019.11.021 | s2cid = 211064753 | doi-access = free }}</ref>

===Available forms===
Flutamide is available in the form of 125&nbsp;mg [[oral administration|oral]] [[capsule (pharmacy)|capsule]]s and 250&nbsp;mg oral [[tablet (pharmacy)|tablet]]s.<ref name="Meyers2018">{{cite book| vauthors = Brueggemeier RW | chapter = Analogs and Antagonists of Male Sex Hormones | veditors = Meyers RA |title=Translational Medicine: Molecular Pharmacology and Drug Discovery| chapter-url = https://books.google.com/books?id=kuhPDwAAQBAJ&pg=PA46|date=2 March 2018|publisher=Wiley|isbn=978-3-527-68719-0 | doi = 10.1002/3527600906.mcb.200500066.pub2 |pages=46–| doi-broken-date = 1 November 2024 }}</ref><ref name="MicromedexPharmacopeia2002">{{cite book|author1=Thomson Micromedex|author2=United States Pharmacopeia|title=Consumer Drug Reference 2003|url=https://books.google.com/books?id=x4jRPi_qOvwC|date=November 2002|publisher=Consumer Reports Books|isbn=978-0-89043-971-5}}</ref>

==Side effects==
The [[side effect]]s of flutamide are [[sex]]-dependent. In men, a variety of side effects related to [[androgen deprivation]] may occur, the most common being [[gynecomastia]] and [[breast tenderness]].<ref name="FaridaFaiza2013">{{cite journal | vauthors = Chentli F, Belhimer F | title = Severe gynecomastia due to anti androgens intake: A case report and literature review | journal = Indian Journal of Endocrinology and Metabolism | volume = 17 | issue = 4 | pages = 730–732 | date = July 2013 | pmid = 23961495 | pmc = 3743379 | doi = 10.4103/2230-8210.113770 | doi-access = free }}</ref> Others include [[hot flash]]es, [[muscle atrophy|decreased muscle mass]], [[osteoporosis|decreased bone mass]] and an associated increased risk of [[bone fracture|fracture]]s, [[depression (mood)|depression]],<ref name="MydloGodec2015" /> and [[sexual dysfunction]] including reduced [[libido]] and [[erectile dysfunction]].<ref name="Lehne2013">{{cite book| vauthors = Lehne RA | chapter = Chapter 103: Anticancer Drugs II: Hormonal Agents, Targeted Drugs, and Other Noncytotoxic Anticancer Drugs |title=Pharmacology for Nursing Care| chapter-url = https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA1297|year=2013|publisher=Elsevier Health Sciences|isbn=978-1-4377-3582-6|pages=1297–}}</ref> In women, flutamide is, generally, relatively well tolerated, and does not interfere with [[ovulation]].<ref name="Azziz2007"/> The only common side effect of flutamide in women is [[dry skin]] (75%), which can be attributed to a reduction of androgen-mediated [[sebum production]].<ref name="Azziz2007" /><ref name="pmid10495361" /> General side effects that may occur in either sex include [[dizziness]], [[lack of appetite]], [[gastrointestinal]] side effects such as [[nausea]], [[vomiting]], and [[diarrhea]], a [[Urine#Color|greenish-bluish discoloration]] of the [[urine]],<ref name="pmid10495361" /> and [[hepatic]] changes.<ref name="MydloGodec2015" /><ref name="Lehne2013" /><ref name="RobertsSnyder1996">{{cite book| vauthors = Roberts J, Snyder DL, Friedman E | chapter = Pharmacology of Cancer Chemotherapeutic and Immunotherapeutic Agents |title=Handbook of Pharmacology on Aging| chapter-url=https://books.google.com/books?id=xVIJOFh5mfMC&pg=PA334|date=14 August 1996|publisher=CRC Press|isbn=978-0-8493-8306-9|pages=334–}}</ref> Because flutamide is a pure antiandrogen, unlike [[steroidal antiandrogen]]s like [[cyproterone acetate]] and [[megestrol acetate]] (which additionally possess [[progestogen]]ic activity), it does not appear to have a risk of [[cardiovascular]] side effects (e.g., [[thromboembolism]]) or [[Water retention (medicine)|fluid retention]].<ref name="Pratt1994" /><ref name="MydloGodec2015" /><ref name="DenisGriffiths1999">{{cite book | vauthors = Piotrowski Z, Greenberg RE | chapter = Antiandrogen Monotherapy in the Treatment of Prostate Cancer | veditors = Denis LJ, Griffiths K, Kaisary AV, Murphy GP |title=Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment| chapter-url = https://books.google.com/books?id=GreZlojD-tYC&pg=PA280|date=1 March 1999|publisher=CRC Press|isbn=978-1-85317-422-3|pages=279–280}}</ref>

{{Side effects of combined androgen blockade with flutamide}}

{{Side effects of combined androgen blockade with nonsteroidal antiandrogens}}

===Gynecomastia===
Flutamide, as a monotherapy, causes [[gynecomastia]] in 30 to 79% of men, and also produces [[breast tenderness]].<ref name="pmid16321765">{{cite journal | vauthors = Di Lorenzo G, Autorino R, Perdonà S, De Placido S | title = Management of gynaecomastia in patients with prostate cancer: a systematic review | journal = The Lancet. Oncology | volume = 6 | issue = 12 | pages = 972–979 | date = December 2005 | pmid = 16321765 | doi = 10.1016/S1470-2045(05)70464-2 }}</ref><ref name="FaridaFaiza2013" /> However, more than 90% of cases of gynecomastia with NSAAs including flutamide are mild to moderate.<ref name="Gillatt2006">{{cite journal | vauthors = Gillatt D | title = Antiandrogen treatments in locally advanced prostate cancer: are they all the same? | journal = Journal of Cancer Research and Clinical Oncology | volume = 132 | issue = S1 | pages = S17–S26 | date = August 2006 | pmid = 16845534 | doi = 10.1007/s00432-006-0133-5 | quote = Unlike CPA, non-steroidal antiandrogens appear to be better tolerated than castration, allowing patients to maintain sexual activity, physical ability, and bone mineral density, but these agents have a higher incidence of gynecomastia and breast pain (mild to moderate in > 90% of cases). | s2cid = 23888640 }}</ref><ref name="GoldspielKohler1990">{{cite journal | vauthors = Goldspiel BR, Kohler DR | title = Flutamide: an antiandrogen for advanced prostate cancer | journal = DICP | volume = 24 | issue = 6 | pages = 616–623 | date = June 1990 | pmid = 2193461 | doi = 10.1177/106002809002400612 | quote = [...] They [in patients treated with flutamide] observed mild gynecomastia in 30 patients (57 percent), moderate gynecomastia in 19 (36 percent), and massive gynecomastia in 4 patients (8 percent). Complaints of nipple and areolar tenderness were noted in 50/53 patients (94 per- cent)." Airhart et al. reported that 42 percent of patients receiving flutamide 750 mg/d or 1500 mg/d developed gynecomastia within 12 weeks of starting treatment with an apparent direct correlation between the dose of flutamide administered and the severity of gynecomastia.25 In another study, two of five evaluable patients developed moderate gynecomastia with mild tenderness at four and eight weeks after starting flutamide 750 mg/d. Patients with preexisting gynecomastia as a result of previous endocrine therapy with estrogens sustained no worsening of their gynecomastia and may have improved symptomatically." Keating et al." | s2cid = 26125621 }}</ref><ref name="Pratt1994">{{cite book| vauthors = Pratt WB | chapter = Drugs Affecting Endocrine Function |title=The Anticancer Drugs| chapter-url =https://books.google.com/books?id=nPR1L4K5HuEC&pg=PA220|year=1994|publisher=Oxford University Press|isbn=978-0-19-506739-2|pages=219–220}}</ref> [[Tamoxifen]], a [[selective estrogen receptor modulator]] (SERM) with predominantly [[antiestrogen]]ic actions, can counteract flutamide-induced gynecomastia and breast pain in men.{{Citation needed|date=December 2017}}

===Diarrhea===
Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs.<ref name="KolvenbagFurr2009" /> In a comparative trial of [[combined androgen blockade]] for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide.<ref name="KolvenbagFurr2009" /> Moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so.<ref name="KolvenbagFurr2009" /> In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for flutamide, 2 to 5% for bicalutamide, and 2 to 4% for [[nilutamide]].<ref name="KolvenbagFurr2009" /> In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications.<ref name="KolvenbagFurr2009" />

===Rare reactions===

====Liver toxicity====
Although rare, flutamide has been associated with severe [[hepatotoxicity]] and death.<ref name="Kaplowitz2002">{{cite book| vauthors = DeLeve LD | chapter = Cancer Chemotherapy | veditors = Kaplowitz N |title=Drug-Induced Liver Disease| chapter-url = https://books.google.com/books?id=d8cgCAAAQBAJ&pg=PA618|date=16 October 2002|publisher=CRC Press|isbn=978-0-203-90912-6|pages=618–619}}</ref><ref name="Aronson2010">{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Drugs in Cancer and Immunology|url=https://books.google.com/books?id=OSj_yr7nU6MC&pg=PT318|date=19 April 2010|publisher=Elsevier|isbn=978-0-08-093288-0|pages=318–319}}</ref><ref name="TholeManso2004">{{cite journal | vauthors = Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A | title = Hepatotoxicity induced by antiandrogens: a review of the literature | journal = Urologia Internationalis | volume = 73 | issue = 4 | pages = 289–295 | year = 2004 | pmid = 15604569 | doi = 10.1159/000081585 | s2cid = 24799765 }}</ref> By 1996, 46 cases of severe [[cholestasis|cholestatic]] [[hepatitis]] had been reported, with 20 fatalities.<ref name="Kaplowitz2002" /> There have been continued case reports since, including [[liver transplant]]s and death.<ref name="pmid21301018" /><ref name="pmid11685939">{{cite journal | vauthors = García Cortés M, Andrade RJ, Lucena MI, Sánchez Martínez H, Fernández MC, Ferrer T, Martín-Vivaldi R, Peláez G, Suárez F, Romero-Gómez M, Montero JL, Fraga E, Camargo R, Alcántara R, Pizarro MA, García-Ruiz E, Rosemary-Gómez M | title = Flutamide-induced hepatotoxicity: report of a case series | journal = Revista Espanola de Enfermedades Digestivas | volume = 93 | issue = 7 | pages = 423–432 | date = July 2001 | pmid = 11685939 }}</ref> A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths.<ref name="ĐajićBokan2020">{{cite journal| vauthors = Malešević N, Bokan G, Đajić V |title=Flutamide Induced Liver Injury in Female Patients|journal=European Journal of Medical and Health Sciences|volume=2|issue=5|year=2020|issn=2593-8339|doi=10.24018/ejmed.2020.2.5.476|doi-access=free}}</ref>

Based on the number of prescriptions written and the number of cases reported in the [[MedWatch]] database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000).<ref name="Kaplowitz2002" /><ref name="pmid7490837">{{cite journal | vauthors = Wysowski DK, Fourcroy JL | title = Flutamide hepatotoxicity | journal = The Journal of Urology | volume = 155 | issue = 1 | pages = 209–212 | date = January 1996 | pmid = 7490837 | doi = 10.1016/S0022-5347(01)66596-0 }}</ref> However, other research has suggested that the true incidence of significant hepatotoxicity with flutamide may be much greater, as high as 0.18 to 10%.<ref name="pmid29958919">{{cite journal | vauthors = Hejmej A, Bilinska B | title = The effects of flutamide on cell-cell junctions in the testis, epididymis, and prostate | journal = Reproductive Toxicology | volume = 81 | pages = 1–16 | date = October 2018 | pmid = 29958919 | doi = 10.1016/j.reprotox.2018.06.014 | bibcode = 2018RepTx..81....1H | quote = Despite its efficacy, some patients develop severe hepatotoxicity (cholestatic hepatitis) in the first 3–4 months of therapy (reported incidence of less than 1% to about 10%) [60,61] | s2cid = 49613890 }}</ref><ref name="ChitturiFarrell2013">{{cite book | vauthors = Chitturi S, Farrell GC |title=Drug-Induced Liver Disease |chapter=Adverse Effects of Hormones and Hormone Antagonists on the Liver|year=2013|pages=605–619|publisher=Academic Press |doi=10.1016/B978-0-12-387817-5.00033-9|isbn=9780123878175 |quote=The frequency of liver injury with flutamide ranges from 0.18% to 5% of persons exposed, [...]}}</ref>
<ref name="pmid28379593" /><ref name="pmid21301018">{{cite journal | vauthors = Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, Buckel E, Contreras L | title = Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature | journal = Annals of Hepatology | volume = 10 | issue = 1 | pages = 93–98 | year = 2011 | pmid = 21301018 | doi = 10.1016/S1665-2681(19)31595-9 | doi-access = free }}</ref><ref name="Aronson2009">{{cite book| vauthors = Aronson JK | chapter = Antiandrogens |title=Meyler's Side Effects of Endocrine and Metabolic Drugs| chapter-url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA153|date=21 February 2009|publisher=Elsevier|isbn=978-0-08-093292-7|pages=153–}}</ref><ref name="pmid10215102">{{cite journal | vauthors = Cetin M, Demirci D, Unal A, Altinbaş M, Güven M, Unlühizarci K | title = Frequency of flutamide induced hepatotoxicity in patients with prostate carcinoma | journal = Human & Experimental Toxicology | volume = 18 | issue = 3 | pages = 137–140 | date = March 1999 | pmid = 10215102 | doi = 10.1177/096032719901800301 | bibcode = 1999HETox..18..137C | s2cid = 32523042 | doi-access = free }}</ref> Flutamide is also associated with [[Elevated transaminases|liver enzyme elevation]]s in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5&nbsp;times upper normal limit) occur only in 3 to 5%.<ref name="Jafri2014">{{cite journal | vauthors = Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM | title = Bicalutamide-induced hepatotoxicity: A rare adverse effect | journal = The American Journal of Case Reports | volume = 15 | pages = 266–270 | year = 2014 | pmid = 24967002 | pmc = 4068966 | doi = 10.12659/AJCR.890679 }}</ref><ref name="LiverTox">{{Cite book|url=https://livertox.nih.gov/Flutamide.htm|title = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|year = 2012|publisher = National Institute of Diabetes and Digestive and Kidney Diseases| pmid=31643176 }}</ref> The risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide.<ref name="KolvenbagFurr2009" /><ref name="DansetteSnyder2012" /><ref name="RamonDenis2007" /> Lower doses of the medication appear to have a possibly reduced but still significant risk.<ref name="pmid21301018" /><ref name="BruniPeruzzi2012">{{cite journal | vauthors = Bruni V, Peruzzi E, Dei M, Nannini S, Seravalli V, Sisti G, Fambrini M | title = Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females | journal = Fertility and Sterility | volume = 98 | issue = 4 | pages = 1047–1052 | date = October 2012 | pmid = 22795685 | doi = 10.1016/j.fertnstert.2012.06.018 | doi-access = free }}</ref> Liver function should be monitored regularly with [[liver function test]]s during flutamide treatment.<ref name="Diamanti-KandarakisNestler2009">{{cite book | vauthors = Ünlühizarci K, Keleştimur F | chapter = Anti-Androgens | veditors = Diamanti-Kandarakis E, Nestler JE, Panidis D, Pasquali R |title=Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment| chapter-url=https://books.google.com/books?id=7ej6ZgqiFEsC&pg=PA75|date=21 December 2009|publisher=Springer Science & Business Media|isbn=978-1-59745-310-3|pages=75–}}</ref> In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.<ref name="Aronson2009" />

The [[mechanism of action]] of flutamide-induced hepatotoxicity is thought to be due to [[mitochondrial toxicity]].<ref name="BallKamalian2016">{{cite journal | vauthors = Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE | title = Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells | journal = Toxicological Sciences | volume = 153 | issue = 2 | pages = 341–351 | date = October 2016 | pmid = 27413113 | pmc = 5036617 | doi = 10.1093/toxsci/kfw126 }}</ref><ref name="CoeJia2007">{{cite journal | vauthors = Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD | title = Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening | journal = Chemical Research in Toxicology | volume = 20 | issue = 9 | pages = 1277–1290 | date = September 2007 | pmid = 17702527 | pmc = 2802183 | doi = 10.1021/tx7001349 }}</ref><ref name="MarroquinHynes2007">{{cite journal | vauthors = Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y | title = Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants | journal = Toxicological Sciences | volume = 97 | issue = 2 | pages = 539–547 | date = June 2007 | pmid = 17361016 | doi = 10.1093/toxsci/kfm052 | doi-access = free }}</ref> Specifically, flutamide and particularly its major metabolite [[hydroxyflutamide]] inhibit [[enzyme]]s in the [[mitochondria]]l [[electron transport chain]] in [[hepatocyte]]s, including [[Electron transport chain#Complex I|respiratory complexes I]] ([[NADH:ubiquinone reductase (H+-translocating)|NADH ubiquinone oxidoreductase]]), [[Electron transport chain#Complex II|II]] ([[succinate dehydrogenase]]), and [[Electron transport chain#Coupling with oxidative phosphorylation|V]] ([[ATP synthase]]), and thereby reduce [[cellular respiration]] via [[adenosine triphosphate|ATP]] depletion and hence decrease cell survival.<ref name="BallKamalian2016" /><ref name="CoeJia2007" /><ref name="MarroquinHynes2007" /> Inhibition of [[taurocholic acid|taurocholate]] (a [[bile acid]]) efflux has also been implicated in flutamide-induced hepatotoxicity.<ref name="BallKamalian2016" /><ref name="KostrubskyStrom2007">{{cite journal | vauthors = Kostrubsky SE, Strom SC, Ellis E, Nelson SD, Mutlib AE | title = Transport, metabolism, and hepatotoxicity of flutamide, drug-drug interaction with acetaminophen involving phase I and phase II metabolites | journal = Chemical Research in Toxicology | volume = 20 | issue = 10 | pages = 1503–1512 | date = October 2007 | pmid = 17900172 | doi = 10.1021/tx7001542 }}</ref> In contrast to flutamide and hydroxyflutamide, which severely compromise hepatocyte cellular respiration ''in vitro'', bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic.<ref name="BallKamalian2016" /><ref name="MarroquinHynes2007" /> It is thought that the [[nitro compound|nitroaromatic]] [[functional group|group]] of flutamide and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a [[cyanide|cyano group]] in place of the nitro [[moiety (chemistry)|moiety]], greatly reducing the potential for such toxicity.<ref name="CoeJia2007" /><ref name="BoelsterliHo2006">{{cite journal | vauthors = Boelsterli UA, Ho HK, Zhou S, Leow KY | title = Bioactivation and hepatotoxicity of nitroaromatic drugs | journal = Current Drug Metabolism | volume = 7 | issue = 7 | pages = 715–727 | date = October 2006 | pmid = 17073576 | doi = 10.2174/138920006778520606 }}</ref>

The hepatotoxicity of flutamide appears to depend on [[hydrolysis]] of flutamide [[catalysis|catalyzed]] by an [[arylacetamide deacetalyse]] [[enzyme]].<ref name="pmid28379593" /> This is analogous to the hepatotoxicity that occurs with the [[withdrawn drug|withdrawn]] [[paracetamol]] (acetominophen)-related medication [[phenacetin]].<ref name="pmid28379593" /> In accordance, the combination of [[paracetamol]] (acetaminophen) and flutamide appears to result in additive to synergistic hepatotoxicity, indicating a potential [[drug interaction]].<ref name="pmid28379593" /><ref name="KostrubskyStrom2007" />

Hepatotoxicity with flutamide may be cross-reactive with that of [[cyproterone acetate]].<ref name="FisherBandiniCasale2011">{{cite book | vauthors = Fisher AD, Bandini E, Casale H, Maggi M | chapter = Paraphilic Disorders: Diagnosis and Treatment | title = Hormonal Therapy for Male Sexual Dysfunction | date = 29 November 2011 | pages = 94–110 | publisher = Wiley | doi = 10.1002/9781119963820.ch8 | hdl = 2158/426102 | isbn = 9780470657607 }}</ref>

====Others====
Flutamide has also been associated with [[interstitial pneumonitis]] (which can progress to [[pulmonary fibrosis]]).<ref name="Aronson2010" /> The incidence of interstitial pneumonitis with flutamide was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients.<ref name="pmid12353966">{{cite journal | vauthors = Bennett CL, Raisch DW, Sartor O | title = Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect | journal = Annals of Internal Medicine | volume = 137 | issue = 7 | pages = 625 | date = October 2002 | pmid = 12353966 | doi = 10.7326/0003-4819-137-7-200210010-00029 | quote = An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period. }}</ref> A variety of [[case report]]s have associated flutamide with [[photosensitivity]].<ref name="Aronson2010" /> Flutamide has been associated with several case reports of [[methemoglobinemia]].<ref name="pmid9120948">{{cite journal | vauthors = Khan AM, Singh NT, Bilgrami S | title = Flutamide induced methemoglobinemia | journal = The Journal of Urology | volume = 157 | issue = 4 | pages = 1363 | date = April 1997 | pmid = 9120948 | doi = 10.1016/s0022-5347(01)64982-6 }}</ref><ref name="pmid10388026" /> Bicalutamide does not appear to share this risk with flutamide.<ref name="pmid10388026" /> Flutamide has also been associated with reports of [[sulfhemoglobinemia]] and [[neutropenia]].<ref name="pmid10388026" />

===Birth defects===
Out of the available [[endocrine-disrupting compound]]s looked at, flutamide has a notable effect on [[anogenital distance]] in rats.<ref name="SchwartzChristiansen2018">{{cite journal | vauthors = Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T | title = Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders | journal = Archives of Toxicology | volume = 93 | issue = 2 | pages = 253–272 | date = February 2019 | pmid = 30430187 | doi = 10.1007/s00204-018-2350-5 | doi-access = free | bibcode = 2019ArTox..93..253S }}</ref><ref name="KitaMeyer2016">{{cite journal | vauthors = Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ | title = Manipulation of pre and postnatal androgen environments and anogenital distance in rats | journal = Toxicology | volume = 368-369 | pages = 152–161 | date = August 2016 | pmid = 27639664 | doi = 10.1016/j.tox.2016.08.021 | doi-access = free | bibcode = 2016Toxgy.368..152K }}</ref>)

==Pharmacology==

===Pharmacodynamics===
[[File:Hydroxyflutamide.svg|thumb|right|225px|[[Hydroxyflutamide]], the [[active metabolite|active form]] of flutamide.]]

====Antiandrogenic activity====
{{Affinities of selected androgen receptor ligands}}

{{Relative potencies of selected antiandrogens in rats}}

[[File:Androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in male rats.png|thumb|right|325px|Androgen receptor antagonistic potency of [[spironolactone]], [[cyproterone acetate]], and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight).<ref name="pmid14751673" /> [[Bicalutamide]] is a much more potent androgen receptor antagonist than flutamide both in animals and in humans.<ref name="pmid8717469">{{cite journal | vauthors = Furr BJ | title = The development of Casodex (bicalutamide): preclinical studies | journal = European Urology | volume = 29 | issue = Suppl 2 | pages = 83–95 | year = 1996 | pmid = 8717469 | doi = 10.1159/000473846 }}</ref><ref name="pmid8560673">{{cite journal | vauthors = Furr BJ, Tucker H | title = The preclinical development of bicalutamide: pharmacodynamics and mechanism of action | journal = Urology | volume = 47 | issue = 1A Suppl | pages = 13–25; discussion 29–32 | date = January 1996 | pmid = 8560673 | doi = 10.1016/S0090-4295(96)80003-3 }}</ref><ref name="pmid12496872">{{cite journal | vauthors = Kolvenbag GJ, Furr BJ, Blackledge GR | title = Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity | journal = Prostate Cancer and Prostatic Diseases | volume = 1 | issue = 6 | pages = 307–314 | date = December 1998 | pmid = 12496872 | doi = 10.1038/sj.pcan.4500262 | s2cid = 33497597 }}</ref><ref name="pmid26024831">{{cite journal | vauthors = Nakai Y, Tanaka N, Anai S, Miyake M, Tatsumi Y, Fujimoto K | title = A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide | journal = Hormones & Cancer | volume = 6 | issue = 4 | pages = 161–167 | date = August 2015 | pmid = 26024831 | doi = 10.1007/s12672-015-0226-1 | pmc = 10355925 | s2cid = 10625154 }}</ref>]]

Flutamide acts as a [[binding selectivity|selective]], [[competitive antagonist|competitive]], [[silent antagonist]] of the [[androgen receptor]] (AR).<ref name="LemkeWilliams2012" /> Its [[active metabolite|active form]], [[hydroxyflutamide]], has between 10- and 25-fold higher [[affinity (pharmacology)|affinity]] for the AR than does flutamide, and hence is a much more potent AR antagonist in comparison.<ref name="LemkeWilliams2012" /><ref name="Pratt1994" /><ref name="FiggChau2010">{{cite book| vauthors = Shen HC, Taplin ME, Balk SP | chapter = Androgen Receptor Antagonists | veditors = Figg W, Chau CH, Small EJ |title=Drug Management of Prostate Cancer| chapter-url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA71|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=71–}}</ref><ref name="HarveyWhitneyBooks1990">{{cite book|title=DICP: The Annals of Pharmacotherapy|url=https://books.google.com/books?id=N-JJAQAAIAAJ|year=1990|publisher=Harvey Whitney Books Company|page=617|quote=Additionally, 2-hydroxyflutamide has approximately a 25-fold greater affinity for androgen receptors than does flutamide.}}</ref> However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR.<ref name="LemkeWilliams2012" /><ref name="MasielloCheng2002">{{cite journal | vauthors = Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP | title = Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor | journal = The Journal of Biological Chemistry | volume = 277 | issue = 29 | pages = 26321–26326 | date = July 2002 | pmid = 12015321 | doi = 10.1074/jbc.M203310200 | doi-access = free }}</ref> Flutamide has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which flutamide is used appear to compensate for this.<ref name="CarrellPeterson2010">{{cite book| vauthors = Wheeler CJ, Keye WR, Peterson CM | chapter = Polycyctic Ovary Syndrome | veditors = Carrell DT, Peterson CM |title=Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice|chapter-url=https://books.google.com/books?id=lcBEheiufVcC&pg=PA163|date=23 March 2010|publisher=Springer Science & Business Media|isbn=978-1-4419-1436-1|pages=163–}}</ref> In accordance with its selectivity for the AR, flutamide does not interact with the [[progesterone receptor|progesterone]], [[estrogen receptor|estrogen]], [[glucocorticoid receptor|glucocorticoid]], or [[mineralocorticoid receptor]],<ref name="pmid9420861">{{cite journal | vauthors = Diamanti-Kandarakis E, Tolis G, Duleba AJ | title = Androgens and therapeutic aspects of antiandrogens in women | journal = Journal of the Society for Gynecologic Investigation | volume = 2 | issue = 4 | pages = 577–592 | date = 1995 | pmid = 9420861 | doi = 10.1177/107155769500200401 | s2cid = 32242838 }}</ref> and possesses no intrinsic [[progestogen]]ic, [[estrogen (medication)|estrogen]]ic, [[glucocorticoid]], or [[antigonadotropic]] activity.<ref name="pmid10495361" /><ref name="JamesonGroot2010">{{cite book | vauthors = Barner RB, Ehrmann DA, Rosenfield RL | chapter = Hyperandrogenism, Hirsutism, and the Polycystic Ovary Syndrome | veditors = Jameson JL, De Groot LJ |title=Endocrinology: Adult and Pediatric| chapter-url=https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA2401|date=18 May 2010|publisher=Elsevier Health Sciences|isbn=978-1-4557-1126-0|pages=2401–}}</ref> However, it can have some indirect estrogenic effects via increased levels of [[estradiol]] secondary to AR blockade, and this involved in the [[gynecomastia]] it can produce. Because flutamide does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not cause [[menstrual irregularity|menstrual irregularities]] in women.<ref name="pmid25845307" /><ref name="JamesonGroot2010" /> This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate.<ref name="pmid25845307" /> Similarly to nilutamide, bicalutamide, and [[enzalutamide]], flutamide crosses the [[blood–brain barrier]] and exerts central antiandrogen actions.<ref>{{cite book|title=Hormones - Antineoplastics: Advances in Research and Application: 2011 Edition: ScholarlyPaper|url=https://books.google.com/books?id=wpCvw4TF2ZMC&pg=PA9|date=9 January 2012|publisher=ScholarlyEditions|isbn=978-1-4649-4785-8|pages=9–}}</ref>

Flutamide has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen in [[bioassay]]s.<ref name="pmid2788775"/><!-- defined by Template:Affinities of selected androgen receptor ligands --><ref name="pmid14751673">{{cite journal | vauthors = Yamasaki K, Sawaki M, Noda S, Muroi T, Takakura S, Mitoma H, Sakamoto S, Nakai M, Yakabe Y | title = Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals | journal = Toxicology | volume = 195 | issue = 2–3 | pages = 177–186 | date = February 2004 | pmid = 14751673 | doi = 10.1016/j.tox.2003.09.012 | bibcode = 2004Toxgy.195..177Y }}</ref> This is in spite of the fact that hydroxyflutamide has on the order of 10-fold lower affinity for the AR relative to cyproterone acetate.<ref name="pmid2788775" /><!-- defined by Template:Affinities of selected androgen receptor ligands --><ref name="Feau2009">{{cite web | vauthors = Feau C | date = 2009 | title = Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators | publisher = Saint Jude Children's Research Hospital | location = Memphis TN | url = http://www.dtic.mil/docs/citations/ADA499611 | archive-url = https://web.archive.org/web/20170611033434/http://www.dtic.mil/docs/citations/ADA499611 | archive-date=2017-06-11 }}</ref> Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide.<ref name="Furr1997">{{cite journal| vauthors = Furr BJ |title=Relative potencies of flutamide and 'Casodex'|journal=Endocrine-Related Cancer|volume=4|issue=2|year=1997|pages=197–202|issn=1351-0088|doi=10.1677/erc.0.0040197|doi-broken-date=1 November 2024 }}</ref> In addition, whereas bicalutamide has an elimination half-life of around 6&nbsp;days, hydroxyflutamide has an elimination half-life of only 8 to 10&nbsp;hours, a roughly 17-fold difference.<ref name="Furr1997" /> In accordance, at dosages of 50&nbsp;mg/day bicalutamide and 750&nbsp;mg/day flutamide (a 15-fold difference), circulating levels of flutamide at [[steady-state (pharmacokinetics)|steady-state]] have been found to be approximately 7.5-fold lower than those of bicalutamide.<ref name="Furr1997" /> Moreover, whereas flutamide at this dosage has been found to produce a 75% reduction in [[prostate-specific antigen]] levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide.<ref name="Furr1997" /> In accordance, 50&nbsp;mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750&nbsp;mg/day flutamide in a large clinical trial for prostate cancer.<ref name="Furr1997" /> Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs.<ref name="Furr1997" /> Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide.<ref name="Furr1997" />

[[Dose-ranging study|Dose-ranging studies]] of flutamide in men with benign prostatic hyperplasia and prostate cancer alone and in combination with a GnRH agonist have been performed.<ref name="pmid8638357">{{cite journal | vauthors = Narayan P, Trachtenberg J, Lepor H, Debruyne FM, Tewari A, Stone N, Das S, Jimenez-Cruz JF, Shearer R, Klimberg I, Schellhammer PF, Costello AJ | title = A dose-response study of the effect of flutamide on benign prostatic hyperplasia: results of a multicenter study | journal = Urology | volume = 47 | issue = 4 | pages = 497–504 | date = April 1996 | pmid = 8638357 | doi = 10.1016/S0090-4295(99)80484-1 | hdl-access = free | s2cid = 10400855 | hdl = 2066/23543 }}</ref><ref name="pmid9170575">{{cite journal | vauthors = Akaza H, Isaka S, Usami M, Kanetake H, Kotake T, Koiso K, Aso Y | title = Recommended dose of flutamide with LH-RH agonist therapy in patients with advanced prostate cancer | journal = International Journal of Urology | volume = 3 | issue = 6 | pages = 468–471 | date = November 1996 | pmid = 9170575 | doi = 10.1111/j.1442-2042.1996.tb00578.x | s2cid = 11365242 | doi-access =  }}</ref>

Flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats.<ref name="pmid3059063">{{cite journal | vauthors = Shain SA, Huot RI | title = Antiandrogen effects in models of androgen responsive cancer | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 4B | pages = 711–718 | date = October 1988 | pmid = 3059063 | doi = 10.1016/0022-4731(88)90022-2 }}</ref>

{{Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor}}

{{Plasma levels and binding potential of flutamide and bicalutamide during first week}}

====CYP17A1 inhibition====
Flutamide and hydroxyflutamide have been found ''in vitro'' to [[enzyme inhibitor|inhibit]] [[CYP17A1]] (17α-hydroxylase/17,20-lyase), an [[enzyme]] which is required for the [[biosynthesis]] of androgens.<ref name="AyubLevell1987">{{cite journal | vauthors = Ayub M, Levell MJ | title = Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro | journal = Journal of Steroid Biochemistry | volume = 28 | issue = 1 | pages = 43–47 | date = July 1987 | pmid = 2956461 | doi = 10.1016/0022-4731(87)90122-1 }}</ref> In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients<ref name="AyubLevell1990">{{cite journal | vauthors = Ayub M, Levell MJ | title = Suppression of plasma androgens by the antiandrogen flutamide in prostatic cancer patients treated with Zoladex, a GnRH analogue | journal = Clinical Endocrinology | volume = 32 | issue = 3 | pages = 329–339 | date = March 1990 | pmid = 2140542 | doi = 10.1111/j.1365-2265.1990.tb00874.x | s2cid = 22823754 }}</ref> and women with [[polycystic ovary syndrome]].<ref name="pmid10495361" /> In a directly comparative study of flutamide monotherapy (375{{nbsp}}mg once daily) versus bicalutamide monotherapy (80{{nbsp}}mg once daily) in Japanese men with prostate cancer, after 24{{nbsp}}weeks of treatment flutamide decreased [[dehydroepiandrosterone]] (DHEA) levels by about 44% while bicalutamide increased them by about 4%.<ref name="pmid26024831"/> As such, flutamide is a weak inhibitor of androgen biosynthesis.<ref name="CarrellPeterson2010"/> However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the medication markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated [[negative feedback]] on the [[hypothalamic–pituitary–gonadal axis]] in this context.<ref name="Becker2001" />

====Other activities====
Flutamide has been identified as an [[agonist]] of the [[aryl hydrocarbon receptor]].<ref name="pmid27569425">{{cite journal | vauthors = Gao X, Xie C, Wang Y, Luo Y, Yagai T, Sun D, Qin X, Krausz KW, Gonzalez FJ | title = The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4 | journal = Biochemical Pharmacology | volume = 119 | pages = 93–104 | date = November 2016 | pmid = 27569425 | pmc = 5061623 | doi = 10.1016/j.bcp.2016.08.021 }}</ref><ref name="pmid25867062">{{cite journal | vauthors = Koch DC, Jang HS, O'Donnell EF, Punj S, Kopparapu PR, Bisson WH, Kerkvliet NI, Kolluri SK | title = Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1 | journal = Oncogene | volume = 34 | issue = 50 | pages = 6092–6104 | date = December 2015 | pmid = 25867062 | doi = 10.1038/onc.2015.55 | doi-access = free }}</ref> This may be involved in the [[hepatotoxicity]] of flutamide.<ref name="pmid27569425" />

===Pharmacokinetics===
The [[absorption (pharmacokinetics)|absorption]] of flutamide is complete upon [[oral administration|oral ingestion]].<ref name="Flutamide-Label" /> Food has no effect on the [[bioavailability]] of flutamide.<ref name="Flutamide-Label" /> [[Steady-state (pharmacokinetics)|Steady-state]] levels of [[hydroxyflutamide]], the [[active metabolite|active form]] of flutamide, are achieved after 2 to 4&nbsp;days administration.<ref name="pmid10495361" /> Levels of hydroxyflutamide are approximately 50-fold higher than those of flutamide at [[steady state (pharmacokinetics)|steady-state]].<ref name="DeVitaLawrence2015">{{cite book| vauthors = DeVita VT, Lawrence TS, Rosenberg SA |title=Lymphomas and Leukemias: Cancer: Principles & Practice of Oncology|url=https://books.google.com/books?id=n8ehCgAAQBAJ&pg=PT1029|date=29 September 2015|publisher=Wolters Kluwer Health|isbn=978-1-4963-3828-0|pages=1029–}}</ref>

The [[plasma protein binding]] of flutamide and hydroxyflutamide are high; 94 to 96% and 92 to 94%, respectively.<ref name="Flutamide-Label" /> Flutamide and its metabolite hydroxyflutamide are known to be transported by the [[multidrug resistance-associated protein 1]] (MRP1; ABCC1).<ref name="pmid18691054">{{cite journal | vauthors = Zhou SF, Wang LL, Di YM, Xue CC, Duan W, Li CG, Li Y | title = Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development | journal = Current Medicinal Chemistry | volume = 15 | issue = 20 | pages = 1981–2039 | date = 2008 | pmid = 18691054 | doi = 10.2174/092986708785132870 }}</ref><ref name="pmid12750271">{{cite journal | vauthors = Grzywacz MJ, Yang JM, Hait WN | title = Effect of the multidrug resistance protein on the transport of the antiandrogen flutamide | journal = Cancer Research | volume = 63 | issue = 10 | pages = 2492–2498 | date = May 2003 | pmid = 12750271 | doi =  }}</ref>

Flutamide is [[metabolized]] by [[CYP1A2]] (via α-[[hydroxylation]]) in the [[liver]] during [[first-pass metabolism]]<ref name="Lehne2013"/> to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion),<ref name="pmid10495361" /> and to at least five other, minor [[metabolite]]s.<ref name="ChabnerLongo2010">{{cite book| vauthors = Chabner BA, Longo DL |title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=WL4arNFsQa8C&pg=PA679|date=8 November 2010|publisher=Lippincott Williams & Wilkins|isbn=978-1-60547-431-1|pages=679–}}</ref> Flutamide has at least 10&nbsp;inactive metabolites total, including 4-nitro-3-fluoro-methylaniline.<ref name="Flutamide-Label-2" />

Flutamide is [[excretion|excreted]] in various forms in the [[urine]], the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.<ref name="AcademicPress2001">{{cite book|title=Analytical Profiles of Drug Substances and Excipients|url=https://books.google.com/books?id=uEcv7SFDWBEC&pg=PA155|date=19 March 2001|publisher=Academic Press|isbn=978-0-08-086122-7|pages=155–}}</ref>

Flutamide and hydroxyflutamide have [[elimination half-life|elimination half-lives]] of 4.7&nbsp;hours and 6&nbsp;hours in adults, respectively.<ref name="Flutamide-Label-2">{{Cite web|url=http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Flutamide_monograph_1April2014.pdf|title = Error}}</ref><ref name="Gulley2011"/><ref name="ChabnerLongo2010" /> However, the half-life of hydroxyflutamide is extended to 8&nbsp;hours after a single dose and to 9.6&nbsp;hours at [[steady state (pharmacokinetics)|steady state]]) in [[elderly]] individuals.<ref name="Flutamide-Label-2" /><ref name="DenisGriffiths1999" /><ref name="LemkeWilliams2012" /><ref name="ChabnerLongo2010" /><ref name="Flutamide-Label" /> The elimination half-lives of flutamide and hydroxyflutamide are regarded as too short to allow for once-daily dosing, and for this reason, flutamide is instead administered three times daily at 8-hour intervals.<ref name="Acosta2009">{{cite book| vauthors = Acosta WR |title=LWW's Foundations in Pharmacology for Pharmacy Technicians|url=https://archive.org/details/lwwsfoundationsi0000acos|url-access=registration|date=1 October 2009|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6624-1|pages=[https://archive.org/details/lwwsfoundationsi0000acos/page/300 300]–}}</ref> In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives,<ref name="DenisGriffiths1999" /> and this allows for once-daily administration in their cases.<ref name="WeinKavoussi2011">{{cite book| vauthors = Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA |author-link4 = Alan W. Partin |title=Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2939|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2939–}}</ref>

==Chemistry==
Unlike the hormones with which it competes, flutamide is not a [[steroid]]; rather, it is a substituted [[anilide]]. Hence, it is described as ''nonsteroidal'' in order to distinguish it from older steroidal antiandrogens such as [[cyproterone acetate]] and [[megestrol acetate]].

===Synthesis===
[[File:Flutamide synthesis.png|thumb|center|500px|Synthesis.<ref>{{Cite journal | doi = 10.1021/ed080p1439| title = Microscale Synthesis and Spectroscopic Analysis of Flutamide, an Antiandrogen Prostate Cancer Drug| journal = Journal of Chemical Education| volume = 80| issue = 12| pages = 1439| year = 2003| vauthors = Stabile RG, Dicks AP | bibcode = 2003JChEd..80.1439S}}</ref><ref name="pmid6031711"/><ref>{{Cite journal | doi = 10.1080/00397910500464848| title = Novel and Gram-Scale Green Synthesis of Flutamide| journal = Synthetic Communications| volume = 36| issue = 7| pages = 859–864| year = 2006| vauthors = Bandgar BP, Sawant SS | s2cid = 98825198}}</ref> Patents:<ref>{{Cite patent|country=DE|number=2130450|pubdate=1972-12-21|title=Substituierte Anilide [Substituted anilides]|assign=[[Schering AG|Sherico Ltd.]] | inventor = Neri RO, Topliss JG }}</ref><ref>{{Cite patent|country=DE|number=2261293|pubdate=1973-07-05|title=Substituierte Imidate [Substituted imidates]|assign1=[[Schering AG|Sherico Ltd.]]| inventor = Gold EH }}</ref><ref>{{cite patent | inventor = Gold E | country = US | number = 3847988 | gdate = 1974 | assign1 = Merck Sharp and Dohme Corp }}</ref><ref>{{cite patent | inventor = Neri RO, Topliss JG | country = US | number = 4144270 | gdate = 1979 | assign1 = Merck Sharp and Dohme Corp }}</ref>]]

[[Schotten–Baumann reaction|Schotten–Baumann]] reaction between 4-nitro-3-(trifluoromethyl)aniline [393-11-3] ('''1''') with isobutanoyl chloride [79-30-1] ('''2''') in the presence of triethylamine.

==History==
Flutamide was first synthesized in 1967 by Neri and colleagues at [[Schering-Plough|Schering Plough Corporation]].<ref name="Elks2014" /><ref name="SmithWilliams2005">{{cite book| vauthors = Thurston DE | chapter = The Chemotherapy of Cancer | veditors = Smith HJ, Williams G |title=Smith and Williams' Introduction to the Principles of Drug Design and Action | edition = Fourth | chapter-url = https://books.google.com/books?id=P2W6B9FQRKsC&pg=PA489|date=10 October 2005|publisher=CRC Press|isbn=978-0-203-30415-0|pages=489–}}</ref><ref name="DenisGriffiths1999" /><ref name="pmid6031711">{{cite journal | vauthors = Baker JW, Bachman GL, Schumacher I, Roman DP, Tharp AL | title = Synthesis and bacteriostatic activity of some nitrotrifluoromethylanilides | journal = Journal of Medicinal Chemistry | volume = 10 | issue = 1 | pages = 93–95 | date = January 1967 | pmid = 6031711 | doi = 10.1021/jm00313a020 }}</ref> It was originally synthesized as a [[bacteriostatic agent]], but was subsequently, and serendipitously found to possess antiandrogen activity.<ref name="pmid10495361" /><ref name="pmid6031711" /> The code name of flutamide during development was SCH-13521.<ref name="Boettcher2014">{{cite book| vauthors = Vojtišková M, Poláčkova M, Viklický V, Voráčová B, Hilgertová J | chapter = Comparison of the biological effects of three types of testosterone inhibitors in mice. | veditors = Boettcher B |title=Immunological Influence on Human Fertility: Proceedings of the Workshop on Fertility in Human Reproduction, University of Newcastle, Australia, July 11-13, 1977| chapter-url = https://books.google.com/books?id=4r7iBQAAQBAJ&pg=PA167|date=12 May 2014|publisher=Elsevier Science|isbn=978-1-4832-6895-8|pages=167–}}</ref> Clinical research of the medication began in 1971,<ref>{{cite book|title=The Irish Reports: Containing Reports of Cases Argued and Determined in the Court of Appeal, the High Court of Justice, the Court of Bankruptcy, in Ireland, and the Irish Land Commission|url=https://books.google.com/books?id=FQhMAQAAIAAJ|year=1990|publisher=Incorporated Council of Law Reporting for Ireland|page=501}}</ref> and it was first marketed in 1983, specifically in [[Chile]] under the brand name Drogenil and in [[West Germany]] under the brand name Flugerel.<ref name="Publishing2013">{{cite book|author=William Andrew Publishing|title=Pharmaceutical Manufacturing Encyclopedia, 3rd Edition|url=https://books.google.com/books?id=_J2ti4EkYpkC&pg=PA1695|date=22 October 2013|publisher=Elsevier|isbn=978-0-8155-1856-3|pages=1695–}}</ref><ref name="Ireland2013">{{cite book|title=The Irish Reports: Containing Reports of Cases Argued and Determined in the Court of Appeal, the High Court of Justice, the Court of Bankruptcy, in Ireland, and the Irish Land Commission|url=https://books.google.com/books?id=FQhMAQAAIAAJ|year=1990|publisher=Incorporated Council of Law Reporting for Ireland|pages=501–502}}</ref> Flutamide was not introduced in the [[United States]] until 1989; it was specifically approved by the U.S. [[Food and Drug Administration]] for the treatment of metastatic prostate cancer in combination with a [[gonadotropin-releasing hormone]] (GnRH) [[gonadotropin-releasing hormone analogue|analogue]].<ref name="Regitz-Zagrosek2012">{{cite book| vauthors = Cleve A, Fritzemeier KH, Haendler B, Heinrich N, Möller C, Schwede W, Wintermantel T | chapter = Pharmacology and clinical use of sex steroid hormone receptor modulators | veditors = Regitz-Zagrosek V |title=Sex and Gender Differences in Pharmacology| chapter-url = https://books.google.com/books?id=J3VxihGDh9wC&pg=PA575|date=2 October 2012|publisher=Springer Science & Business Media|isbn=978-3-642-30725-6|pages=575–}}</ref> The medication was first studied for the treatment of hirsutism in women in 1989.<ref name="pmid2147859">{{cite journal | vauthors = Sciarra F, Toscano V, Concolino G, Di Silverio F | title = Antiandrogens: clinical applications | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 37 | issue = 3 | pages = 349–362 | date = November 1990 | pmid = 2147859 | doi = 10.1016/0960-0760(90)90484-3 | s2cid = 20274398 }}</ref><ref name="pmid1683319">{{cite journal | vauthors = Motta T, Maggi G, Perra M, Azzolari E, Casazza S, D'Alberton A | title = Flutamide in the treatment of hirsutism | journal = International Journal of Gynaecology and Obstetrics | volume = 36 | issue = 2 | pages = 155–157 | date = October 1991 | pmid = 1683319 | doi = 10.1016/0020-7292(91)90772-w | s2cid = 37481872 }}</ref><ref name="pmid7868809">{{cite journal | vauthors = Motta T, Maggi G, D'Alberton A | title = Flutamide and hirsutism | journal = Journal of Endocrinological Investigation | volume = 17 | issue = 8 | pages = 673 | date = September 1994 | pmid = 7868809 | doi = 10.1007/BF03349685 | s2cid = 2237184 }}</ref> It was the first "pure antiandrogen" to be studied in the treatment of hirsutism.<ref name="pmid2147859" /> Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995.<ref name="BéguéBonnet-Delpon2008">{{cite book| vauthors = Bégué JP, Bonnet-Delpon D | chapter = Flourinated Drugs |title=Bioorganic and Medicinal Chemistry of Fluorine| chapter-url = https://books.google.com/books?id=QMVSvZ-R7I0C&pg=PA327|date=2 June 2008|publisher=John Wiley & Sons|isbn=978-0-470-28187-1|pages=327–}}</ref>

==Society and culture==

===Generic names===
''Flutamide'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, {{abbrlink|DCF|Dénomination Commune Française}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/flutamide.html|title = Flutamide: Uses, Dosage, Side Effects & Warnings}}</ref><ref name="IndexNominum2000" /><ref name="Elks2014" /> Its names in [[Latin language|Latin]], [[German language|German]], and [[Spanish language|Spanish]] are ''flutamidum'', ''flutamid'', and ''flutamida'', respectively.<ref name="Drugs.com" /><ref name="IndexNominum2000" /> The medication has also been referred to by the name ''niftolide''.<ref name="Elks2014" />

===Brand names===
Brand names of flutamide include or have included Cebatrol, Cytomid, Drogenil, Etaconil, Eulexin, Flucinom, Flumid, Flutacan, Flutamid, Flutamida, Flutamin, Flutan, Flutaplex, Flutasin, Fugerel, Profamid, and Sebatrol, among others.<ref name="Drugs.com" /><ref name="IndexNominum2000" /><ref name="Elks2014" />

===Availability===
Flutamide is marketed widely throughout the world, including in the [[United States]], [[Canada]], [[Europe]], [[Australia]], [[New Zealand]], [[South Africa]], [[Central America|Central]] and [[South America]], [[East Asia|East]] and [[Southeast Asia]], [[India]], and the [[Middle East]].<ref name="Drugs.com" /><ref name="IndexNominum2000" />

==Research==

===Prostate cancer===
The combination of an [[estrogen (medication)|estrogen]] and flutamide as a form of [[combined androgen blockade]] for the treatment of prostate cancer has been researched.<ref name="VozianovReznikov1995">{{cite journal | vauthors = Vozianov AF, Reznikov AG, Varga SV | title = Endocrine changes underlying clinical effects of low-dose estrogen-antiandrogen treatment of prostatic cancer | journal = Endocrine Regulations | year = 1995 | volume = 29 | issue = 1 | pages = 25–28 | issn = 0013-7200 }}</ref><ref name="pmid9005063">{{cite journal | vauthors = Vozianov OF, Rieznikov OH, Klymenko IO, Varga SV, Synitsyn PV, Chaĭkovs'ka LV, Vozianov SO, Arystova TI | title = [The correlation of the hormonal and clinical effects in patients with prostatic cancer undergoing niftolid treatment in combination with low doses of synestrol] | language = uk | journal = Likars'ka Sprava | issue = 1–2 | pages = 107–110 | date = 1996 | pmid = 9005063 | url = https://www.researchgate.net/publication/14203603 | trans-title = The correlation of the hormonal and clinical effects in patients with prostatic cancer undergoing niftolid treatment in combination with low doses of synestrol }}</ref><ref name="VozianovReznikov1998">{{cite journal | vauthors = Vozianov AF, Reznikov AG, Klimenko IA, Chaikovskaya LV | title = Benefits of low dose estrogen-antiandrogen treatment of prostate cancer | journal = Naunyn-Schmiedebergs Archiv für Pharmakologie | volume = 358 | issue = 1 | date = January 1998 | page = R532 | issn = 0028-1298 }}</ref><ref name="ReznikovChaikovskaya1998">{{cite journal | vauthors = Reznikov AG, Chaikovskaya LV | title = Mechanisms of potentiating effect of low dose estrogens on flutamide-induced suppression of normal and cancerous prostate | journal = Naunyn-Schmiedebergs Archiv für Pharmakologie | volume = 358 | issue = 1 | date = January 1998 | page = R545 | issn = 0028-1298 }}</ref><ref name="ReznikovChaikovskaya1999">{{cite journal | vauthors = Reznikov, AG, Chaikovskaya, LV, Polyakova, LI, Sachinskaya, OV, Bakhmach EV | title = Effects of combined treatment with niftolide and low doses of antitumor estrogen preparation, chlorotrianizene, on rat prostate | journal = Eksperimentalʹnai͡a onkologii͡a [Experimental Oncology] | date = September 1999 | volume = 21 | issue = 3–4 | pages = 269–273 | issn = 0204-3564 | url = https://www.researchgate.net/publication/288711102}}</ref>

===Enlarged prostate===
Flutamide has been studied in the treatment of [[benign prostatic hyperplasia]] (BPH; enlarged prostate) in men in several clinical studies.<ref name="pmid7509536">{{cite journal | vauthors = Oesterling JE | title = Endocrine therapies for symptomatic benign prostatic hyperplasia | journal = Urology | volume = 43 | issue = 2 Suppl | pages = 7–16 | date = February 1994 | pmid = 7509536 | doi = 10.1016/0090-4295(94)90212-7 }}</ref><ref name="pmid2477936">{{cite journal | vauthors = Stone NN | title = Flutamide in treatment of benign prostatic hypertrophy | journal = Urology | volume = 34 | issue = 4 Suppl | pages = 64–8; discussion 87–96 | date = October 1989 | pmid = 2477936 | doi = 10.1016/0090-4295(89)90236-7 }}</ref> It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the [[5α-reductase inhibitor]] [[finasteride]].<ref name="pmid9101011">{{cite journal | vauthors = Lee M, Sharifi R | title = Benign prostatic hyperplasia: diagnosis and treatment guideline | journal = The Annals of Pharmacotherapy | volume = 31 | issue = 4 | pages = 481–486 | date = April 1997 | pmid = 9101011 | doi = 10.1177/106002809703100415 | s2cid = 20498549 }}</ref> Unfortunately, it has been associated with side effects in these studies including gynecomastia and breast tenderness (in about 50% of patients), gastrointestinal disturbances such as nausea, diarrhea, and [[flatulence]], and hepatotoxicity, although sexual function including libido and erectile potency were maintained.<ref name="pmid9101011" />

===Breast cancer===
Flutamide was studied for the treatment of advanced breast cancer in two [[Phases of clinical research#Phase II|phase II]] [[clinical trial]]s but was found to be ineffective.<ref name="pmid1975167">{{cite journal | vauthors = Howell A, Dodwell DJ, Anderson H | title = New endocrine approaches to breast cancer | journal = Baillière's Clinical Endocrinology and Metabolism | volume = 4 | issue = 1 | pages = 67–84 | date = March 1990 | pmid = 1975167 | doi = 10.1016/S0950-351X(05)80316-7 }}</ref><ref name="pmid28245550">{{cite journal | vauthors = Rahim B, O'Regan R | title = AR Signaling in Breast Cancer | journal = Cancers | volume = 9 | issue = 3 | page = 21 | date = February 2017 | pmid = 28245550 | pmc = 5366816 | doi = 10.3390/cancers9030021 | doi-access = free }}</ref><ref name="pmid3354065">{{cite journal | vauthors = Zhao TP, He GF | title = A phase II clinical trial of flutamide in the treatment of advanced breast cancer | journal = Tumori | volume = 74 | issue = 1 | pages = 53–56 | date = February 1988 | pmid = 3354065 | doi = 10.1177/030089168807400109 | s2cid = 12506218 }}</ref><ref name="pmid3192386">{{cite journal | vauthors = Perrault DJ, Logan DM, Stewart DJ, Bramwell VH, Paterson AH, Eisenhauer EA | title = Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study | journal = Investigational New Drugs | volume = 6 | issue = 3 | pages = 207–210 | date = September 1988 | pmid = 3192386 | doi = 10.1007/BF00175399 | s2cid = 46483946 }}</ref> Out of a total of 47&nbsp;patients, only three short-term responses occurred.<ref name="pmid1975167" /> However, the patients in the studies were selected irrespective of AR, {{abbrlink|ER|estrogen receptor}}, {{abbrlink|PR|progesterone receptor}}, or [[HER2/neu|HER2]] status, which were all unknown.<ref name="pmid28245550" /><ref name="pmid28474005">{{cite journal | vauthors = Wu Y, Vadgama JV | title = Androgen Receptor as a Potential Target for Treatment of Breast Cancer | journal = International Journal of Cancer Research and Molecular Mechanisms | volume = 3 | issue = 1 | date = April 2017 | pmid = 28474005 | pmc = 5412726 | doi = 10.16966/2381-3318.129 }}</ref>

===Psychiatric disorders===
Flutamide has been studied in the treatment of [[bulimia nervosa]] in women.<ref name="NaessénHirschberg2011">{{cite book | vauthors = Naessén S, Hirschberg AL |title=Handbook of Behavior, Food and Nutrition |chapter=Sex Hormones and Appetite in Women: A Focus on Bulimia Nervosa|year=2011|pages=1759–1767|publisher=Springer |doi=10.1007/978-0-387-92271-3_114|isbn=978-0-387-92270-6 }}</ref><ref name="pmid22946772">{{cite journal | vauthors = McElroy SL, Guerdjikova AI, Mori N, O'Melia AM | title = Current pharmacotherapy options for bulimia nervosa and binge eating disorder | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 14 | pages = 2015–2026 | date = October 2012 | pmid = 22946772 | doi = 10.1517/14656566.2012.721781 | s2cid = 1747393 }}</ref><ref name="pmid8883576">{{cite journal | vauthors = Bergman L, Eriksson E | title = Marked symptom reduction in two women with bulimia nervosa treated with the testosterone receptor antagonist flutamide | journal = Acta Psychiatrica Scandinavica | volume = 94 | issue = 2 | pages = 137–139 | date = August 1996 | pmid = 8883576 | doi = 10.1111/j.1600-0447.1996.tb09838.x | s2cid = 20033667 }}</ref><ref name="pmid15643104">{{cite journal | vauthors = Sundblad C, Landén M, Eriksson T, Bergman L, Eriksson E | title = Effects of the androgen antagonist flutamide and the serotonin reuptake inhibitor citalopram in bulimia nervosa: a placebo-controlled pilot study | journal = Journal of Clinical Psychopharmacology | volume = 25 | issue = 1 | pages = 85–88 | date = February 2005 | pmid = 15643104 | doi = 10.1097/01.jcp.0000150222.31007.a9 | s2cid = 45297334 }}</ref>

Flutamide was found to be effective in the treatment of [[obsessive–compulsive disorder]] (OCD) in men with comorbid [[Tourette's syndrome]] in one small [[randomized controlled trial]].<ref name="pmid31814547">{{cite journal | vauthors = Nomani H, Mohammadpour AH, Moallem SM, YazdanAbad MJ, Barreto GE, Sahebkar A | title = Anti-Androgen Drugs in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review | journal = Current Medicinal Chemistry | volume = 27 | issue = 40 | pages = 6825–6836 | date = December 2019 | pmid = 31814547 | doi = 10.2174/0929867326666191209142209 | s2cid = 208956450 }}</ref> Conversely, it was ineffective in patients with OCD in another study.<ref name="pmid31814547" /> More research is necessary to determine whether flutamide is effective in the treatment of OCD.<ref name="pmid31814547" />

== References ==
{{Reflist}}

== Further reading ==
{{refbegin|30em}}
* {{cite book | vauthors = Sogani PC, Whitmore WF | chapter = Flutamide and Other Antiandrogens in the Treatment of Advanced Prostatic Carcinoma | title = Endocrine Therapies in Breast and Prostate Cancer | volume = 39 | pages = 131–145 | year = 1988 | pmid = 2908604 | doi = 10.1007/978-1-4613-1731-9_9 | isbn = 978-1-4612-8974-6 | series = Cancer Treatment and Research | publisher = Springer }}
* {{cite journal | vauthors = Brogden RN, Clissold SP | title = Flutamide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer | journal = Drugs | volume = 38 | issue = 2 | pages = 185–203 | date = August 1989 | pmid = 2670515 | doi = 10.2165/00003495-198938020-00003 | s2cid = 262018256 }}
* {{cite journal | vauthors = Neri R | title = Pharmacology and pharmacokinetics of flutamide | journal = Urology | volume = 34 | issue = 4 Suppl | pages = 19–21; discussion 46–56 | date = October 1989 | pmid = 2477934 | doi = 10.1016/0090-4295(89)90230-6 }}
* {{cite journal | vauthors = Newling DW | title = The use of flutamide as monotherapy in the treatment of advanced prostate cancer | journal = Progress in Clinical and Biological Research | volume = 303 | pages = 117–121 | year = 1989 | pmid = 2674980 }}
* {{cite journal | vauthors = Labrie F, Dupont A, Cusan L, Manhès G, Bergeron N, Lacourcière Y, Pineault S, Bélanger A, Monfette G, Emond J | title = Combination therapy with castration and flutamide: today's treatment of choice for prostate cancer | journal = Journal of Steroid Biochemistry | volume = 33 | issue = 4B | pages = 817–821 | date = October 1989 | pmid = 2689788 | doi = 10.1016/0022-4731(89)90499-8 }}
* {{cite journal | vauthors = Goldspiel BR, Kohler DR | title = Flutamide: an antiandrogen for advanced prostate cancer | journal = DICP | volume = 24 | issue = 6 | pages = 616–623 | date = June 1990 | pmid = 2193461 | doi = 10.1177/106002809002400612 | s2cid = 26125621 }}
* {{cite journal | vauthors = Brogden RN, Chrisp P | title = Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer | journal = Drugs & Aging | volume = 1 | issue = 2 | pages = 104–115 | date = March 1991 | pmid = 1794008 | doi = 10.2165/00002512-199101020-00003 | s2cid = 260959546 }}
* {{cite journal | vauthors = Labrie F | title = Mechanism of action and pure antiandrogenic properties of flutamide | journal = Cancer | volume = 72 | issue = 12 Suppl | pages = 3816–3827 | date = December 1993 | pmid = 8252497 | doi = 10.1002/1097-0142(19931215)72:12+<3816::aid-cncr2820721711>3.0.co;2-3 | s2cid = 2195250 | doi-access = free }}
* {{cite journal | vauthors = Iversen P, Melezinek I, Schmidt A | title = Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function | journal = BJU International | volume = 87 | issue = 1 | pages = 47–56 | date = January 2001 | pmid = 11121992 | doi = 10.1046/j.1464-410x.2001.00988.x | s2cid = 28215804 | doi-access = free }}
* {{cite journal | vauthors = Ibáñez L, de Zegher F | title = Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women | journal = Human Reproduction Update | volume = 12 | issue = 3 | pages = 243–252 | year = 2006 | pmid = 16407452 | doi = 10.1093/humupd/dmi054 | doi-access = free }}
* {{cite journal | vauthors = Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, Buckel E, Contreras L | title = Acute and fulminant hepatitis induced by flutamide: case series report and review of the literature | journal = Annals of Hepatology | volume = 10 | issue = 1 | pages = 93–98 | year = 2011 | pmid = 21301018 | doi = 10.1016/S1665-2681(19)31595-9 | doi-access = free }}
* {{cite journal | vauthors = Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A | title = Flutamide-induced hepatotoxicity: ethical and scientific issues | journal = European Review for Medical and Pharmacological Sciences | volume = 21 | issue = 1 Suppl | pages = 69–77 | date = March 2017 | pmid = 28379593 }}
{{refend}}

{{Androgens and antiandrogens}}
{{Acne agents}}
{{Other dermatological preparations}}
{{Androgen receptor modulators}}
{{Aryl hydrocarbon receptor modulators}}

[[Category:Anilides]]
[[Category:Anti-acne preparations]]
[[Category:Aryl hydrocarbon receptor agonists]]
[[Category:CYP17A1 inhibitors]]
[[Category:Enantiopure drugs]]
[[Category:Hair loss medications]]
[[Category:Hair removal]]
[[Category:Hepatotoxins]]
[[Category:Hormonal antineoplastic drugs]]
[[Category:Nitrobenzene derivatives]]
[[Category:Nonsteroidal antiandrogens]]
[[Category:Prodrugs]]
[[Category:Progonadotropins]]
[[Category:Propionamides]]
[[Category:Prostate cancer]]
[[Category:Trifluoromethyl compounds]]