Flutamide acts as aselectiveantagonist of theandrogen receptor (AR), competing withandrogens liketestosterone anddihydrotestosterone (DHT) for binding to ARs in tissues like theprostate gland. By doing so, it prevents their effects and stops them from stimulating prostate cancer cells to grow. Flutamide is aprodrug 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]
Flutamide was first described in 1967 and was first introduced for medical use in 1983.[16] It became available in the United States in 1989. The medication has largely been replaced by newer and improved NSAAs, namelybicalutamide andenzalutamide, due to their betterefficacy,tolerability,safety, and dosing frequency (once per day), and is now relatively little-used.[4][17] Flutamide is a therapeutic alternative on theWorld Health Organization's List of Essential Medicines.[18]
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 asleuprorelin orcetrorelix. 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]
There have been studies to investigate the benefit of adding an antiandrogen to surgicalorchiectomy 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]
Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment withantiandrogens 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.[19]
Flutamide has been found to be similarly effective in the treatment of prostate cancer tobicalutamide, although indications of inferior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels with bicalutamide, were observed.[20][21] The medication, at a dosage of 750 mg/day (250 mg three times daily), has also been found to be equivalent in effectiveness to 250 mg/day oralcyproterone acetate as amonotherapy in the treatment of prostate cancer in a large-scale clinical trial of 310 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.[22]
A dosage of 750 mg/day flutamide (250 mg/three times a day) is roughly equivalent in terms of effectiveness to 50 mg/day bicalutamide when used as the antiandrogen component incombined androgen blockade in the treatment ofadvanced prostate cancer.[23]
The combination of flutamide with anestrogen such asethinylestradiol 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.[32]
Flutamide has been researched and used extensively in the treatment ofandrogen-dependentskin andhair conditions in women includingacne,seborrhea,hirsutism, andscalp hair loss, as well as inhyperandrogenism (e.g., inpolycystic ovary syndrome orcongenital 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.[33][34][35][36] 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,[37][38][39] but has a far lower and only small risk of hepatotoxicity in comparison.[40][41][42]
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.[43] This is related to its high effectiveness and minimal side effects.[43]
Flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies.[44][45] In a long-term study of 230 women with acne, 211 of whom also had seborrhea, very-low-dose flutamide alone or in combination with anoral contraceptive caused a marked decrease in acne and seborrhea after 6 months of treatment, with maximal effect by 1 year of treatment and benefits maintained in the years thereafter.[44][46] In the study, 97% of the women reported satisfaction with the control of their acne with flutamide.[47] In another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months.[48][2] In contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications.[48][49] 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.[45][50][2]
Improvement of facial hirsutism in a woman with hyperandrogenism before (top) and after (bottom) treatment with 125 mg/day flutamide and an oral contraceptive for 6 months (click image to view a larger version).[35]: 368
Flutamide has been found to be effective in the treatment of hirsutism (excessivebody/facial hair growth) in numerous studies.[33][51][37] It possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate.[51][33] 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.[2][33] It has been used to treat hirsutism at dosages ranging from 62.5 mg/day to 750 mg/day.[43] 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 mg/day, 250 mg/day, and 375 mg/day.[33][49][52] In addition, a study found that combination of 125 mg/day flutamide with finasteride was no more effective than 125 mg/day flutamide alone in the treatment of hirsutism.[53] 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.[33] However, the risk has been found to remain even at very low doses.[12]
Flutamide has been found to be effective in the treatment of femalepattern hair loss in a number of studies.[54][55][56][57] In one study of 101 pre- and postmenopausal women, flutamide alone or in combination with an oral contraceptive produced a marked decrease in hair loss scores after 1 year of treatment, with maximum effect after 2 years of treatment and benefits maintained for another 2 years.[57][58] In a small study of flutamide with an oral contraceptive, the medication caused an increase in cosmetically acceptance hair density in 6 of 7 women with diffuse scalp hair loss.[59] In a comparative study, flutamide significantly improved scalp hair growth (21% reduction inLudwig scores) in hyperandrogenic women after 1 year of treatment, whereascyproterone acetate andfinasteride were ineffective.[57][60]
Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs.[40] In a comparative trial ofcombined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide.[40] Moreover, 6% of flutamide-treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so.[40] 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% fornilutamide.[40] In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications.[40]
Although rare, flutamide has been associated with severehepatotoxicity and death.[75][14][76] By 1996, 46 cases of severecholestatichepatitis had been reported, with 20 fatalities.[75] There have been continued case reports since, includingliver transplants and death.[77][78] A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with flutamide, including 7 liver transplantations and 2 deaths.[79]
Based on the number of prescriptions written and the number of cases reported in theMedWatch database, the rate of serious hepatotoxicity associated with flutamide treatment was estimated in 1996 as approximately 0.03% (3 per 10,000).[75][80] 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%.[81][82][12][77][83][84] Flutamide is also associated withliver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%.[85][86] The risk of hepatotoxicity with flutamide is much higher than with nilutamide or bicalutamide.[40][41][42] Lower doses of the medication appear to have a possibly reduced but still significant risk.[77][87] Liver function should be monitored regularly withliver function tests during flutamide treatment.[88] In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.[83]
Flutamide has also been associated withinterstitial pneumonitis (which can progress topulmonary fibrosis).[14] 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.[13] A variety ofcase reports have associated flutamide withphotosensitivity.[14] Flutamide has been associated with several case reports ofmethemoglobinemia.[95][15] Bicalutamide does not appear to share this risk with flutamide.[15] Flutamide has also been associated with reports ofsulfhemoglobinemia andneutropenia.[15]
Androgen receptor antagonistic potency ofspironolactone,cyproterone acetate, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight).[99]Bicalutamide is a much more potent androgen receptor antagonist than flutamide both in animals and in humans.[100][101][102][21]
Flutamide acts as aselective,competitive,silent antagonist of theandrogen receptor (AR).[5] Itsactive form,hydroxyflutamide, has between 10- and 25-fold higheraffinity for the AR than does flutamide, and hence is a much more potent AR antagonist in comparison.[5][68][103][104] However, at high concentrations, unlike flutamide, hydroxyflutamide is able to weakly activate the AR.[5][105] 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.[106] In accordance with its selectivity for the AR, flutamide does not interact with theprogesterone,estrogen,glucocorticoid, ormineralocorticoid receptor,[107] and possesses no intrinsicprogestogenic,estrogenic,glucocorticoid, orantigonadotropic activity.[2][108] However, it can have some indirect estrogenic effects via increased levels ofestradiol secondary to AR blockade, and this involved in thegynecomastia it can produce. Because flutamide does not have any estrogenic, progestogenic, or antigonadotropic activity, the medication does not causemenstrual irregularities in women.[44][108] This is in contrast to steroidal antiandrogens like spironolactone and cyproterone acetate.[44] Similarly to nilutamide, bicalutamide, andenzalutamide, flutamide crosses theblood–brain barrier and exerts central antiandrogen actions.[109]
Flutamide has been found to be equal to slightly more potent than cyproterone acetate and substantially more potent than spironolactone as an antiandrogen inbioassays.[98][99] 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.[98][110] Hydroxyflutamide shows about 2- to 4-fold lower affinity for the rat and human AR than does bicalutamide.[111] In addition, whereas bicalutamide has an elimination half-life of around 6 days, hydroxyflutamide has an elimination half-life of only 8 to 10 hours, a roughly 17-fold difference.[111] In accordance, at dosages of 50 mg/day bicalutamide and 750 mg/day flutamide (a 15-fold difference), circulating levels of flutamide atsteady-state have been found to be approximately 7.5-fold lower than those of bicalutamide.[111] Moreover, whereas flutamide at this dosage has been found to produce a 75% reduction inprostate-specific antigen levels in men with prostate cancer, a fall of 90% has been demonstrated with this dosage of bicalutamide.[111] In accordance, 50 mg/day bicalutamide has been found to possess equivalent or superior effectiveness to 750 mg/day flutamide in a large clinical trial for prostate cancer.[111] Also, bicalutamide has been shown to be 5-fold more potent than flutamide in rats and 50-fold more potent than flutamide in dogs.[111] Taken together, flutamide appears to be a considerably less potent and efficacious antiandrogen than is bicalutamide.[111]
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.[112][113]
Flutamide increases testosterone levels by 5- to 10-fold in gonadally intact male rats.[114]
Flutamide and hydroxyflutamide have been foundin vitro toinhibitCYP17A1 (17α-hydroxylase/17,20-lyase), anenzyme which is required for thebiosynthesis of androgens.[121] In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients[122] and women withpolycystic ovary syndrome.[2] In a directly comparative study of flutamide monotherapy (375mg once daily) versus bicalutamide monotherapy (80mg once daily) in Japanese men with prostate cancer, after 24weeks of treatment flutamide decreaseddehydroepiandrosterone (DHEA) levels by about 44% while bicalutamide increased them by about 4%.[21] As such, flutamide is a weak inhibitor of androgen biosynthesis.[106] 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-mediatednegative feedback on thehypothalamic–pituitary–gonadal axis in this context.[36]
Flutamide ismetabolized byCYP1A2 (via α-hydroxylation) in theliver duringfirst-pass metabolism[7] to its main metabolite hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion),[2] and to at least five other, minormetabolites.[3] Flutamide has at least 10 inactive metabolites total, including 4-nitro-3-fluoro-methylaniline.[128]
Flutamide isexcreted in various forms in theurine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.[129]
Flutamide and hydroxyflutamide haveelimination half-lives of 4.7 hours and 6 hours in adults, respectively.[128][4][3] However, the half-life of hydroxyflutamide is extended to 8 hours after a single dose and to 9.6 hours atsteady state) inelderly individuals.[128][6][5][3][1] 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.[130] In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives,[6] and this allows for once-daily administration in their cases.[131]
Unlike the hormones with which it competes, flutamide is not asteroid; rather, it is a substitutedanilide. Hence, it is described asnonsteroidal in order to distinguish it from older steroidal antiandrogens such ascyproterone acetate andmegestrol acetate.
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.
Flutamide was first synthesized in 1967 by Neri and colleagues atSchering Plough Corporation.[9][140][6][134] It was originally synthesized as abacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity.[2][134] The code name of flutamide during development was SCH-13521.[141] Clinical research of the medication began in 1971,[142] and it was first marketed in 1983, specifically inChile under the brand name Drogenil and inWest Germany under the brand name Flugerel.[143][144] Flutamide was not introduced in theUnited 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 agonadotropin-releasing hormone (GnRH)analogue.[145] The medication was first studied for the treatment of hirsutism in women in 1989.[146][147][148] It was the first "pure antiandrogen" to be studied in the treatment of hirsutism.[146] Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995.[149]
Flutamide is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andJANTooltip Japanese Accepted Name.[150][8][9] Its names inLatin,German, andSpanish areflutamidum,flutamid, andflutamida, respectively.[150][8] The medication has also been referred to by the nameniftolide.[9]
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.[150][8][9]
Flutamide has been studied in the treatment ofbenign prostatic hyperplasia (BPH; enlarged prostate) in men in several clinical studies.[156][157] It has been found to reduce prostate volume by about 25%, which is comparable to the reduction achieved with the5α-reductase inhibitorfinasteride.[158] 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, andflatulence, and hepatotoxicity, although sexual function including libido and erectile potency were maintained.[158]
Flutamide was studied for the treatment of advanced breast cancer in twophase IIclinical trials but was found to be ineffective.[159][160][161][162] Out of a total of 47 patients, only three short-term responses occurred.[159] However, the patients in the studies were selected irrespective of AR,ERTooltip estrogen receptor,PRTooltip progesterone receptor, orHER2 status, which were all unknown.[160][163]
^Mungadi IA, Shittu OB, Abdulwahab-Ahmed A (30 November 2013)."Prostate Cancer". In Mungadi IA, Mbibu HN, Eltahawy E, Abdulwahab-Ahmed A (eds.).Manual of Medical Treatment in Urology. JP Medical Ltd. pp. 120–.ISBN978-93-5090-844-0.
^abcdefgGiorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A (March 2017). "Flutamide-induced hepatotoxicity: ethical and scientific issues".European Review for Medical and Pharmacological Sciences.21 (1 Suppl):69–77.PMID28379593.
^abBennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect".Annals of Internal Medicine.137 (7): 625.doi:10.7326/0003-4819-137-7-200210010-00029.PMID12353966.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.
^Wirth MP, Hakenberg OW, Froehner M (1 January 2008)."Adjuvant Hormonal Treatment - The Bicalutamide Early Prostate Cancer Program". In Moser L (ed.).Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42.ISBN978-3-8055-8524-8.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].
^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.
^Noguchi K, Uemura H, Harada M, Miura T, Moriyama M, Fukuoka H, et al. (February 2001). "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".International Journal of Clinical Oncology.6 (1):29–33.doi:10.1007/PL00012076.PMID11706524.S2CID23123697.
^Schulze H, Senge T (October 1990). "Influence of different types of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testosterone surge in patients with metastatic carcinoma of the prostate".The Journal of Urology.144 (4):934–941.doi:10.1016/S0022-5347(17)39625-8.PMID2144596.
^Tsushima T, Nasu Y, Saika T, Maki Y, Noda M, Suyama B, et al. (2001). "Optimal starting time for flutamide to prevent disease flare in prostate cancer patients treated with a gonadotropin-releasing hormone agonist".Urologia Internationalis.66 (3):135–139.doi:10.1159/000056592.PMID11316974.S2CID38018788.
^Labrie F, Dupont A, Belanger A, Lachance R (October 1987). "Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist".The Journal of Urology.138 (4):804–806.doi:10.1016/S0022-5347(17)43380-5.PMID3309363.
^Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. (August 1989). "A controlled trial of leuprolide with and without flutamide in prostatic carcinoma".The New England Journal of Medicine.321 (7):419–424.doi:10.1056/NEJM198908173210702.PMID2503724.
^Schnorr D (7 March 2013)."Palliativtherapie des hämatogen metastasierten Prostatakarzinoms". In Hinkelbein W, Miller K, Wiegel T (eds.).Prostatakarzinom — urologische und strahlentherapeutische Aspekte: urologische und strahlentherapeutische Aspekte [Prostate carcinoma — urological and radiotherapeutic aspects: urological and radiotherapeutic aspects]. Springer-Verlag. pp. 99–.ISBN978-3-642-60064-7.
^Ostrzenski A (2002)."Hyperandrogenism".Gynecology: Integrating Conventional, Complementary, and Natural Alternative Therapy. Lippincott Williams & Wilkins. pp. 86–.ISBN978-0-7817-2761-7.
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^Müderris II, Bayram F, Ozçelik B, Güven M (February 2002). "New alternative treatment in hirsutism: bicalutamide 25 mg/day".Gynecological Endocrinology.16 (1):63–66.doi:10.1080/gye.16.1.63.66.PMID11915584.S2CID6942048.
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^Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S (October 2011). "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".Gynecological Endocrinology.27 (10):823–829.doi:10.3109/09513590.2010.526664.PMID21117864.S2CID20250916.
^abSchmidt TH, Shinkai K (October 2015). "Evidence-based approach to cutaneous hyperandrogenism in women".Journal of the American Academy of Dermatology.73 (4):672–690.doi:10.1016/j.jaad.2015.05.026.PMID26138647.
^van Zuuren EJ, Fedorowicz Z, Carter B (November 2012). "Evidence-based treatments for female pattern hair loss: a summary of a Cochrane systematic review".The British Journal of Dermatology.167 (5):995–1010.doi:10.1111/j.1365-2133.2012.11166.x.PMID23039053.S2CID205263486.
^Paradisi R, Porcu E, Fabbri R, Seracchioli R, Battaglia C, Venturoli S (April 2011). "Prospective cohort study on the effects and tolerability of flutamide in patients with female pattern hair loss".The Annals of Pharmacotherapy.45 (4):469–475.doi:10.1345/aph.1P600.PMID21487083.S2CID38456195.
^Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women".Current Pharmaceutical Design.5 (9):707–723.doi:10.2174/1381612805666230111201150.PMID10495361.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].
^Reinert AE, Simon JA (July 2017). ""Did You Climax or Are You Just Laughing at Me?" Rare Phenomena Associated With Orgasm".Sexual Medicine Reviews.5 (3):275–281.doi:10.1016/j.sxmr.2017.03.004.PMID28454896.
^"Casodex Product Monograph"(PDF). Retrieved24 September 2018.Table 1 Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality [...] Increased Liver Enzyme Test: [...] [Number of Patients (%)] [...] CASODEX Plus LHRH Analog (n=401): 30 (7 [7.5%) [...] Flutamide Plus LHRH Analog (n=407): 46 (11 [11.3%]).
^"NU-Bicalutamide Product Monograph"(PDF). Retrieved24 September 2018.Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure and interstitial lung disease (see WARNINGS AND PRECAUTIONS) have been observed in post-marketed data and fatal outcomes have been reported for both. [...] The most common adverse events leading to withdrawal of study medication were abnormal liver function tests (1.5%) [...] Table 1 Incidence Of Adverse Events (≥ 5% In Either Treatment Group) Regardless Of Causality [...] Increased Liver Enzyme Testb [Number of Patients (%)] [...] CASODEX Plus LHRH Analogue (n=401): 30 (7 [7.5%]) [...] Flutamide Plus LHRH Analogue (n=407): 46 (11 [11.3%]) [...] During the first few months of use, you may be monitored by your physician for signs of changes in your liver function. In approximately 2.0% of patients, such changes may lead to withdrawal of therapy.
^Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)".Eur. Urol. 29 Suppl 2:96–104.doi:10.1159/000473847.PMID8717470.Casodex has been administered to over 3,900 subjects and patients and, in general, has been well tolerated. [...] Elevations of liver transaminases have been seen with Casodex, but these are usually transient, resolving either on continued therapy or on temporary cessation of therapy. In a randomised comparison with flutamide, elevations of transaminases were both less frequent and less severe than with flutamide. No cases of fulminant hepatic failure or death due to hepatic failure have been seen with Casodex in any of the clinical trials.
^Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review".The Lancet. Oncology.6 (12):972–979.doi:10.1016/S1470-2045(05)70464-2.PMID16321765.
^Goldspiel BR, Kohler DR (June 1990). "Flutamide: an antiandrogen for advanced prostate cancer".DICP.24 (6):616–623.doi:10.1177/106002809002400612.PMID2193461.S2CID26125621.[...] 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."
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