flutamide flutamide flutamide, sold under the brand name eulexin among others, is a nonsteroidal antiandrogen (nsaa) which is used primarily to treat prostate cancer. it is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. it is taken by mouth, usually three times per day. flutamideclinical datatrade nameseulexin, othersother namesniftolide; sch-13521; 4'-nitro-3'-trifluoromethyl-isobutyranilideahfs/drugs.commonographmedlineplusa697045pregnancycategory d routes ofadministrationby mouthdrug classnonsteroidal antiandrogenatc codel02bb01 (who) legal statuslegal status in general: ℞ (prescription only) pharmacokinetic databioavailabilitycomplete (>90%)protein bindingflutamide: 94–96%hydroxyflutamide: 92–94%metabolismliver (cyp1a2)metaboliteshydroxyflutamideelimination half-lifeflutamide: 5–6 hourshydroxyflutamide: 8–10 hoursexcretionurine (mainly)feces (4.2%)identifiers iupac name 2-methyl-n-propanamide cas number13311-84-7 ypubchem cid3397iuphar/bps6943drugbankdb00499 ychemspider3280 yunii76w6j0943ekeggd00586 ychebichebi:5132 ychemblchembl806 ycomptox dashboard (epa)dtxsid7032004 echa infocard100.033.024 chemical and physical dataformulac11h11f3n2o3molar mass276.215 g·mol−13d model (jsmol)interactive imagemelting point111.5 to 112.5 °c (232.7 to 234.5 °f) smiles cc(c)c(=o)nc1=cc(=c(c=c1)(=o))c(f)(f)f inchi inchi=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) ykey:mkxkfyhwdhiyrv-uhfffaoysa-n y (verify) side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. 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 liver damage, lung disease, sensitivity to light, elevated methemoglobin, elevated sulfhemoglobin, and deficient neutrophils. numerous cases of liver failure and death have been reported, which has limited the use of flutamide. flutamide acts as a selective antagonist of the androgen receptor (ar), competing with androgens 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. flutamide was first described in 1967 and was first introduced for medical use in 1983. 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, tolerability, safety, and dosing frequency (once per day), and is now relatively little-used. it is on the world health organization's list of essential medicines. medical uses prostate cancer gnrh is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (lh) and follicle-stimulating hormone (fsh). lh stimulates the testes to produce testosterone, which is metabolized to dht by the enzyme 5α-reductase. 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. 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. unfortunately, therapies which lower testosterone levels, such as orchiectomy or gnrh analogue administration, also have significant side effects. compared to these therapies, treatment with 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. 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. 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 oral cyproterone acetate as a monotherapy 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. 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 in combined androgen blockade in the treatment of advanced prostate cancer. flutamide has been used to prevent the effects of the testosterone flare at the start of gnrh agonist therapy in men with prostate cancer. the combination of flutamide with an 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. skin and hair conditions flutamide has been researched and used extensively in the treatment of androgen-dependent skin and hair conditions in women including acne, seborrhea, hirsutism, and 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. 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, but has a far lower and only small risk of hepatotoxicity in comparison. 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. this is related to its high effectiveness and minimal side effects. acne and seborrhea flutamide has been found to be effective in the treatment of acne and seborrhea in women in a number of studies. 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 an oral 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. in the study, 97% of the women reported satisfaction with the control of their acne with flutamide. in another study, flutamide decreased acne and seborrhea scores by 80% in only 3 months. in contrast, spironolactone decreased symptoms by only 40% in the same time period, suggesting superior effectiveness for flutamide for these indications. 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. excessive hair growth 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).: 368 flutamide has been found to be effective in the treatment of hirsutism (excessive body/facial hair growth) in numerous studies. it possesses moderate effectiveness for this indication, and the overall quality of the evidence is considered to be moderate. 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. it has been used to treat hirsutism at dosages ranging from 62.5 mg/day to 750 mg/day. 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. 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. 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. however, the risk has been found to remain even at very low doses. scalp hair loss flutamide has been found to be effective in the treatment of female pattern hair loss in a number of studies. 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. 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. in a comparative study, flutamide significantly improved scalp hair growth (21% reduction in ludwig scores) in hyperandrogenic women after 1 year of treatment, whereas cyproterone acetate and finasteride were ineffective. other uses flutamide has been used in case reports to decrease the frequency of spontaneous orgasms, for instance in men with post-orgasmic illness syndrome. available forms flutamide is available in the form of 125 mg oral capsules and 250 mg oral tablets. side effects the side effects 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. others include hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, and sexual dysfunction including reduced libido and erectile dysfunction. in women, flutamide is, generally, relatively well tolerated, and does not interfere with ovulation. 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. general side effects that may occur in either sex include dizziness, lack of appetite, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, and hepatic changes. because flutamide is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or fluid retention. side effects of combined androgen blockade with flutamide side effectflutamide 750 mg/daya + gnrh agonist (n = 294) (%)b,cplacebo + gnrhagonist (n = 285) (%)b,c hot flashes6157 decreased libido3631 erectile dysfunction3329 diarrhea124 severe4<1 nausea/vomiting1110 gynecomastia911 others79 other gastrointestinal disorders64 anemia6nd footnotes: a = 250 mg three times per day at 8-hour intervals. b = phase iii studies of combined androgen blockade (flutamide + gnrh agonist) in men with advanced prostate cancer. c = incidence ≥5% regardless of causality. sources: see template. side effects of combined androgen blockade with nonsteroidal antiandrogens side effectbicalutamide 50 mg/day + gnrh agonist (n = 401) (%)a,bflutamide 750 mg/dayc + gnrh agonist (n = 407) (%)a,b hot flashes52.653.3 pain (general)35.431.2 back pain25.425.8 asthenia22.221.4 constipation21.717.0 pelvic pain21.217.2 infection17.714.0 nausea14.013.6 peripheral edema13.210.3 anemiad12.714.7 dyspnea12.77.9 diarrhea12.226.3 nocturia12.213.5 hematuria12.06.4 abdominal pain11.311.3 dizziness10.28.6 bone pain9.210.6 gynecomastia9.07.4 rash8.77.4 urinary tract infection8.78.8 chest pain8.58.4 hypertension8.57.1 coughing8.25.9 pharyngitis8.05.7 paresthesia7.79.8 elevated liver enzymese7.511.3 markedly elevatedf0.52.5 leading to withdrawal1.52.0 weight loss7.59.6 headache7.26.6 flu-like symptoms7.04.9 myasthenia6.74.7 insomnia6.79.6 erectile dysfunction6.78.6 flatulence6.55.4 hyperglycemia6.56.6 dyspepsia6.55.7 decreased appetite6.27.1 sweating6.24.9 bronchitis6.02.7 breast pain/tenderness5.73.7 urinary frequency5.77.1 elevated alkaline phosphatase5.55.9 weight gain5.54.4 arthritis5.27.1 anxiety5.02.2 urinary retention5.03.4 urinary impairment4.73.7 pneumonia4.54.7 pathological fracture4.27.9 depression4.08.1 vomiting4.06.9 rhinitis3.75.4 urinary incontinence3.77.9 footnotes: a = phase iii studies of combined androgen blockade (bicalutamide or flutamide + gnrh agonist) in men with advanced prostate cancer. b = incidence >5% regardless of causality. c = 250 mg three times per day at 8-hour intervals. d = anemia includes hypochromic anemia and iron deficiency anemia. e = abnormal liver function tests reported as adverse events. f =