798
Severe leucopenia, fatal in some cases, has been reported Fluroblastin; Uflahext; Utoral; Pol.: Efudix; Port.: Cinkef-U; Polycystic ovary syndrome. Flutamide has been used, in patients given fluorouracil or fluorouracil prodrugs (such Rus,: Flurox (nypoKc); S,A r, : Efudix; Floracor; Fluracedyl; usually with metformin, in the management of polycystic as tegafur) with sorivudine.2'3 A metabolite of sorivudine Fluroblastin; Singapore: Efudixt;f Swed.: Flurablastint; Switz.: ovary syndrome (p. 2253.3);'·' additive effects have been appears to inhibit dihydropyrimidine dehydrogenase, the Efudix; Thai. : Effcil; Fivoflut; Fluroxt; Turk.: Fluro-5; Oncosil; reported with this combination. Oncouradlt; UK; Efudix; USA: Adrucil; Carac; Efudex; Fluoro primary enzyme responsible for the inactivation of l. Ibd.iiez et al. Additive effects of insulin-sensitizing and anti-androgen plex; Venez. : Fivoflu; Fluroblastin. l,, fluorouracil. 3 A fatality has also been reported in a patient treatment in young nonobcse women with hyperinsulinism, treated with the oral prodrug capecitabine who was also hyperandrogenism, dyslipidemia, and anovulation. J C!in Endocrinol Multi�ingredient Preparations. Austria: Verrumal; Cz.: Verrumal; Metab 2002; 87: 2870-4. given brivudine.4 Ger. : Actikerall; Verrumal; Gr.: Verruca Hermal; Hong Kong: 2. Ibdfte7: L, et al. Low-dose flutamide-metformin therapy reverses insulin 1. Czejka MJ, et al. Clinical pharmacokinetics of 5-f\uorouracil: influence of Verrumal; Hung. : Verrumal; Israel: Verrumal; Malaysia: Verru resistance and reduce� fat mass in nonobese adolescents with ovarian the biomodulating agents interferon, dipyridamole and folic acid alone mal; Pol.: Verrumal; Port. : Verrucare; Verrumal; Singapore: hyperandrogenism. J C!in Endocrinol Metab 2003; 88: 2600-6. and in combination. Arzneimittelfo rschung 1993; 43: 387-90. Verrumal; Switz. : Actikerall; Verrumal; Thai.: Verrumal; Turk. : 3. Gambineri A, et al. Effect of flutamide and metformin administered 2. Lancet 1993; 342: Yawata M. Deaths due to drug interaction. 1166. Verrutol; UK: Actikerall. alone or in combination in dieting obese women with polycystic ovary 3. Diasio RB . Sorivudine and 5-fluorouracil; a clinically significant drug syndrome. Clin Endocrinol (Oxf) 2004; 60: 241-9. drug interaction due to inhibition of dihydropyrimidine dehydrogenase. 4. Gambineri A, et a!. Treatment with flutamide, metfonnin, and their Br Clin Pharmaco/ 1998; 46: 1-4. 1 Pharmacopoeial Preparations combination added to a 4. R.3.tz Bravo AE, et al. Fatal drug-drug interaction of brivudine and BP 2014: Fluorouracil Cream; Fluorouracil Injection; with polycystic capecitabine. Acta Oncol 2009; 48: 631-3. USP 36: Fluorouracil Cream; Fluorouracil Injection; Fluorouracil controlled study. Topical Solution. 5. Ibd.iiez L, et al. Low-dose pioglita:mne, flutamide, metformin plus an Gastrointestinal drugs. Pretreatment with cimetidine for 4 estro-progestagen for non-obese young women with polycystic ovary efficacy and persistent safety over 30 months. weeks increased plasma concentrations of fluorouracil 26: 869-73. after intravenous and oral doses in 6 patients.1 The effect was probably due to a combination of hepatic enzyme inhibition and reduced hepatic blood flow, No such effect Adverse Effects and Precautions was seen after single doses of cimetidine in 5 patients or pretreatment for just 1 week in 6. Care is required in The most frequently reported adverse effects with flutamide are hot flushes and reversible gynaecomastia or breast patients given both drugs together. tenderness, sometimes accompanied by galactorrhoea. 1. Harvey VJ. et al. The influence of cimetidine on the pharmacokinetics of 5-fluorouracil. Br J Clin Phannacol l984; IS: 421-30. Nausea, vomiting, diarrhoea, increased appetite, anorexia, and sleep disturbances may occur. There have been reports of skin reactions, including epidermal necrolysis, and of Pharmacokinetics liver damage, sometimes fatal. Other adverse effects Absorption of fluorouracil from the gastrointestinal tract is reported in patients receiving flutamide include anaemias, unpredictable and fluorouracil is usually given intrave haemolysis, headache, dizziness, malaise, blurred vision, nously. Little is absorbed when fluorouracil is applied to anxiety, depression, decreased libido, impotence, and healthy skin. Ph, Bur, 8; (Flutamide). A pale yellow, crystalline powder. hypertension, Abdominal pain, chest pain, dyspnoea, and After intravenous injection fluorouracil is cleared rapidly Practically insoluble in water; freely soluble in alcohol and cough have been reported rarely. Discoloration of the urine from plasma with a mean half-life of about 16 minutes, It is in acetone; practically insoluble in heptane. Protect from to amber or yellow-green can be caused by the presence of distributed throughout body tissues and fluids (including light. flutamide and/or its metabolites. crossing the blood-brain barrier to appear in the CSF), and USP 36; (Flutamide). A pale yellow, crystalline powder. Flutamide should be used with care in patients with disappears from the plasma within about 3 hours. Within Practically insoluble in water, in liquid paraffin, and in cardiovascular disease because of the possibility of fluid the target cell fluorouracil is converted to 5-fluorouridine petroleum spirit; freely soluble in acetone, in ethyl acetate, retention. It should also be used with caution in patients monophosphate and floxuridine monophosphate (5- and in methyl alcohol; soluble in chloroform and in ether. with hepatic impairment and is contra-indicated in those fluorodeoxyuridine monophosphate), the former under Store in airtight containers. Protect from light. with severe impairment. Regular liver function testing is going conversion to the triphosphate which can be recommended in all patients; therapy should be stopped or incorporated into RNA while the latter inhibits thymidylate dosage reduced if there is evidence of hepatotoxicity. synthetase. About 15% of an intravenous dose is excreted Uses and Administration unchanged in the urine within 6 hours. The remainder is Flutarnideis a nonsteroidal compound with anti-androgenic Effects on the blood. A report1 of methaemoglobinaemia inactivated mainly in the liver and is catabolised via properties which appears to act by inhibiting the uptake in an elderly man was attributed to flutamide. A study2 of dihydropyrimidine dehydrogenase (DPD) similarly to and/or binding of androgens in target tissues. It is used, 45 patients given flutamide found no cases of methaemo endogenous uracil. A large amount is excreted as respiratory usually with gonadorelin analogues, in the palliative globinaemia, but the authors noted a further 3 published carbon dioxide; urea and other metabolites are also treatment of prostatic carcinoma (p. 712.3), The usual oral case reports. produced. dose is 250mg three times daily. When used in combination I. et a!. DICP Ann therapy UK licensed product information recommends that Schott AM, Flutamide-induced methemoglobinemia. References. Pharmacother 1991; 25: 600-l. I. Ploylearmsaeng S-A, et al. How may anticancer chemotherapy with flutamide treatment should be started at least 3 days before 2. Schulz et al. Lack of methemoglobinemia with flutamide. Ann fluorouracil be individualised? Clin Phannacokinet 2006; 45: 567-92. the gonadorelin analogue to suppress any 'flare' reaction; 35: 21-5. however, in some other countries it is recommended that Chronopharmacology. Plasma concentrations of fluoro treatment with both agents be begun simultaneously for uracil during continuous intravenous infusion are Effects on the liver. Hepatitis occurred in a 79-year-old 1 optimum effect. reported to undergo circadian variations of as much as man taking flutamide 7 50 mg daily as sole therapy after a prostatectomy, 1 but a subsequent study2 in 1091 patients 50% of the mean, peak concentrations occurring in the Congenital adrenal hyperplasia. For mention of the use middle of the night, 1 The variation may be due to a circa given flutamide 250mg three times daily as part of a regi of flutamide with testolactone to block androgenic effects men for prostate cancer found marked signs of liver dian variation in the activity of the enzyme dihydropyri in congenital adrenal hyperplasia, see p. 1603.2. midine dehydrogenase in blood,' but striking interpatient damage only in 4, of whom only 2 had clinical evidence variations in peak concentrations of fluorouracil and peak of hepatotoxicity. In the USA, the FDA had 46 reports of Hirsutism and alopecia. Anti-androgens (usually cypro enzyme activity suggest that any adjustment of infusion patients with hepatotoxicity associated with flutamide up terone or spironolactone) are widely used for the drug times would need to be individualised. 2 It has been sug to December 1994. Of these patients, 20 died from pro treatment of hirsutism (p, 2262.1), Flutamide has no parti gested that pharmacokinetic monitoring should be investi gressive liver disease. 3 Further cases have continued to be cular advantage in this context; 1·2 one study has found gated as a means of individualising fluorouracil doses with reported,4-7 including in women receiving low doses for flutamide to be more effective than spironolactone in inhi� the aim of improving efficacy and reducing toxicity. 3 hirsutism. 7·8 Early tapering of the dose, stopping therapy, biting hirsutism, 3 but others found them to be of similar l. Petit E, et al. Circadian rhythm-varying plasma concentration of 5- or switching to another anti-androgen may resolve hepa efficacy,4·5 and the risk of hepatotoxicity with flutamide is fluorouracil during a five-day continuous venous infusion at a constant totoxic effects.9 Patients with chronic viral hepatitis may rate in cancer patients. Cancer Res 1988; 48: 1676---9. a problem.' Nonetheless, flutamide has continued to be be at higher risk of developing hepatotoxicity with - 2. Harris BE, et al. Relationship between dihydropyrimidine dehydrogen investigated. 6 10 anti-androgen therapy.10 ase activity and plasma 5-fluorouracillevels with evidence for circadian Flutamide has also been investigated11 in women with Ann Intern Med 1989; variation of enzyme activity and plasma drug levels in cancer patients 1. Hart W, Stricker BHC. Flutamide and hepatitis. female-pattern hair loss (female androgenetic alopecia), 110: 943-4. receiving 5-fluorouradl by protracted continuous inf'usion. Cancer Res 1990; 50: 197-201. 1. Rittmaster RS. Hyperandrogenism-what is normal? N Engl J Med 1992; 2. Gomez J-L, et al. Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients. Am Med 1992; 92: 465-70. 3. Young AM, et a!. Can pharmacokinetic monitoring improve clinical usc 327: 194--6. 1 of fluorouracil. Clin Pharmacokinet 1999; 36: 391-8. 2. Rittmaster RS. Hirsutism. Lancet 1997; 349: 191-5. 3. Wysowski DK, Fourcroy JL. Flu tamide hepatotoxicity. J Ural (Baltimorl') 3. Cusan L, er al. Comparison of flutamidc omd spironolactone in the 1996; 155: 209-12. Correction ibid: 396. treatment of hirsutism: a randomized controlled trial. Pertil Steril l994; 4. Garcia Cortes M, et a!. Flutamide-induced hepatotoxicity: report of a case P epa a ons series. Rev Esp Dig 2001; 93: 423-32. Correction. ibid.; 634. ..r...... r ti ... 61: 281-7. . .. . 4. et al. 5. Lubbert C. et und schwerc Leberfunktionsstorung bei der (details are given in Volume B) Erenus M, Comparison of the efficacy of spironolactone versus ProprietaryPreparations flutamide in the treatment of hirsutism. Fertil Steril l994; 61: 613-6. hormonablativen Behandlung des Prostatakarzinoms. Internist (Berl) 2004; 45: 333-40. Arg,: Acler; Efudix; Oncofut; 5. Moghetti P, et al. Comparison of spironolactone, flutamide, and Single-ingredient Preparations. 6. Osculati A. Castiglioni C. Fatal liver complications with flutamide. Lancet Triosules; Austral.: Efudix; Belg.: Efudix; Fluracedyl; Fluroblas� finasteride efficacy in the treatment of hirsutism: a randomized, double Clin Endorrinol Metab 2000; 85: 89-94. 2006; 367: 1140-1. blind, placebo-controlled trial. 1 tine; Braz.: Efurix; Fauldfluor; Neugrast; Canad.: Efudex; 6. Muderris IT. et al. Treatment of hirsutism with lowest-dose flutamide 7. Brahm J, et a!. Acute and fulminant hepatitis induced by flutamidc: case Fluoroplext; Chile: Efudix; Fluoracilot; China: An Te Fan ( (62.5 mg/day). 14: 38-41. series report and review of the literature. Ann Hepatol 20Jl; 10: 93-8. 8. t!J'fL); Fu Ke Fu Mi Te ('it*'i'h Fu Ruo Xin (i!li1';'1V\3i.); 7. Ventmoli S, et Low-dose flutamide (125 mg/day) as maintenance Castelo-Branco C, Del Pino M. Hepatotoxicity during low-dose 25: Fu Shi Ke (tkB>foJ); Gefente Hua Kang Da (:f/"J!I!it;); therapy in the treatment of hirsutism. Horm Res 2001; 56: 25-3 1. flutamidc treatment for hirsutism. Gynecol Endocrinol 2009; 419-22. (ilF'T); 9. Lin ADY, et al. Antiandrogen-assodated hepatotoxicity in the Ning Lan Xin (')'�/V(); Pu Li Da (l!f}Jit;); Sen Ting 8. Gambineri A, et al. Effect of flutamide and metformin administered (l$,3ft!f); management of advanced prostate cancer. Chin Med Assoc 2003; 66: Sinofuan Zuo Ding ({lcJE); Cz.: La-Fut; Denm,: alone or in combination in dieting obese women with polycystic ovary 1 (>'!;IT); syndrome. Clin Endocrinol (Oxf) 2004; 60: 241-9. 735-40. Flurablastin;('!'A Fin.:li\'!<); Flurablastin; Fr.: Efudix; Ger.: Benda; 9. Calaf J, et al. Spanish Working Group for Hirsutism. Long-term efficacy 10. Pu Y-S, et al. Antiandrogen hepatotoxicity in patients with chronic viral Efudix; Haemato-fut; Neofluort: Onkofluort: Ribofluor; Gr.: and tolerability of flutamide combined with oral contraception in hepatitis. Eur Uro/ 1999; 36: 293-7. Fluracedyl; Fluroblastin; Uraciflor; Hong Kong: Efudix; Hung.: moderate to severe hirsutism: a 12-month, double-blind, parallel clinical Efudix; India: Fiveflurot; Fivocil; Fivoflu; Flocil; Flonida; Flor trial. J Clin Endocrinol Metab 2007; 92: 3446-52. ae; Fhicil; Fludin; Fluonco; Fluracil; Flutas; Kucil; Oncofluor; 10. Unluhizarci K, et a!. A comparison between finasteride, flutamide, and Effects on the lungs. In a review1 of 7 8 cases of pneumo Oncourcil; Indon.: Curacil; Fluracedyl; Irl. : Efudix; Israel: finasteride flutamide combination in the treatment of hirsutism. 1 nitis reported to the FDA between 1998 and 2000 that 32: 37-40. were associated with bicalutamide, flutamide, or niluta Efudix; Malaysia: Fluracedyl; Mex. : Acoflut; Carebin; Efudix; 1 I. Paradisi R, et al. Prospective cohort study on the effects and tolerability of Flurox; Tecflu; Neth.: Efudix; Fluracedyl; Norw.: Flurablastin; flutamide in patients with female pattern hair loss. Ann Phannacother mide, it was found that 14 patients had died of respiratory NZ: Efudix; Philipp.: Fivoflu; Fluonco; Fluoxant; Fluracedyl; 2011; 45: 469-75. failure. It was estimated that the incidence of pneumonitis
All cross-references refer to entries in Volume A 799
was highest for nilutamide (0. 77% ), but lower for flut int; Fluprosin; Profamid; Fin.: Eulexint; Profamid; Fr.: Eulex 1 Fosbretabulin (r!NNJ amide (0.04%) and bicalutamide (0.01 %). ine; Prostadirex; Ger.: Flumidt; Fluta; Fugerelt; Prosticat; Gr.: l. Bennett CL, et at. Pneumonitis associated with nonsteroidal Adiprostt; Andraxan; Antipros; Elbat; Fludnom; Flutaplex; CMP; Combretastatin Phosphate:CS-A4 .(combretastatin antiandrogens: presumptive evidence of a class effect. Ann Intern Med Palistop; Prostamide; Rikital; Rosiniol; Tremexal; Hong Kong: Fosbretabulina; FosbretM abuline; Fosbretabulinum; NSC- 2002; 137: 625. Codalant; Fugere}; Hung.: F1uprost; Flutam; Flutasin; Fugere!; A4); (cornbrerastatin);
The symbol denotes a preparation no longer actively marketed The symbol denotes a substance whose use may be restricted in certain sports (see p. viii) t ®