Flutamide is indicated for the adult population only in the treatment of stage B2-C and stage D2 metastatic carcinoma of the prostate.
There has been some off-label use for the treatment of hair loss, hirsutism, polycystic ovarian syndrome, and acne. Flutamide has been shown to have fewer side effects in women but continues to have hepatotoxic effects in this population.
In the treatment of acne and seborrhea in women, low-dose flutamide has shown to effectively decrease acne after 6 months of treatment with peak benefit at 1 year of use. Other agents have been used in the past for their antiandrogenic effects, such as spironolactone, but flutamide has shown to be the superior antiandrogenic treatment of acne in women, with up to 90% resolution of acne as compared to 40% with spironolactone.
Flutamide has been effective in treating female pattern hair loss. Flutamide can be taken alone or in conjunction with oral birth control in the treatment of hair loss, and this regiment has proven to be superior to cyproterone acetate and finasteride.
In the treatment of hirsutism, flutamide has been shown to have equal or greater effectiveness at treating symptomatology although it has a risk of hepatic injury compared to other agents such as finasteride, cyproterone acetate, and spironolactone.
First discovered in 1967, it was originally made for use as an antibiotic. It was developed by the Schering Plough Corporation of Germany and later was discovered to have antiandrogenic properties. Clinical trials began in 1971, and the drug was finally released to the public in 1983 in Germany. In 1989, flutamide was approved by the United States Food and Drug Administration. Flutamide was the first nonsteroidal antiandrogen drug on the market. Other nonsteroidal antiandrogen pharmaceuticals that have been released are nilutamide, which was introduced in 1989, and bicalutamide, which was introduced in 1995.
Flutamide is a nonsteroidal antiandrogen that competitively binds androgen receptors throughout the body. This inhibits cell growth in prostate cancer by inhibiting testosterone’s stimulatory effects. The drug has a half-life of 6 hours, meaning dosing will have to occur a minimum of 3 times a day to maintain adequate serum levels. The liver metabolizes flutamide mainly via the CYP3A4 and other cytochrome enzymes such as CYP1A2. Flutamide is primarily excreted in the urine, with less than 5% being excreted in the feces.
Flutamide is taken as a 250 mg oral capsule given every 8 hours.
For stage B2-C prostatic carcinoma, it is advised that patients take flutamide in combination with a gonadotropin-releasing hormone analog that is started eight weeks before the initiation of radiation therapy and continued throughout the course of radiation treatment.
For stage D2 metastatic carcinoma of the prostate, it is advised that the patient take flutamide in combination with a gonadotropin-releasing hormone analog.
Flutamide comes with a black box warning due to the risk of hepatic failure. Hospitalization and death have occurred, although rarely, due to flutamide use. This is due to cholestatic hepatitis which leads to failure. This is a result of the mitochondrial toxicity that occurs due to flutamide major metabolite hydroxyflutamide. This metabolite inhibits enzymes that are necessary for the electron transport chain within the mitochondria of the hepatocyte. This leads to a halt of cellular respiration and ultimately cellular death. Hepatic failure would most likely be evident within the first 3 months of use. If the hepatic injury does occur in a patient, discontinuation of flutamide my help reverses the injury. The rate at which this adverse effect occurs is estimated at three persons in 10,000 or 0.03% of all patients who use the drug. Due to this risk, it is advised to perform liver function tests if symptoms are suggestive of hepatic dysfunction. Such signs to watch for are abdominal pain, anorexia, nausea, vomiting, jaundice, and right upper quadrant pain and tenderness. It is advised to discontinue therapy if jaundice develops or if alanine aminotransferase increased to two times the upper limit of normal.
The most common adverse effect of flutamide use is hot flashes, which occur in over 50% of patients. It has also been shown to decrease libido in 36% of the patients taking it. Impotence occurs in 31%. Diarrhea, nausea, and vomiting occur in approximately 1 in 10 patients. Gynecomastia occurs in 9% of patients. Less common but not rare complications are anorexia, edema, leukopenia, and rash. Rarely hemolytic anemia, methemoglobinemia, along with increased aspartate aminotransferase, alanine aminotransferase, bilirubin, and blood urea nitrogen.
Rarely, flutamide has been associated with interstitial pneumonitis that may lead to pulmonary fibrosis. This has been seen in approximately 0.04% of patients.
It is contraindicated to use flutamide in patients with a hypersensitivity to flutamide or in those with the severe hepatic disease.
It is advised to not concomitantly use flutamide alongside drugs such as idelalisib and ivacaftor as this will result in serious adverse effects. Idelalisib strongly inhibits the enzyme CYP3A4 in the liver and intestines resulting in increasing the level of flutamide in the body. A metabolite of Ivacaftor, M1, has the same effect potentially if taken with flutamide. Other drugs with similar effects on the CYP3A4 enzyme but with less serious complications are crofelemer, dabrafenib, elvitegravir, cobicistat, emtricitabine, tenofovir, iloperidone, letermovir, and mitotane. These drugs do not necessarily require alternatives, but patients should be monitored closely for adverse effects. Other drugs that come with precautions are teriflunomide which inhibits CYP1A2 leading to increased levels of flutamide in the serum and warfarin. Flutamide increases the effects of warfarin leading to increased prothrombin time in patients taking both. Other substances to be mindful of when treating a patient with flutamide are maitake and taurine. Maitake is a mushroom with possible antitumor effects as shown in animal and in-vitro trials. Maitake has been shown to increase serum levels of flutamide. Taurine is an organic compound that found its way into popular energy drinks. Flutamide has been shown to interact with taurine, but it is unknown the significance of this interaction.
There is a risk for severe hepatic injury leading to hepatic failure. There is a potential for aniline toxicity which may cause methemoglobinemia or hemolytic anemia. Risk of cardiovascular disease may increase due to androgen deprivation.
Flutamide is indicated for the adult population only in the treatment of stage B2-C and stage D2 metastatic carcinoma of the prostate, female pattern hair loss and PCOS. The drug may be prescribed by the urologist, dermatologist, gynecologist, primary care physician, nurse practitioner and oncologist. However, it is important that all healthcare workers who prescribe flutamide be aware of the black box warning related to liver failure. In addition, the pharmacist must make sure that the patient is on no other medications that can compromise liver function. Thus, at every visit, the patient must be examined and the liver function evaluated. It is advised to discontinue therapy if jaundice develops or if alanine aminotransferase increased to two times the upper limit of normal.
|||Bachelot A,Chabbert-Buffet N,Salenave S,Kerlan V,Galand-Portier MB, Anti-androgen treatments. Annales d'endocrinologie. 2010 Feb; [PubMed PMID: 20096826]|
|||Paparodis R,Dunaif A, The Hirsute woman: challenges in evaluation and management. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2011 Sep-Oct; [PubMed PMID: 21856600]|
|||Iguchi T,Tamada S,Kato M,Yasuda S,Otoshi T,Hamada K,Yamasaki T,Nakatani T, Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: a retrospective study. International journal of clinical oncology. 2019 Feb 11; [PubMed PMID: 30741370]|
|||Sarrabay A,Hilmi C,Tinwell H,Schorsch F,Pallardy M,Bars R,Rouquié D, Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach. Toxicology and applied pharmacology. 2015 Dec 15; [PubMed PMID: 26485406]|
|||Koss WA,Frick KM, Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition. Hormones and behavior. 2019 Jan 17; [PubMed PMID: 30653980]|
|||Rodríguez-Lozano DC,Piña-Medina AG,Hansberg-Pastor V,Bello-Alvarez C,Camacho-Arroyo I, Testosterone Promotes Glioblastoma Cell Proliferation, Migration, and Invasion Through Androgen Receptor Activation. Frontiers in endocrinology. 2019; [PubMed PMID: 30778332]|
|||Chojnacka K,Hejmej A,Zarzycka M,Tworzydlo W,Bilinski S,Pardyak L,Kaminska A,Bilinska B, Flutamide induces alterations in the cell-cell junction ultrastructure and reduces the expression of Cx43 at the blood-testis barrier with no disturbance in the rat seminiferous tubule morphology. Reproductive biology and endocrinology : RB [PubMed PMID: 27036707]|
|||Kunath F,Grobe HR,Rücker G,Motschall E,Antes G,Dahm P,Wullich B,Meerpohl JJ, Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer. The Cochrane database of systematic reviews. 2014 Jun 30; [PubMed PMID: 24979481]|
|||Fransson P,Lund JA,Damber JE,Klepp O,Wiklund F,Fosså S,Widmark A, Quality of life in patients with locally advanced prostate cancer given endocrine treatment with or without radiotherapy: 4-year follow-up of SPCG-7/SFUO-3, an open-label, randomised, phase III trial. The Lancet. Oncology. 2009 Apr; [PubMed PMID: 19286422]|
|||Fagerlund A,Cormio L,Palangi L,Lewin R,Santanelli di Pompeo F,Elander A,Selvaggi G, Gynecomastia in Patients with Prostate Cancer: A Systematic Review. PloS one. 2015; [PubMed PMID: 26308532]|
|||Nishiyama T,Ishizaki F,Anraku T,Shimura H,Takahashi K, The influence of androgen deprivation therapy on metabolism in patients with prostate cancer. The Journal of clinical endocrinology and metabolism. 2005 Feb; [PubMed PMID: 15562007]|
|||Azarchi S,Bienenfeld A,Lo Sicco K,Marchbein S,Shapiro J,Nagler AR, Androgens in Women: Hormone modulating therapies for skin disease (Part II). Journal of the American Academy of Dermatology. 2018 Oct 9; [PubMed PMID: 30312645]|