Flutamide


Article Author:
Donavon Johnson


Article Editor:
Sidharth Sonthalia


Editors In Chief:
Stephen Leslie
Karim Hamawy


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Orawan Chaigasame
Carrie Smith
Abdul Waheed
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James Hughes
Beata Beatty
Nazia Sadiq
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Phillip Hynes
Tehmina Warsi


Updated:
5/1/2019 10:43:00 AM

Indications

Flutamide is indicated for the adult population only in the treatment of stage B2-C and stage D2 metastatic carcinoma of the prostate.[1]

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.[2]

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.[3]

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.[1]

First discovered in 1967, it was originally made for use as an antibiotic.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.

Mechanism of Action

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.[4]

Administration

Flutamide is taken as a 250 mg oral capsule given every 8 hours.[5]

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.[6]

For stage D2 metastatic carcinoma of the prostate, it is advised that the patient take flutamide in combination with a gonadotropin-releasing hormone analog.[6]

Adverse Effects

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.[7]

The most common adverse effect of flutamide use is hot flashes[8], 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%[9]. Diarrhea, nausea, and vomiting occur in approximately 1 in 10 patients. Gynecomastia occurs in 9% of patients[10]. 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.[11]

Rarely, flutamide has been associated with interstitial pneumonitis that may lead to pulmonary fibrosis. This has been seen in approximately 0.04% of patients.

Contraindications

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.[12]

Toxicity

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.

Enhancing Healthcare Team Outcomes

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.[7] 


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Flutamide - Questions

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Which of the following drug combinations would you prefer in a 69-year old male with metastatic castration-resistant prostate cancer (mCRPC) who also suffered from myocardial infarction one-year back which was managed with coronary artery bypass surgery [CABP]?



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A 30-year-old lean unmarried female presents with jaundice, itching in her palms and soles, severe lethargy, right upper quadrant abdominal pain, nausea and anorexia for the past 15 days. She also has a history of having irregular cycles, adult-onset acne over the lower face with a pre-menstrual flare-up, increased facial hairs and thinning of the scalp hair for about two years. She was diagnosed to have polycystic ovarian syndrome (PCOS) although her hormonal (androgens, insulin, prolactin) assays were within normal limits. She is currently taking oral contraceptives (containing cyproterone acetate) and spironolactone with minimal improvement in her cutaneous symptoms. Three months ago, she was started on oral flutamide which resulted in improvement in her acne, hair loss and thinning. No baseline tests were done before starting these two medications. Liver function tests reveal total bilirubin of 25.8 mg/dl, ALT 1415 IU/ml, AST 1207 IU/ml, and Alk-Phos 743 IU/mL. Which of the following is the next best step in the management of this patient?



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What black box warning accompanies the use of flutamide?



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Flutamide has one indication for use approved by the United States Food and Drug Administration. What is this use?



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A 66-year-old male presents to the clinic with a recent diagnosis of carcinoma of the prostate stage B2-C. Flutamide therapy is initiated. Which of the following medications is most often used in conjunction with flutamide for this disease?



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A 64-year-old man was diagnosed with carcinoma of the prostate with metastasis to the lumbar spine. The patient has been on finasteride therapy with flutamide. What side effects of this treatment are most likely to be found in this patient?



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A 75-year-old male with prostate cancer has suboptimally responded to the management despite surgical castration. He is being planned for oral anti-androgen therapy. The patient also gives a history of irritable bowel syndrome (IBS) with off and on diarrhea and almost daily alcohol intake. His past history includes epilepsy that started with generalized tonic-clonic seizures around 3 years back for which he is on oral phenytoin. Occupationally he has worked for 40 years in a glass manufacturing factory. His chest XR-CT scan and spirometry confirmed interstitial lung disease (ILD), although his breathing is well-controlled on salmeterol - budesonide combination rotahaler. Which of the following antiandrogens should you prefer in addition to leuprolide for his further medical management?



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Flutamide - References

References

Bachelot A,Chabbert-Buffet N,Salenave S,Kerlan V,Galand-Portier MB, Anti-androgen treatments. Annales d'endocrinologie. 2010 Feb;     [PubMed]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]

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