VA Class:AN900
Flutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 2, 3, 5, 6, 7, 9, 11, 16, 19, 23, 24, 25, 26, 27
Flutamide is used in combination with a gonadotropin-releasing hormone (GnRH) analog (e.g., goserelin, leuprolide acetate) in the treatment of prostate cancer that is clinically localized, such as that confined to the prostate but with extensive involvement of one lobe or with involvement of both lobes (stage B2) and that localized to the periprostatic area but extending beyond the capsule and possibly affecting seminal vesicles (stage C).1, 20, 22, 23 Flutamide also is used in combination with a GnRH analog in the treatment of metastatic prostate cancer that involves distant lymph nodes, bone, or visceral organs (stage D2).1, 3, 5, 6, 7, 20 For additional information on combined antiandrogenic and GnRH analog therapy, see Uses: Prostate Cancer in Leuprolide Acetate 10:00.
Prostate specific antigen (PSA) concentrations should be determined periodically during combined flutamide and GnRH analog therapy to monitor therapeutic response, including successful remission or possible progression of cancer.1, 12 If PSA concentrations increase substantially and consistently during flutamide therapy, the possibility of clinical progression should be evaluated.1 Progression noted after gonadal ablation (i.e., pharmacologic treatment with a GnRH analog or orchiectomy) and antiandrogen therapy may represent growth that is not androgen dependent.6 For patients who have an objective progression of disease together with an elevated PSA, treatment with a GnRH analog without flutamide may be considered.1, 7 Withdrawal of flutamide in such patients can be associated with a decrease in PSA.7 The mechanism of this response to flutamide withdrawal has not been determined, but may involve the development of mutations at the androgen receptor.7, 23
Flutamide is metabolized in part to 4-nitro-3-fluoro-methylaniline.1 Toxicities associated with aniline exposure and flutamide therapy include methemoglobinemia, hemolytic anemia, and cholestatic jaundice.1 Methemoglobin concentrations should be monitored periodically in susceptible patients (e. g., those with glucose-6-phosphate dehydrogenase deficiency, hemoglobin M disease, smokers).1
Patients should be advised of the possibility of facial flushing during flutamide therapy1, 31 and that alcohol could exacerbate this effect.31 Patients who experience such intolerance during therapy with the drug should avoid alcohol consumption.31
Flutamide is administered orally1, 2, 3, 5, 6, 7, 12, 14, 17 without regard to meals.29
Because of the intended labeled use of flutamide, safety and efficacy of the drug have not been established in women or children.1, 29 Flutamide is not intended for use in women and should not be used in women, particularly for nonserious or nonlife-threatening conditions.1
For use in combination with a gonadotropin-releasing hormone (GnRH) analog in the management of clinically localized (stage B2 or C) or metastatic (stage D2) prostate cancer, the usual dosage of flutamide is 250 mg 3 times daily.1, 2, 3, 5, 6, 7, 12, 14, 17, 24, 25, 27, 28 In patients with clinically localized (stages B2 and C) prostatic cancer, treatment with flutamide and the GnRH analog should be initiated 8 weeks prior to and continued during radiation therapy.1 In patients with metastatic (stage D2) prostate cancer, treatment with flutamide and the GnRH analog should be initiated on the same day.1 The duration of combined therapy with flutamide and a GnRH analog depends on the clinical response of the patient and usually should continue until progression of the disease in patients with metastatic stage D2 prostate cancer.1
Periodic monitoring of serum prostate specific antigen (PSA) may be useful for assessing the patient's response to therapy.1 For patients with objective progression of disease and an elevated serum PSA, temporary withdrawal of flutamide therapy while continuing therapy with the GnRH analog may be considered.1
Discontinuance of Therapy for Hepatic Toxicity
Hepatic injury, manifested by elevated serum transaminase concentrations, jaundice, hepatic encephalopathy, and death related to acute hepatic failure, has been reported in patients receiving flutamide.1, 30 Liver failure associated with flutamide has required hospitalization in some cases and rarely has been fatal.1, 30 Onset of hepatic injury occurred within the first 3 months of flutamide therapy in about half of the cases reported.1 Hepatic injury was reversible in some patients following discontinuance of the drug.1, 30 Serum transaminase should be measured prior to starting flutamide therapy, and the drug is not recommended in patients with baseline serum ALT (SGPT) concentrations exceeding twice the upper limit of normal.1 Measurement of serum transaminase concentrations should be performed monthly for the first 4 months of flutamide therapy and periodically thereafter.1 Liver function tests also should be performed at the first sign or symptom of liver dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness, unexplained flu-like symptoms).1, 30 If liver function test results are elevated (i.e., transaminases increase to 2-3 times the upper limit of normal) or if jaundice occurs, flutamide therapy should be discontinued immediately and liver function tests monitored closely until resolution.1
Dosage in Hepatic and Renal Impairment
Flutamide is extensively metabolized to at least 6 metabolites.1
No information is available concerning use of flutamide in patients with hepatic impairment.1 The manufacturer states that flutamide should not be used in patients with severe hepatic impairment.1 Serum transaminase concentrations should be measured prior to initiation of flutamide therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter in all patients receiving flutamide.1 (See Discontinuance of Therapy for Hepatic Toxicity, in Dosage and Administration: Dosage.)
In individuals with chronic renal insufficiency receiving a single 250-mg dose of flutamide, there was no correlation between creatinine clearance and plasma concentrations of the drug.1 Renal impairment did not affect peak concentrations or AUCs of the drug and principal active metabolite.1 In individuals with a creatinine clearance of less than 29 mL/minute, the half-life of the active metabolite is slightly prolonged.1 Adjustment of flutamide dosage in patients with renal impairment generally is unnecessary.1
Flutamide, a toluidine derivative, is a nonsteroidal antiandrogen1, 2, 3, 5, 6, 7, 9, 11, 16, 19, 23, 24, 25, 26, 27 that is structurally and pharmacologically related to bicalutamide and nilutamide.2, 10, 23, 26
Flutamide is a pure antiandrogen, possessing no intrinsic hormonal activity;3, 24, 25 the antiandrogenic mechanism of action of the drug is via androgen-receptor antagonism.24, 25 Flutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis.1, 3, 8, 9, 10, 11, 12, 24, 25 Flutamide is a selective antiandrogen with no estrogenic, antiestrogenic, progestational, antiprogestational, antigonadotropic, or adrenocortical activity in various animal models.3
Flutamide is metabolized in vivo to 2-hydroxyflutamide, which appears to be principally responsible for the antiandrogenic activity;3 this metabolite is a potent competitive inhibitor of androgen-receptor binding,3, 25 exhibiting 1.5 times the antiandrogenic potency of flutamide in animal models.3 The relative binding affinity of 2-hydroxyflutamide at the androgen receptor is less than that of bicalutamide but similar to that of nilutamide.4, 12, 13, 14, 15 In addition to blocking the binding of dihydrotestosterone (DHT) at androgen receptors,1, 3, 12, 24, 25 flutamide inhibits androgen uptake into target cells, and decreases the number of intraprostatic androgen receptors by secondarily (i.e., subsequent to DHT-binding blockade) preventing translocation of the androgen-receptor complex into cellular nuclei.1, 3, 12, 24, 25 Metabolism of adrenal androgen precursors of testosterone (e.g., dehydroepiandrosterone [DHEA]) to inactive metabolites increases in castrated patients with prostatic cancer receiving flutamide.3
Common pharmacologic therapies for prostate cancer (i.e., gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effect of the drug.3, 25 Androgen receptors in the hypothalamus are blocked by flutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone.2, 3, 24, 25 As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy.6 However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade.3, 6, 16, 26, 27 Concomitant administration of antiandrogens such as nilutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy.6, 10, 11, 18 (See Cautions in Leuprolide Acetate 10:00.)
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 125 mg* | ||
Flutamide Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions August 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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