flutamide

Action and Spectrum

Flutamide is a nonsteroidal antiandrogen that blocks androgen receptors throughout the body, counteracting the growth-promoting effects of testosterone in prostate cancer. Due to its short half-life of about 6 hours, it requires administration at least three times daily to maintain effective blood levels. The drug is mainly broken down in the liver by enzymes such as CYP3A4 and CYP1A2, and it is largely eliminated through the urine, with minimal excretion in the feces (less than 5%). 

Drug Interaction

Adverse Reaction

Frequency defined: 

>10%: 

Diarrhea (30%) 

Impotence (33%) 

Breast tenderness  

Increased serum AST 

Rectal hemorrhage  

1% to 10% 

Anxiety 

Gastric distress 

Proctitis 

Constipation 

Hematuria 

Anemia 

Muscle weakness  

<1% 

Skin photosensitivity 

Urine discoloration 

Hepatic failure 

Thrombophlebitis 

Black Box Warning

Flutamide therapy has been associated with serious liver toxicity, including rare cases of liver failure and death. Signs of liver damage may include elevated liver enzymes, jaundice, hepatic encephalopathy, and, in some cases, fatal acute liver failure. In certain patients, liver function improved after stopping the medication. Notably, around half of these cases occurred within the first three months of treatment. 

Before beginning therapy, liver enzymes—specifically serum transaminases—should be checked, and treatment should not start if ALT levels are more than twice the upper limit of normal. During treatment, liver enzymes should be monitored monthly for the first four months, then at regular intervals. Liver function tests must also be done promptly if symptoms of liver dysfunction appear, such as nausea, vomiting, abdominal pain, fatigue, appetite loss, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness. If jaundice develops or ALT levels exceed twice the normal limit, treatment should be stopped immediately and liver function closely monitored until recovery. 

Contraindication / Caution

Contraindication 

Hypersensitivity 

Cautions 

Caution is advised when flutamide is combined with certain medications due to the risk of serious side effects. Co-administration with idelalisib or ivacaftor is particularly discouraged, as both can raise flutamide levels in the body—idelalisib through strong inhibition of CYP3A4 and ivacaftor via its active metabolite (M1). 

Other medications that affect CYP3A4, including crofelemer, dabrafenib, elvitegravir, cobicistat, emtricitabine, tenofovir, iloperidone, letermovir, and mitotane, may also alter flutamide metabolism, although the associated risks are typically less severe. These drugs can still be used with careful monitoring for potential side effects. 

Additional precautions are necessary with teriflunomide, which inhibits CYP1A2 and may raise flutamide concentrations, and warfarin, whose anticoagulant effect may be enhanced by flutamide, increasing the risk of bleeding due to prolonged prothrombin time. 

Pregnancy / Lactation

Pregnancy consideration: Based on animal reproduction research data, flutamide may cause fetal harm and potential fetal loss. 

Lactation: excretion of flutamide in breast milk is unknown.  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no evidence of risk to the fetus in the first trimester or the later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Flutamide is a nonsteroidal antiandrogen that works by blocking androgen receptors, preventing both natural and external sources of testosterone from exerting their effects. It also inhibits testosterone-driven DNA synthesis in prostate cells and reduces the uptake of androgens by the prostate nucleus, contributing to its effectiveness in managing prostate cancer. 

Pharmacokinetics 

Absorption 

Flutamide is rapidly and fully absorbed after oral administration. 

Distribution 

Although the exact volume of distribution is not available, flutamide shows high protein binding, ranging from 94% to 96%. 

Metabolism 

It undergoes extensive and rapid metabolism, with the parent drug accounting for only about 2.5% of plasma radioactivity one hour after dosing. The primary active metabolite is 2-hydroxyflutamide. 

Elimination/Excretion 

The drug and its metabolites are mainly excreted through the urine, while a small portion (approximately 4.2%) is eliminated via feces within 72 hours. 

Half-life: The active alpha-hydroxylated metabolite has a plasma half-life of around 6 hours. 

Clearance: Specific clearance data are not available. 

Pharmacodynamics 

Flutamide is a nonsteroidal antiandrogen with strong antiandrogenic activity demonstrated in animal studies. It works by blocking androgen uptake and/or preventing androgen from binding to nuclear receptors in target tissues. Since prostate cancer is typically androgen-dependent, flutamide helps suppress tumor growth by interfering with androgen signaling, like the effects of androgen deprivation (e.g., surgical castration).

Adminstartion

Flutamide is typically administered at a dose of 250 mg three times daily (totaling 750 mg per day) for advanced prostate cancer.  

Patient Information Leaflet

Generic Name: Flutamide 

Pronounced: FLOO-tuh-mide 

Why do we use Flutamide?  

Flutamide is an anti-androgen medication primarily used to treat androgen-dependent cancers, such as prostate cancer, and conditions linked to excess androgen levels, including polycystic ovary syndrome (PCOS). It serves as a key example of drugs in the anti-androgen class.