Flutamide

Flutamide is an antineoplastic/antiandrogenic agent belonging to the pharmacological class of non-steroidal androgen receptor inhibitors.

The FDA has approved flutamide to treat prostate cancer that may be locally advanced or has metastasized (spread to other parts of the body).

Flutamide is rapidly and completely absorbed from the gastrointestinal tract and exhibits a high level of plasma protein binding, ranging from 94-96%. It undergoes extensive liver metabolism, forming the primary active metabolite, 2-hydroxyflutamide. Excretion primarily occurs through urine (as unchanged drugs and metabolites) and minimally via faeces (4%).

The most common side effects of flutamide include breast enlargement in males, sleepiness, nausea, and vomiting.

Flutamide is available in the form of an oral Capsule.

The molecule is available in India, the United States, Canada, the United Kingdom, Italy, Australia, Germany, France, Japan and Spain.

Flutamide is an antineoplastic/antiandrogenic agent belonging to the pharmacological class of non-steroidal androgen receptor inhibitors.

Flutamide binds to the androgen receptor to inhibit endogenous and exogenous testosterone effects. Furthermore, testosterone-stimulated prostatic DNA synthesis is potently inhibited by flutamide. It can also prevent testosterone from being taken up by the prostatic nucleus.

Flutamide is available in the form of oral Capsule.

Capsule: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally thrice daily; it can be taken with or without food as directed.

Flutamide can be used in the following health conditions:

• Prostate Cancer in men
• off-label: For the treatment of hair loss, hirsutism, polycystic ovarian syndrome, and acne.

In Prostate cancer

By blocking testosterone's ability to bind to prostate cancer cells, bypassing their ability to produce testosterone and preventing their proliferation, flutamide suppresses the effects of androgens. Lowering testosterone levels, relieving urinary issues, and decreasing prostate tumours all contribute to slowing down or stopping the proliferation of cancer cells. It treats metastatic prostate cancer in conjunction with radiation therapy, reducing testosterone levels to prevent cancer cells from growing and facilitating urination.

•It is indicated to use flutamide capsules in conjunction with LHRH-agonists to treat locally circumscribed cases of both Stage D2 and Stage B2-C metabolic cancer of the prostate.

•Low-dose flutamide effectively reduces acne and seborrhea in women, demonstrating a substantial decrease in acne after six months of therapy, with the peak benefit achieved at one year of use.

•The treatment is also effective for female pattern hair loss, either as a standalone option or in combination with oral contraceptives, proving superior to cyproterone acetate and finasteride.

Orally: Flutamide is typically taken orally as a single dose.

•Flutamide should be administered to patients with stage B2-C prostatic cancer in conjunction with a gonadotropin-releasing hormone analogue beginning eight weeks before the start of radiation therapy and continuing for the duration of the radiation treatment.

•When treating stage D2 metastatic prostate cancer, patients should take flutamide together with an analog of gonadotropin-releasing hormone.

If a dose of flutamide is missed, take the next dose at the scheduled time. Nevertheless, taking two doses to make up for a missed one is not recommended.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Capsule: 125mg

Flutamide is available in the form of oral Capsules.

Dose Adjustment in Adult Patients:

Recommended dosage: 250 mg PO every 8 hours, for a total daily dose of 750 mg, when used with analogs of gonadotropin-releasing hormone (GnRH/LHRH)

Patients should incorporate cruciferous vegetables like cauliflower, cabbage, broccoli, spinach, and kale into their diet when undergoing flutamide treatment for prostate cancer. These foods can impede the growth of prostate cancer and decrease the risk of its development. It is advised to minimize the consumption of red meat or a meat-rich diet, as cooking meat may elevate the risk of prostate cancer. Similarly, reducing dairy product intake is suggested to mitigate the risk. Including antioxidant-rich foods such as berries, spinach, kidney beans, and dark chocolate is encouraged. A diet with fibre-containing foods like beans, peas, lentils, whole grains, nuts, and seeds supports improved digestion.

The dietary restriction should be individualized as per patient requirements.

Flutamide may be contraindicated in the following conditions:-

• Anyone who has previously experienced hypersensitivity to any of the product's constituents.
• In patients with severe hepatic impairment

• Consider evaluating the baseline hepatic enzymes before initiating Flutamide treatment.
• Flutamide capsules are exclusively intended for men; they are not indicated for women and should not be used, especially for non-serious or non-life-threatening conditions.
• The metabolite 4-nitro-3-fluoro-methylaniline, produced by flutamide, can lead to toxicities resembling aniline exposure, such as methemoglobinemia, hemolytic anaemia, and cholestatic jaundice. Individuals at risk (e.g., those with glucose-6-phosphate dehydrogenase deficiency, haemoglobin M disease, and smokers) should have methemoglobin levels monitored.
• Gynecomastia occurred in 9% of patients during clinical trials when using flutamide with medical castration.

• Patients must be informed that concurrent administration of flutamide capsules and the drug for medical castration is necessary. Interrupting or discontinuing medication should only be done after consulting their physician.

It is unsafe to consume flutamide with alcohol.

It is not recommended for use during breastfeeding.

It is not recommended for use during pregnancy.

Limit intake of grilled meat and saturated fats for safety.

The adverse reactions related toFlutamide can be categorized as

• Common Adverse Effects: Hot flashes, decreased libido, impotence, diarrhoea, and nausea/vomiting.
• Less Common Adverse Effects: Gynecomastia, anorexia, oedema, leukopenia, and rash
• Rare Adverse Effects: Malignant breast neoplasms.

Reports from postmarketing

Hemolytic anaemia, macrocytic anaemia, methemoglobinemia, sulfhemoglobinemia, bullous eruptions, photosensitivity reactions (including erythema, ulceration, and epidermal necrolysis) and urine discolouration

The clinically relevant drug interactions of flutamide are briefly summarized here.

• Drug-Drug Interaction: Flutamide may interact with other medications that contain laxatives (methylcellulose), anticoagulants (warfarin), anabolic steroids (oxymetholone, oxandrolone), and testosterone.
• Drug-Food Interaction: To reduce the risk of diarrhoea, it is recommended to refrain from dairy products, including milk, yoghurt, and cheese.
• Drug-Disease Interaction: People with elevated liver enzymes or illness should use flutamide cautiously.

The common side effects of flutamide include nausea, vomiting, diarrhoea, hot flashes, and difficulty sleeping. Other potential effects are loss of appetite, dark-coloured urine, breast enlargement in males, abdominal pain, anaemia, breast tenderness, constipation, decreased libido, depression, dizziness, indigestion, flatulence, increased liver enzymes, weakness, weight gain, erectile dysfunction, hair loss, a butterfly-shaped rash across the nose and cheeks, and difficulty breathing, shortness of breath, wheezing, or coughing.

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

If flutamide is given to a pregnant woman, it could harm the fetus. There aren't enough reliable, well-controlled research on expectant mothers. Patients should be informed of the possible risks to the fetus if they use this medication while pregnant or if they get pregnant while taking it. Women of childbearing potential are advised to avoid becoming pregnant.

Data

Flutamide at doses of 30, 100, or 200 mg/kg/day (about 3, 9, or 19 times the human dose) reduced the offspring of pregnant rats' survival rate throughout 24 hours. Rat pregnancies given two higher dosages showed a slight increase in minute differences in vertebral and sternal development. Furthermore, the male rats were feminised at the two higher treatment levels. Rabbits receiving the maximum dose (15 mg/kg/day, or 1.4 times the human level) had a lower rate of survival in their offspring.

• Nursing Mothers

Lactating women are not advised to use flutamide. Evidence about the presence of flutamide in human milk, its effects on nursing infants, or its impact on milk supply is not currently available.

• Pediatric Use

As per the FDA, Flutamide is not indicated in the pediatric population.

Geriatric Use

The safety and efficacy of flutamide in geriatric patients have yet to be extensively studied. Dosage adjustments may not be necessary based on age alone. Caution and close monitoring for potential adverse effects are recommended in this population.

Dose Adjustment in Kidney Impairment Patients:

Renal impairment: No dosage adjustment is required.

Dose Adjustment in Hepatic Impairment Patients:

Patients with liver function disorders should take caution while administering Flutamide because the drug is extensively metabolized in the liver.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of flutamide.

Signs and Symptoms

Overconsumption of Flutamide could lead to Breast tenderness, gynecomastia, and increased AST.

Management

There is no specific antidote or treatment for excessive Flutamide intake, so treatment typically involves symptomatic and supportive measures. Measures may include gastric lavage or induced emesis to remove unabsorbed medication, followed by supportive care to maintain vital functions. Dialysis might not be beneficial due to flutamide's extensive protein binding and large volume of distribution. Continuous observation and appropriate, timely medical interventions to address specific symptoms or complications are recommended.

Pharmacodynamics:

Flutamide has been shown to have antiandrogenic solid properties in animal experiments. It blocks the nuclear binding of androgen in target tissues, androgen absorption, or both to provide its antiandrogenic effect. It is well established that prostate cancer is androgen-sensitive and that treatment aimed at blocking the effects of testosterone or eliminating its source—such as castration—will have an impact. Flutamide treatment has been associated with elevated levels of plasma testosterone and estradiol.

Pharmacokinetics:

• Absorption: Flutamide is swiftly and entirely absorbed from the gastrointestinal tract, demonstrating a peak plasma concentration within approximately 1-2 hours post-administration. The drug's half-life is notably short, lasting around 6 hours.
• Distribution: Flutamide exhibits a high level of plasma protein binding, ranging from 94-96%, while its major active metabolite, 2-hydroxyflutamide, displays a slightly lower binding percentage of 92-94%.
• Metabolism: In the liver, flutamide undergoes rapid and extensive metabolism, primarily transforming into the primary active metabolite, 2-hydroxyflutamide. Other metabolites such as 4-nitro-3-fluoro-methylaniline and 2-amino-5-nitro-4-(trifluoromethyl) phen,ol are also formed.
• Excretion: The elimination of flutamide primarily occurs through urine, where both unchanged drugs and metabolites are excreted. A minor proportion is also eliminated via the faeces, constituting approximately 4% of the total excretion. The elimination half-life of 2-hydroxyflutamide is roughly 6 hours.

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