Flutamide

Flutamide is an oral non-steroidal antiandrogen of the anilide group. Prostate cancer is androgen-sensitive and responds to treatment that counteracts androgens or removes their source, for example castration. In animal studies flutamide has potent antiandrogenic effects, and given together with surgical or medical castration it suppresses both testicular and adrenal androgen activity.

Mechanism of Action

• Androgen receptor blockade: flutamide binds to the androgen receptor and blocks the action of both the body’s own and administered testosterone.
• Inhibition of androgen uptake: it acts by inhibiting androgen uptake and/or the nuclear binding of androgen in target tissues, and it inhibits testosterone-stimulated DNA synthesis in the prostate.
• Hormone levels: in patients who have not been castrated, flutamide tends to raise plasma testosterone and oestradiol concentrations.
• Use before radical treatment: in clinical trials of flutamide with LHRH agonists as neoadjuvant therapy for localised prostate carcinoma before radical surgery or radiotherapy, survival was not shown to rise, but tumour size fell, morbidity and surgical sequelae decreased, and disease progression was delayed.

Pharmacokinetics

• Absorption: flutamide is well absorbed after oral dosing, and food does not affect absorption.
• Metabolism: conversion to metabolites is rapid and extensive; at least six were identified in plasma up to 8 hours after a dose. The main plasma metabolite is a biologically active alpha-hydroxylated derivative (2-hydroxyflutamide), which accounted for 23% of plasma radioactivity one hour after dosing and peaks about 2 hours after the dose. CYP1A2 is the main enzyme converting flutamide to this active metabolite. The main urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.
• Distribution: flutamide is 94–96% bound to plasma proteins and its active metabolite 92–94%.
• Elimination: the plasma half-life of the active metabolite is about 6 hours in adults and 8 hours in healthy elderly volunteers. About 45% of a dose is excreted in urine and 2% in faeces during the first two days, and metabolism and excretion are essentially complete within two days. Flutamide is not removed by dialysis.
• Special populations: kidney or liver impairment can change the pharmacokinetics of flutamide and the dose needed, but the requirements have not been established.

Advanced prostate carcinoma in which suppression of the effects of testosterone is indicated:

• Initial treatment: in combination with an LHRH agonist.
• Adjuvant therapy: in patients who are being treated with an LHRH agonist or who have had surgical castration.

• Hypersensitivity to flutamide or to any of the excipients.

The reactions reported most often with flutamide alone in clinical studies are gynaecomastia and/or breast tenderness, sometimes with galactorrhoea; they disappear when treatment is stopped or the dose is reduced. With an LHRH agonist, the most frequent reactions are hot flushes, decreased libido, impotence, diarrhoea, nausea and vomiting. Apart from diarrhoea, these also occur with LHRH agonists alone at a similar frequency, and the high rate of gynaecomastia seen with flutamide alone falls greatly in the combination. Flutamide carries a low cardiovascular risk, significantly lower than that of diethylstilbestrol. The SmPC lists the reactions separately for flutamide alone and for flutamide with an LHRH agonist.

Flutamide alone

Very common (≥1/10): gynaecomastia and/or breast tenderness, sometimes with galactorrhoea.

Common (≥1/100 to <1/10): increased appetite; insomnia; diarrhoea, nausea, vomiting; fatigue; transient liver dysfunction.

Rare (≥1/10,000 to <1/1,000): herpes zoster; oedema, ecchymosis, lymphoedema; lupus-like syndrome; anorexia; anxiety, depression; dizziness; blurred vision; gastric discomfort, ulcer-type pain, heartburn, constipation; pruritus; headache, weakness, malaise, thirst, chest pain.

Very rare (<1/10,000): breast neoplasm in men (two cases of malignant breast tumour were reported); hepatitis; photosensitivity.

Not known: QT interval prolongation.

Decreased libido and decreased sperm counts are also listed for flutamide alone; the SmPC table gives their frequencies.

Flutamide with an LHRH agonist

Very common (≥1/10): hot flushes, decreased libido, impotence; diarrhoea, nausea, vomiting.

Rare (≥1/10,000 to <1/1,000): anaemia, leucopenia, oedema, thrombocytopenia; anorexia; depression, anxiety; somnolence, confusion, nervousness; hypertension; non-specific gastrointestinal disorders; jaundice; erythema; neuromuscular symptoms; genitourinary symptoms; gynaecomastia; injection-site irritation; abnormal liver function tests, increased blood urea nitrogen and serum creatinine.

Very rare (<1/10,000): haemolytic anaemia, macrocytic anaemia, methaemoglobinaemia, sulfhaemoglobinaemia; hyperglycaemia and worsening of diabetes mellitus; interstitial lung disease; cholestatic jaundice, hepatic encephalopathy, hepatic necrosis, deaths after severe liver injury; photosensitivity, erythema, ulceration, bullous eruptions, epidermal necrolysis; change in urine colour to amber or yellow-green.

• Oral anticoagulants: in patients on long-term oral anticoagulants, the prothrombin time rose after flutamide monotherapy was started. Close monitoring of the prothrombin time is recommended, and the anticoagulant dose may need adjusting.
• Medicines that prolong the QT interval or can cause torsade de pointes: use together with flutamide needs careful assessment, because androgen deprivation therapy can also prolong the QT interval. The SmPC names class IA antiarrhythmics (for example quinidine, disopyramide), class III antiarrhythmics (for example amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin and antipsychotics, among others.
• Theophylline: higher plasma theophylline concentrations have been reported in patients receiving flutamide. Theophylline is mainly metabolised by CYP1A2, the main enzyme that converts flutamide to its active metabolite 2-hydroxyflutamide.
• Food: tablets may be taken with or without food.

Flutamide is taken by mouth and is for men only.

Recommended Dose

• 250 mg (one tablet) three times daily, at 8-hour intervals.
• With an LHRH agonist: starting flutamide 1–3 days before the LHRH agonist gives a greater reduction in the incidence and severity of the agonist’s symptomatic flare-up. It is therefore recommended to start one tablet three times daily either at the same time as the LHRH agonist or 24 hours or more before it, and then to continue at the same dose.
• With radiotherapy or surgery: the SmPC advises starting flutamide eight weeks before radiotherapy and continuing for its duration, or twelve weeks before prostatectomy.

Special Populations

• Renal or hepatic impairment: flutamide is extensively metabolised in the liver and eliminated mainly by the kidneys. Impairment can alter its pharmacokinetics and the dose needed, but the dose requirements have not been established. It is not removed by dialysis.
• Women and children: flutamide is not indicated in women, and the SmPC gives no paediatric dosing.

Liver Damage and Liver Function Monitoring

• Before treatment: flutamide should not be started in patients whose serum transaminases exceed 2 to 3 times the upper limit of normal.
• What has been reported: transaminase abnormalities and cholestatic jaundice, as well as hepatic necrosis and hepatic encephalopathy. The liver changes were generally reversible after stopping treatment or reducing the dose, but deaths have been reported after severe liver injury in patients treated with flutamide.
• Monitoring: periodic liver function tests should be considered in all patients. Appropriate laboratory tests should be done monthly during the first 4 months, periodically after that, and at the first symptom or sign of liver dysfunction (for example itching, dark urine, persistent loss of appetite, jaundice, tenderness in the right upper abdomen or unexplained flu-like symptoms).
• When to stop: flutamide must be stopped if the patient has laboratory evidence of liver injury or jaundice (in the absence of biopsy-confirmed liver metastases), or if serum transaminases exceed 2 to 3 times the upper limit of normal, even in patients who have no symptoms.

Men Only

Flutamide is indicated only in male patients.

Hormone Levels, Sperm Count, Fluid Retention and Urine Colour

• In patients who have not had medical or surgical castration, flutamide tends to raise plasma testosterone and oestradiol, and determination of the sperm count should be considered during long-term treatment.
• Fluid retention can occur, so flutamide is used with caution in heart disease.
• The urine may change colour, from amber to yellow-green.

QT Interval

Androgen deprivation therapy can prolong the QT interval. In patients with a history of, or risk factors for, QT prolongation, and in those taking medicines that could prolong it, the doctor weighs the benefit against the risk, including the potential for torsade de pointes, before starting flutamide.

Pregnancy, Breastfeeding and Fertility

The SmPC states that these sections do not apply, because flutamide is not indicated in women. For men, decreased sperm counts are listed among the side effects (see above).

Excipients

• Lactose: each tablet contains 221.7 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.
• Sodium: each tablet contains less than 23 mg (1 mmol) of sodium, that is, it is essentially sodium-free.

Effect on Driving

The SmPC states that this section does not apply. Dizziness, somnolence and blurred vision are listed among the rare side effects.

Do not store above 25 °C. The tablets come in PVC-PVDC/aluminium blisters of 50 or 84 tablets. Keep out of the sight and reach of children.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Flutamide is taken at home, so it is supplied to the patient or to the treating clinic on prescription. Liver function monitoring (monthly during the first 4 months, then periodically) goes with the treatment.