(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Flutamide). A pale yellow, crystalline powder. Practically insoluble in water; freely soluble in alcohol and in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Flutamide). A pale yellow, crystalline powder. Practically insoluble in water, in liquid paraffin, and in petroleum spirit; freely soluble in acetone, in ethyl acetate, and in methyl alcohol; soluble in chloroform and in ether. Store in airtight containers. Protect from light.

Adverse Effects and Precautions

The most frequently reported adverse effects with flutamide are hot flushes and reversible gynaecomastia or breast tenderness, sometimes accompanied by galactorrhoea. Nausea, vomiting, diarrhoea, increased appetite, anorexia, and sleep disturbances may occur. There have been reports of skin reactions, including epidermal necrolysis, and of liver damage, sometimes fatal. Other adverse effects reported in patients receiving flutamide include anaemias, haemolysis, headache, dizziness, malaise, blurred vision, anxiety, depression, decreased libido, impotence, and hypertension. Abdominal pain, chest pain, dyspnoea, and cough have been reported rarely. Discoloration of the urine to amber or yellow-green can be caused by the presence of flutamide and/or its metabolites.

Flutamide should be used with care in patients with cardiovascular disease because of the possibility of fluid retention. It should also be used with caution in patients with hepatic impairment and is contra-indicated in those with severe impairment. Regular liver function testing is recommended in all patients: therapy should be stopped or dosage reduced if there is evidence of hepatotoxicity.

Effects on the blood. A report of methaemoglobinaemia in an elderly man was attributed to flutamide. A study of 45 patients given flutamide found no cases of methaemoglobinaemia, but the authors noted a further 3 published case reports.

Effects on the liver. Hepatitis occurred in a 79-year-old man taking flutamide 750 mg daily as sole therapy after a prostatectomy, but a subsequent study in 1091 patients given flutamide 250 mg three times daily as part of a regimen for prostate cancer found marked signs of liver damage only in 4, of whom only 2 had clinical evidence of hepatotoxicity. In the USA, the FDA had 46 reports of patients with hepatotoxicity associated with flutamide up to December 1994. Of these patients, 20 died from progressive liver disease. Further cases have continued to be reported. Early tapering of the dose, stopping therapy, or switching to another anti-androgen may resolve hepatotoxic effects. Patients with chronic viral hepatitis may be at higher risk of developing hepatotoxicity with anti-androgen therapy.

Effects on the lungs. In a review of 78 cases of pneumonitis reported to the FDA between 1998 and 2000 that were associated with bicalutamide, flutamide, or nilutamide, it was found that 14 patients had died of respiratory failure. It was estimated that the incidence of pneumonitis was highest for nilutamide (0.77%), but lower for flutamide (0.04%) and brcalutamrde (0.01%).

Effects on the skin. Photosensitivity reactions have been reported in patients receiving flutamide. Some consider it to be an early manifestation of SLE.

Gynaecomastia. Gynaecomastia and breast pain are frequent adverse effects of nonsteroidal anti-androgens used to treat prostate cancer. Nearly 90% of patients treated with bicalutamide in the Early Prostate Cancer programme experienced breast pain, gynaecomastia, or both. Some patients who develop gynaecomastia will accept it as a tolerable adverse effect of therapy but others will require specifrc treatment, and a number of different measures have been tried for both prevention and treatment. The risk of breast changes can be reduced by the use of prophylactic low-dose irradiation of the breast area before nonsteroidal anti-androgen therapy is started. However, skin irritation can occur, and the long-term risk for development of breast cancer is unknown. Irradiation is unlikely to be effective once breast enlargement has occurred but it can help to reduce pain. Empirical use of oral analgesics or topical local anaesthetics may be considered for breast pain. Specifrc surgical treatment to reduce breast tissue includes liposuction and breast tissue excision.

Hormonal therapy using tamoxifen or anastrozole has been suggested, largely based on reports of benefit in various patient groups with gynaecomastia. Two randomised controlled studies of men who were treated with bicalutamide for prostate cancer found that prophylactic tamoxifen was effective for the prevention of gynaecomastia and breast pain, but that anastrozole was no better than placebo. One of these studies also assessed the use of these drugs as treatment and found that gynaecomastia and breast pain resolved in at least 65% of patients treated with tamoxifen, but only in about 18% of those treated with anastrozole. Tamoxifen is considered to be more effective than radiotherapy for prevention of gynaecomastia.

Interactions

Flutamide may increase the effect of warfarin, see Antineoplastics.

Pharmacokinetics

Flutamide is reported to be rapidly and completely absorbed from the gastrointestinal tract with peak plasma concentrations occurring 1 hour after a dose. It is rapidly and extensively metabolised; the major metabolite (2-hydroxyflutamide) possesses anti-androgenic properties. The half-life of the metabolite is about 6 hours. Both flutamide and 2-hydroxyflutamide are more than 90% bound to plasma proteins. Excretion is mainly in the urine with only minor amounts appearing in the faeces.

Uses and Administration

Flutamide is a nonsteroidal compound with anti-androgenic properties which appears to act by inhibiting the uptake and/or binding of androgens in target tissues. It is used, usually with gonadorelin analogues, in the palliative treatment of prostatic carcinoma. The usual oral dose is 250 mg three times daily. When used in combination therapy UK licensed product information recommends that flutamide treatment should be started at least 3 days before the gonadorelin analogue to suppress any ‘flare’ reaction; however, in some other countries it is recommended that treatment with both agents be begun simultaneously for optimum effect.

Congenital adrenal hyperplasia. For mention of the use of flutamide with testolactone to block androgenic effects in congenital adrenal hyperplasia.

Hirsutism. Anti-androgens (usually cyproterone or spironolac-tone) are widely used for the drug treatment of hirsutism. Flutamide has no particular advantage in this context; one study has found flutamide to be more effective than spironolactone in inhibiting hirsutism, but others found them to be of similar efficacy, and the risk of hepatotoxicity with flutamide is a problem. Nonetheless, flutamide has continued to be investigated.

Malignant neoplasms. Androgen blockade, which may include the use of flutamide, is used in the management of meta-static hormone-responsive prostate cancer; once the cancer begins to progress despite such therapy, stopping flutamide occasionally produces paradoxical disease regression. Promising preliminary results have also followed the use of flutamide in patients with adenocarcinoma of the pancreas.

Polycystic ovary syndrome. Flutamide has been used, usually with metformin, in the management of polycystic ovary syndrome; additive effects have been reported with this combination.

Preparations

The United States Pharmacopeia 31, 2008: Flutamide Capsules.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed

Argentina: Asoflut; Dedile; Eulexin¤; Flutaplex; Flutax¤; Flutepan; Flutrax; FTDA¤; Olter¤; Australia: Eulexin; Flutamin; Fugerel; Austria: Afluta; Androbloc; Flutabene; Flutahexal; Flutastad; Fugerel; Belgium: Eulexin; Flutaplex¤; Brazil: Biomida; Eulexin; Tecnoflut; Teflut; Canada: Euflex; Chile: Androdor¤; Drogenil; Etaconil; Flulem; Czech Republic: Andraxan; Flucinom; Flutacan; Prostandril; Xadaren; Denmark: Eulexin; Fluprosin; Flutacan¤; Flutaplex¤; Profamid; Finland: Eulexin; Profamid; France: Eulexine; Prostadirex; Germany: Apimid; Flumid; Fluta; Flutamex¤; Flutexin; Fugerel; Prostica; Prostogenat¤; Testac¤; Testotard; Greece: Adiprost; Elbat; Flucinom; Flutaplex; Palistop; Prostamide; Tremexal; Hong Kong: Flutan¤; Fugerel; Hungary: Cytamid; Flutam; Fugerel; India: Cytomid; Prostamid; Ireland: Androstat; Drogenil; Israel: Eulexin; Italy: Drogenil; Eulexin; Fluprost; Virflutam¤; Malaysia: Flutan; Flutaplex; Fugerel¤; Mexico: Eulexin; Fluken; Flulem; Tafenil; Netherlands: Drogenil; Eulexin; Norway: Eulexin; New Zealand: Eulexin; Flutamin; Flutol¤; Portugal: Draxon¤; Eulexin; Russia: Flutamid (Флутамид); Flutaplex (Флутаплекс); South Africa: Eulexin; Flutahexal; Flutaplex; Singapore: Fugerel¤; Spain: Eulexin; Flutandrona; Flutaplex; Grisetin; Oncosal; Prostacur; Sweden: Eulexin; Flutacan¤; Switzerland: Flucinome; Thailand: Flutan; Fugerel; United Kingdom: Chimax; Drogenil; United States: Eulexin¤; Venezuela: Eulexin

FLUTAMIDE (FLUTE-am-eyed)

Other Names for this Medication: Euflex®, Drogenil®, Eulexin ®, Apo-flutamide®, Novo-flutamide®, Pms-flutamide® (Brand Names)

Appearance

Oral Tablets: Round, pale yellow, tablet containing 250 mg of flutamide.

Why this Medication is Used

This medication may be used alone, or in combination with other medications for the treatment of prostate cancer. Flutamide blocks the male hormone that stimulates the growth of prostate cancer cells.

How do you take this Medication

Oral Tablets: Take this drug by mouth, with or without food, as ordered by your doctor.

Precautions

• Other medications may interact with Flutamide. Do not start taking new medications without first checking with your doctor or pharmacist. Tell your doctor if you are taking blood-thinning drugs such as Coumadin® (Warfarin).

• Tell all other doctors or dentists that you are taking Flutamide, before you receive treatment from them.

• Store Flutamide tablets at room temperature. Keep out of the reach of children.

For more information on this medication, please call your doctor, pharmacist or nurse.

Mechanisms of Obstruction and Rationale for Pharmacotherapy

Current pharmacotherapy for Benign Prostatic Hyperplasia (BPH) is based on agents that relax the smooth muscles of prostatic urethra and stroma and those that deprive acinar cells of androgen.

Various agents have been tried in the treatment of BPH (Table). They may be broadly grouped into those affecting the dynamic component of urethral obstruction, namely the smooth muscle and prostatic stroma, and those affecting the glandular elements by androgen deprivation. The mechanism of action of many agents claimed to be useful in Benign Prostatic Hyperplasia is not clearly understood.

Caine has suggested that obstruction due to Benign Prostatic Hyperplasia occurs because of two factors: a dynamic component is thought to occur as a result of the contraction of smooth muscles of the prostate and prostatic urethra and is mediated mostly by adrenergic receptors; and a mechanical component of obstruction is related to the presence of a mass of hyperplastic acinar or stromal tissue that compresses and narrows the urethral lumen. There is some evidence that the presence and density of stromal content in BPH may relate to the severity of obstruction.

Current understanding of the biologic mechanisms of obstruction is limited and does not extend to two common clinical facts. The first is that the size of the prostate does not always correlate with the severity of symptoms or objective signs of obstruction. The second is the discrepancy between the histologic changes of BPH and the presence and severity of symptoms. From a physiologic standpoint, five conditions in patients with symptoms of “BPH” may exist singly or in combination. These are prostatic urethral obstruction, impaired detrusor contractility, detrusor instability, sensory urgency, and primary vesical neck obstruction. All these conditions likely result from varying combinations of prostatic enlargement and subtle neurologic dysfunction, all due to age-related central nervous system degeneration. Alternatively, a hyperplastic prostate during growth may disrupt normal sphincteric function. Thus, it is not surprising that prostatectomy fails to relieve symptoms of prostatism in about 20% of patients because the symptoms may be caused by poorly understood deficits in neurosensory pathways regulating micturition and sphincteric function.

Transurethral prostatectomy is the most common surgical procedure currently performed for the treatment of Benign Prostatic Hyperplasia. Outcome analyses have questioned the results of transurethral resection of the prostate (TURP). Patients undergoing TURP have been reported to be at greater risk from cardiovascular death than patients undergoing open prostatectomy. Recently these findings were disputed, and it was reported that transurethral resection for BPH does not increase long-term mortality and that comorbid illnesses and older age probably account for the apparent increase in long-term mortality after TURP. The morbidity of the procedure remains unchanged, however. In a review in 1962, the morbidity after transurethral resection of the prostate was reported to be 18% and the mortality 2.5%. More recently, the American Urological Association (AUA) cooperative study of 3,885 patients after the procedure revealed an overall complication rate of 18% and 0.2% mortality. Thus, the search for alternative therapies has been prompted by patients’ preferences for less invasive forms of treatment without prohibitive side effects. Apart from pharmacotherapy, other methods undergoing trials for the treatment of Benign Prostatic Hyperplasia include laser ablation, microwave hyperthermia, and prostatic stents. Ultimately, the role of surgical treatment and newer modalities must be based on relative effectiveness, cost, morbidity, effect on quality of life, expectations, and treatment preferences of patients.