Active ingredient: Flutamide Chemical name: 2-methyl-N-[4-nitro-3-(trifluoromethyl)-phenyl]propanamide Structural formula:
H3C
O
CH3
CF3
NO2 Molecular formula: C11H11F3N2O3 Molecular weight: 276.22 CAS Registry No. : 13311-84-7
Each Flutamin tablet contains 250 mg of flutamide. The tablets also contain lactose, cellulose - microcrystalline, starch - maize, starch - pregelatinised maize, sodium lauryl sulfate, silica - colloidal anhydrous and magnesium stearate.
Flutamide is a non-steroidal, orally active antiandrogen. It demonstrates potent antiandrogenic effects by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues. Flutamide exhibits specific antiandrogenic effects, largely directed to the prostate as target organ. When administered orally to intact immature male rats at doses ranging from 1 to 25 mg/kg, flutamide significantly reduced prostate and seminal vesicle weights, without altering other endocrine structures. In studies of dogs with benign prostatic hypertrophy, daily oral administration of flutamide 5 to 50 mg/kg for six weeks reduced the size of the prostate gland and reversed the associated histological and histochemical changes. Studies of the mechanism of flutamide's antiandrogenic action on the ventral prostate gland of the rat indicate that it either inhibits androgen uptake or blocks nuclear binding of androgens in target tissues. While flutamide exerts antiandrogenic action on the accessory sex structures, at pharmacologically active doses it did not decrease sexual activity or spermatogenesis in male rats. Flutamide exhibits specific activity towards androgen dependent receptors with little effect on other hormonal receptors. It lacks oestrogenic, antioestrogenic, progestational and antiprogestational activities.
Analysis of plasma, urine and faeces of three male volunteers following a single oral dose of tritium-labelled flutamide 200 mg revealed that the drug is rapidly and completely absorbed and excreted mainly in the urine. At least six metabolites have been identified in plasma. The distribution and elimination half-lives for flutamide are 0.8 and 7.8 hours respectively, and the corresponding half-lives for its active metabolite, 2-hydroxyflutamide, are 1.7 and 8.1 hours respectively. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl) phenol. Tissue distribution of flutamide was examined in male rats given an oral dose of 14C-flutamide at 5 mg/kg. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite, hydroxyflutamide, was present at higher concentrations than flutamide in all tissues studied. Hydroxyflutamide was relatively concentrated in the rat ventral prostate gland and seminal vesicles, previously demonstrated to be the target organs of pharmacological activity. It was similarly concentrated in the rat pituitary gland. The very rapid and almost complete conversion of flutamide to metabolites strongly suggests that the biological activity shown by this substance is due to an active metabolite. Hydroxyflutamide is the major metabolite in humans and laboratory animals, and has been shown to possess potent antiandrogenic activity.
Management of advanced prostatic carcinoma, in combination with a luteinising hormone releasing hormone (LHRH) agonist, in previously untreated patients. Prevention of disease "flare" associated with the use of LHRH agonists.
Sensitivity to flutamide or any of the components of this preparation. Patients with severe hepatic impairment.
Flutamin is indicated only for use in male patients.
Hepatic Injury
. There have been post-marketing reports of hospitalisation and rarely death due to liver failure in patients taking flutamide. Evidence of hepatic injury included elevated serum transaminase levels, jaundice, hepatic encephalopathy, and death related to acute hepatic failure. The hepatic conditions are usually reversible after prompt discontinuation of therapy. Approximately half of the reported cases occurred within the first three months of treatment with flutamide.
Treatment with flutamide should not be initiated in patients with serum transaminase levels exceeding 2 to 3 times the upper limit of normal. Periodic liver function tests must be performed in all patients. Appropriate laboratory testing should be done monthly for the first 4 months and periodically thereafter at the first sign/symptom of hepatic dysfunction (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained flu-like symptoms). If the patient has laboratory evidence of liver injury or jaundice, in the absence of biopsy-confirmed liver metastases, Flutamin therapy should be discontinued immediately if the patient develops jaundice or if the serum transaminase levels rise to 2 to 3 times the upper limit of normal, even in clinically asymptomatic patients. Liver function tests should be followed-up closely until resolution. When Flutamin is administered in combination with an LHRH agonist, the possible adverse effects of each product must be considered.
Daily administration of flutamide to rats for 52 weeks at doses of 30, 90 or 180 mg/kg/day produced testicular interstitial adenomas at all doses. In a 24 month carcinogenicity study conducted with male rats, daily administration of flutamide at doses of 10, 30 and 50 mg/kg/day was associated with an increased number of testicular interstitial cell adenomas at all doses tested and with dose related increases in mammary gland adenomas and carcinomas. Two reports of malignant male mammary gland neoplasms have been reported in patients being treated with flutamide (see ADVERSE EFFECTS).
No studies have been conducted in pregnant or lactating women. Therefore, the possibility that Flutamin may cause foetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women, must be considered.
Increases in prothrombin time have been noted in patients receiving warfarin therapy and flutamide therapy concomitantly. Therefore close monitoring of prothrombin time is recommended and adjustment of the initiating or maintenance anticoagulant dose may be necessary. Flutamide inhibits steroid metabolism in rat testicular microsomes and alters their content of cytochrome P450. Although this may be organ specific, an effect on hepatic microsomes has not been excluded. Therefore, the metabolism of some drugs by the liver may be affected by flutamide. Although data are not available on potential interaction between flutamide and paracetamol, opioid analgesics or NSAIDs, flutamide may affect the metabolism of these drugs, which are frequently administered to patients with prostate cancer. Cases of increased theophylline plasma concentrations have been reported in patients receiving concomitant theophylline and flutamide.
Cholestatic jaundice, hepatic encephalopathy and hepatic necrosis have been reported. The hepatic conditions were usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with the use of flutamide. The most frequently reported adverse effects experienced during combination therapy of flutamide with LHRH agonists were hot flushes, decreased libido, impotence, diarrhoea, nausea and vomiting. With the exception of diarrhoea, these adverse experiences are known to occur with LHRH agonists alone, and at comparable frequency. The most frequently reported adverse reactions to flutamide monotherapy are gynaecomastia and/or breast tenderness, sometimes accompanied by galactorrhoea; these are greatly reduced when flutamide is administered concomitantly with an LHRH agonist. Two cases of pulmonary embolism have been reported in patients receiving flutamide but a relationship to flutamide has not been established. Very rarely, interstitial lung disease has occurred. Other less frequent adverse reactions reported with flutamide monotherapy and/or combination therapy include:
Gastrointestinal.
Anorexia, constipation.
Central Nervous System.
Insomnia, tiredness, headache, dizziness, malaise.
Haematological.
Anaemia, leucopenia, thrombocytopenia, haemolytic anaemia, macrocytic anaemia, methaemoglobinaemia, sulfhaemoglobinaemia.
Other.
Peripheral oedema; photosensitivity reactions (including erythema, ulceration, bullous eruptions and epidermal necrolysis); change in urine colour to an amber or yellow-green appearance (can be attributed to flutamide and/or its metabolites); injection site irritation and rash associated with the administration of the LHRH agonist.
These other reactions have not been of sufficient severity to require dosage reduction or discontinuation of treatment. If adverse reactions are severe, a reduction in dosage, without loss of efficacy, may be beneficial. Hyperglycemia and aggravated diabetes have been reported very rarely. Two cases of malignant breast neoplasms have been reported in patients being treated with flutamide. One involved a pre-existing nodule which was first detected three to four months before initiation of flutamide monotherapy in a patient with benign prostatic hypertrophy. After one month of treatment, the nodule was excised and was diagnosed as a poorly differentiated ductal carcinoma. The other case was a patient who developed gynaecomastia and a breast nodule after two and six months' treatment respectively with flutamide monotherapy for advanced prostatic carcinoma. Nine months after the initiation of therapy, the nodule was excised and diagnosed as a moderately differentiated invasive ductal tumour, staged T4N0M0, G3.
Laboratory Tests.
Abnormal laboratory test values reported include changes in liver function tests (in 3 to 31% of patients treated with flutamide monotherapy); elevated blood urea nitrogen (BUN) levels; elevated serum creatinine (rarely).
The recommended dosage is one tablet three times a day at intervals of eight hours. Flutamin should be started up to 24 hours prior to the initiation of LHRH agonist.
Symptoms
The single flutamide dose ordinarily associated with symptoms of overdosage or considered to be life-threatening has not been established. One patient survived after ingesting more than 5 g of flutamide as a single dose. No adverse effects were observed.
Treatment
Dialysis may not be of any use as treatment for overdose since flutamide is highly protein bound. As in the management of overdosage with any drug, the possibility that multiple agents may have been taken should be considered. If vomiting does not occur spontaneously, it should be induced if the patient is alert. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
Flutamin,
Flutamide 250 mg tablet: yellow, round, scored, marked " blister pack 100s.
Store below 30degC. Protect from light.
Alphapharm Pty Limited
(ABN 93 002 359 739) Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 www.alphapharm.com.au
FT
" on one side, "G" on the reverse;
S4 - Prescription Only Medicine
24/03/1999
05/10/2012