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Tablets: Pale yellow, round, biconvex, 12.9mm diameter, scored on one side. Each tablet contains flutamide 250mg, lactose, sodium lauryl sulfate, microcrystalline cellulose, maize starch, colloidal anhydrous silica and magnesium stearate.
Flutamide demonstrates potent antiandrogenic effects by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues.
Analysis of plasma, urine and faeces of volunteers treated with tritium-labelled flutamide revealed that the drug is rapidly and completely metabolised. The major plasma metabolite, the alpha-hydroxylated derivative of flutamide, has comparable antiandrogenic activity. Both compounds disappear from plasma, with a half-life of 5 to 6 hours. One hour post-drug, flutamide accounted for 2.4% and hydroxyflutamide 22.9% of total plasma radioactivity.
Approximately 45% of the administered radioactive dose was excreted in urine and 2% in faeces during the first two post-drug days. Metabolism removed more than 50% of the radiolabelled resulting in an apparent slowing of excretion due to retention of the label as tritiated water. Correction for tritium exchange revealed that excretion is essentially complete within two days.
A distribution study in rats with 14C-flutamide showed that while flutamide concentration was generally low in all tissues examined, the metabolite hydroxyflutamide was present in concentrations up to 80 times the flutamide concentration by 6 hours after dosing. Hydroxyflutamide was relatively concentrated in the rat ventral prostate and seminal vesicles, demonstrated to be the target organs of pharmacological activity.
For the palliative treatment of advanced prostatic cancer in previously untreated patients or those who have not responded or who have become refractory to hormonal manipulation.
As a component of the treatment used in the management of locally advanced prostatic carcinoma.
The recommended dosage is one tablet three times a day at eight hourly intervals.
EULEXIN Tablets have been administered as monotherapy with or without surgical castration and in combination with medical (luteinising hormone-releasing hormone [LHRH] agonist) hormonal manipulation.
In combination with an LHRH agonist, treatment must be started simultaneously using both compounds, or Eulexin Tablets may be started 24 hours prior to initiation of the LHRH agonist, to achieve the benefit of the adjunctive therapy.
In localised prostatic carcinoma, administration of Eulexin and an LHRH agonist should begin eight weeks prior to radiation therapy and continue through the course of radiation therapy. Prior to radical prostatectomy, Eulexin should be administered for 3 months.
EULEXIN Tablets are contraindicated in patients exhibiting sensitivity reactions to flutamide or any components of this preparation.
Hepatic Injury: Treatment with Eulexin 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, and at the first symptom/sign of liver 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, EULEXIN therapy should be discontinued 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. The hepatic conditions are usually reversible after discontinuing therapy; however, there have been reports of death following severe hepatic injury associated with the use of flutamide.
In addition, periodic sperm count determinations may be considered in patients on long-term treatment with EULEXIN Tablets.
Since flutamide administration tends to elevate plasma testosterone and oestradiol levels, fluid retention may occur.
When EULEXIN Tablets are administered in combination with LHRH agonists, the possible adverse effects of each product must be considered.
Patients should be informed prior to initiating Eulexin, of the possibility of its causing hepatic dysfunction. Instruct the patient to consult the doctor immediately if symptoms of hepatic dysfunction appear. These include itching of the skin, dark urine (amber or yellow-green urine is not a cause for concern), nausea, vomiting, persistent lack of appetite, yellow eyes or skin, tenderness in the right upper abdomen or "flu-like" symptoms.
Mutagenicity studies of flutamide have been conducted. Flutamide did not exhibit mutagenic potential in any of the test systems used.
Flutamide at doses of 25mg and 75mg/kg did not affect oestrous cycles or interfere with the mating behaviour of male and female rats.
Teratological effects were assessed in rats and rabbits. In pregnant rats, doses up to 200mg/kg did not result in the production of major malformations of offspring. At 100 and 200mg/kg, foetal growth was retarded and the antiandrogenic activity of the drug was evidenced by decreases in the anogenital distance. Survival rates were decreased. In rabbits, doses up to 15mg/kg did not affect the course of pregnancy or development of offspring. When administered to both male and female rats prior to and during the mating period, flutamide treatment at 25mg/kg reduced the pregnancy rate, but had no effect on the course of pregnancy, foetal development (except for the anticipated feminisation of males) or postnatal survival.
Daily administration of flutamide to rats for 52 weeks at doses of 30, 90 or 180mg/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 50mg/kg/day was associated with an increased number of testicular 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 Reactions).
EULEXIN is indicated only for use in male patients. No studies have been conducted in pregnant or lactating women. Therefore, the possibility that EULEXIN may cause foetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women, must be considered.
The most frequently reported adverse reactions to EULEXIN Tablets are gynaecomastia and/or breast tenderness, sometimes accompanied by galactorrhoea. These reactions disappear upon discontinuation of treatment or reduction in dosage.
Less frequent adverse reactions: diarrhoea, nausea, vomiting, increased appetite, insomnia, tiredness, transient abnormal liver function and hepatitis.
Rare adverse reactions: decreased libido, upset stomach, anorexia, ulcer-like pain, heartburn, constipation, oedema, ecchymoses, herpes zoster, pruritus, lupus-like syndrome, headache, dizziness, weakness, malaise, blurred vision, thirst, chest pain, anxiety, lymphoedema.
Reduced sperm counts have been reported rarely in long-term treatment.
Usually these 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.
In addition, haemolytic anaemia, macrocytic anaemia, methaemoglobinaemia, sulfhaemoglobinaemia, photosensitivity reactions (including erythema, ulcerations, bullous eruptions and epidermal necrolysis) and change in urine colour to an amber or yellow-green appearance which can be attributed to flutamide and/or its metabolites. Also observed were cholestatic jaundice, hepatic encephalopathy and hepatic necrosis. 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.
EULEXIN Tablets demonstrate a low potential for cardiovascular liability, and when compared to diethylstilboestrol, this liability has been shown to be significantly lower. Although there have been reports of cardiovascular adverse events in patients on flutamide therapy, the relation of these to flutamide has not yet been elucidated. Hyperglycemia, interstitial lung disease and aggravated diabetes mellitus have been reported very rarely.
Two reports of malignant male breast neoplasms in patients being dosed with Eulexin have been reported. One involved aggravation of a pre-existing nodule which was first detected three to four months before initiation of Eulexin monotherapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma. The other report involved gynaecomastia and a nodule noted two and six months respectively after initiation of Eulexin monotherapy for treatment of 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, no metastases had advanced.
Abnormal laboratory test values reported include changes in liver function tests (e.g. elevated transaminases), elevated blood urea nitrogen (BUN) levels and rarely elevated serum creatinine levels.
It should be remembered that flutamide is an antiandrogen and as such may interact pharmacologically with androgens, oestrogens or other forms of hormonal therapy.
Clinical studies have suggested that flutamide when used with LHRH agonists, may suppress any disease flare which may be caused by the LHRH agonist.
Increases in prothrombin time have been noted in patients receiving oral anticoagulant and flutamide therapy concomitantly. Therefore, close monitoring of prothrombin time is recommended and adjustment of the initiating or maintenance anticoagulant dose may be necessary.
Cases of increased theophylline plasma concentrations have been reported in patients receiving concomitant theophylline and fluamide.
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 grams of flutamide as a single dose. No adverse effects were observed.
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.
Store below 30oC. Protect from excessive moisture. Protect from light.
Prescription Medicine
Bottle of 100 tablets (250mg)
Nil
Schering-Plough
33 Whakatiki Street
Upper Hutt
Wellington NEW ZEALAND
Tel: 04 528 1900
10 August 2004.
© Schering-Plough 2004