Anti-androgens.

Generic

Flutamide (INN) 250mg

Tablets Pale yellow, round, biconvex tablet, with a score on one side and plain on the other.

Treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated; as initial treatment in combination with an LHRH agonist, as adjunctive therapy in patients already receiving LHRH agonist therapy; in surgically castrated patients; in the treatment of patients who have not responded to other form of hormonal manipulation or in patients who cannot tolerate such treatment. In combination with LHRH agonists for the management of locally confined B2-C2 (T2b-T4) prostate carcinoma as initial therapy; bulky primary tumors confined to the prostate (stage B2 or T2b) or extending beyond the capsule (stage C or T3-T4), with or without pelvic node involvement.

Dosage : One 250mg tablet three times daily at 8 hour intervals.

Route of Administration : Oral

When used as an initial treatment with an LHRH agonist, a greater reduction in the incidence and severity of the LHRH agonist flare reaction may be achieved if flutamide is introduced before rather than concomitantly with the agonist. It is, therefore, recommended that flutamide one tablet three times daily should be started at least three days prior to initiation of the LHRH agonist and continued thereafter at the same dose.

In the management of locally confined prostatic carcinoma, the recommended dosage is one 250mg tablet three times a day. Drogenil should be started at least three days prior to initiation of the LHRH agonist. Administration of Drogenil and the LHRH agonist should begin eight weeks prior to radiation therapy and continue through the course of radiation therapy (usually approx. 8 weeks) i.e. a total of approximately 16 weeks.

Dosage adjustment in renal or liver insufficiency : Flutamide may be hepatotoxic. In patients with impaired liver function, long-term treatment with flutamide should only be administered after careful assessment of the individual benefits and risks.

Monitoring advice : Flutamide is highly protein bound and will not be removed by dialysis.

Patients exhibiting sensitivity reactions to flutamide or any component of this preparation.

Flutamide may be hepatotoxic. In patients with impaired liver function, long-term treatment with flutamide should only be administered after careful assessment of the individual benefits and risks.

Hepatic Injury : Transaminase abnormalities, cholestatic jaundice, hepatic necrosis, and hepatic encephalopathy have been reported with the use of flutamide. The hepatic conditions were usually reversible after discontinuing therapy or dosage reduction, although there have been occasional reports of a fatal outcome following severe hepatic injury in patients receiving flutamide.

Treatment with Drogenil should not be initiated in patients with serum transaminase levels exceeding 2-3 times the upper limit of normal. Periodic liver function tests must be performed in 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, Drogenil therapy should be discontinued or the dosage reduced.

Patients should be advised to discontinue flutamide therapy and seek medical advice immediately if any symptoms or signs suggestive of hepatotoxicity occur.

In addition, in patients who have not received medical or surgical castration periodic sperm count determinations may be considered during long-term treatment. In such patients, flutamide administration tends to elevate plasma testosterone and estradiol levels. Fluid retention may occur thus the drug should be used with caution in cardiac disease.

Drogenil is indicated only for use in male patients

Increases in prothrombin time have been reported in patients receiving long-term oral anticoagulant therapy after flutamide monotherapy was initiated. Therefore, close monitoring of prothrombin time is recommended. Adjustment of the anticoagulant dose may be necessary when flutamide is administered concomitantly.

Avoid concomitant administration of potentially hepatotoxic drugs. Patients should avoid excessive alcohol consumption.

Cases of increased theophylline plasma concentrations have been reported in patients receiving concomitant theophylline and Drogenil. Theophylline is primarily metabolised by CYP 1A2 which is the primary enzyme responsible for the conversion of flutamide to its active agent 2-hydroxyflutamide.

Monotherapy : In clinical studies, the most frequently reported adverse reactions to DROGENIL Tablets are gynaecomastia and/or breast tenderness, sometimes accompanied by galactorrhoea. These reactions disappear upon discontinuation of treatment or reduction in dosage.

DROGENIL Tablets demonstrate a low potential for cardiovascular liability, and when compared to diethylstilbestrol this liability has been shown to be significantly lower.

Combination therapy : In clinical studies, the most frequently reported adverse effects experienced during combination therapy of DROGENIL Tablets with LHRH agonist were hot flushes, decreased libido, impotence, diarrhoea, nausea and vomiting. With the exception of diarrhoea, these adverse experiences are known to occur with LHRH agonist alone, and at comparable frequency. In clinical trials, no significant difference in gynaecomastia incidence was observed between the placebo and the flutamide-LHRH agonist treatment groups.

* Two reports of malignant male breast neoplasms in patients being dosed with Drogenil have been reported. One involved aggravation of a pre-existing nodule which was first detected three to four months before initiation of Drogenil 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 Drogenil 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 T4NOMO, G3, no metastases had advanced.

Schering-Plough Ltd

(POM)

28 May 2009