FLUTAN Tablet Ref.[28303] Active ingredients: Flutamide

Initiation of treatment should be under the direction of a specialist. Subsequently, patients should be kept under regular surveillance with particular attention to effects on liver function and spermatogenesis in those patients without orchidectomy.

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 should not be initiated in patients with serum transaminase levels exceeding 2-3 times the upper limit of normal. Liver function tests should be done monthly for the first four 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, flutamide therapy should be discontinued or the dosage reduced (see section 4.8).

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.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Flutan.

The increase in levels of oestradiol may render the patient more susceptible to thromboembolism.

Patients with latent or actual G-6-P deficiency may develop methaemoglobinaemia.

Flutamide is excreted mainly through the kidney. Dosage may require adjustment in patients with renal insufficiency.

Elevated serum creatinine levels have been reported.

For administration to male patients only.

Flutan tablets contains lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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. Flutamide may delay the metabolism of steroids.

Avoid concomitant administration of potentially hepatotoxic drugs.

Avoid excessive alcohol consumption.

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

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Flutan with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

No studies have been conducted in pregnant or lactating women. In animal studies, reproductive toxicity was related to the antiandrogenic activity of this compound (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed with flutamide.

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

Flutamide 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 flutamide 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.

Table 1. Treatment related undesirable effects:

MedDRA frequency convention: Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1,000, <1/100); Rare (>1/10,000, <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data).

Italics - Indicate post-marketing experience

^* Two reports of malignant male breast neoplasms in patients being dosed with flutamide have been reported. One involved aggravation of 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 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 flutamide 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

None known.