FLUTAMIDE Tablet Ref.[9663] Active ingredients: Flutamide

Hepatic injury

Flutamide may be hepatotoxic and should be used with caution in patients with pre-existing hepatic dysfunction only after considering the benefits and potential risks.

There have been reports of elevated serum transaminase levels, cholestatic jaundice, hepatic necrosis and hepatic encephalopathy associated with Flutamide treatment. The hepatic effects were usually reversible following discontinuation of flutamide, although cases have been reported of death after severe liver damage linked to the use of flutamide. Hepatotoxicity, which may be fatal, may occur after several weeks or months of therapy. Hepatic function should be monitored regularly before, during and after initiation of Flutamide therapy. Treatment with Flutamide 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 before initiation and during treatment, especially in patients receiving long term treatment with Flutamide. Appropriate laboratory liver function tests should also be performed for every patient once a month for the first 4 months and then periodically or when the first sign or symptom of hepatic dysfunction occur (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms).

Patients should be advised to discontinue Flutamide therapy and seek medical advice immediately if any symptoms or signs suggestive of hepatotoxicity occur. If the patient presents liver function test results indicative of liver damage, clinical jaundice in the absence of hepatic metastasis confirmed by biopsy, or serum transaminase levels of 2 to 3 times above the normal limits in patients that do not present pathological signs, treatment with flutamide must be suspended.

Impaired renal function

Flutamide should be administered with caution in patients with impaired renal function.

Cardiovascular

Periodic sperm counts should be considered in patients receiving chronic treatment with Flutamide who have not received medical or surgical castration. Flutamide administration may lead to elevated plasma testosterone and oestradiol levels in such patients, resulting in fluid retention. In severe cases this can lead to an increased risk of angina and heart failure. Therefore caution should be exercised in the use of Flutamide if cardiac disease is present. It can exacerbate oedema or ankle swelling in patients prone to these conditions.

An increase in oestradiol levels may predispose to thromboembolic events.

It has been reported in the literature that increased cardiovascular risk (myocardial infarction, cardiac insufficiency, sudden cardiac death) and the adverse effects on independent cardiovascular risk factors (serum lipoproteins, insulin sensitivity and obesity) may be linked to androgen deprivation with LHRH analogues in patients with prostate cancer. It must be evaluated whether the benefits of the combined androgen blockade compensate the potential cardiovascular risk in patients with risk factors. Patients treated whose signs or symptoms suggest the development of a cardiovascular disease must be monitored.

Effect on the QT/QTc interval

The potential QT/QTc prolongation with flutamide has not been studied. 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 Flutamide.

Endocrinology and metabolism

A decreased tolerance to glucose has been observed in males in treatment with combined androgen blockade. This may manifest as diabetes or a loss of glycaemic control in patients with pre-existing diabetes. Monitoring of the blood glucose and/or glycosylated haemoglobin (HbA1c) levels must be considered in patients who are in treatment with flutamide in combination with LHRH agonists.

Musculoskeletal/changes in bone density

Androgen depletion therapy is known to reduce bone mineral density and increase the risk of osteoporotic fractures. In recent studies this has been seen in patients treated with LHRH analogues plus flutamide. The risk of bone fractures increases with the duration of combined androgen blockade. These complications may be potentiated when patients are already osteoporotic due to their advanced age at diagnosis of prostate cancer.

Bone mineral density (BMD) should be measured regularly to identify patients at higher risk for fractures. BMD should be measured at baseline, and then a year later as a minimum. Further measurements can be considered at yearly intervals in men with BMD approaching osteoporosis or those with decreased bone mineral density in whom life expectancy warrants it.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic consumers of alcohol and/or tobacco, a presumed or marked family history of osteoporosis or chronic use of medicinal products that can reduce bone mass such as anticonvulsants or corticosteroids, the combined androgen blockade can represent an additional risk. In these patients the risk and benefit must be weighed up carefully before starting the treatment.

There have been cases of interstitial pneumonitis reported in patients undergoing treatment with flutamide. Patients should be monitored for the development of respiratory symptoms such as dyspnoea during the first few weeks of therapy.

Flutamide is indicated only for use in male patients.

Contraceptive measures must be taken during treatment.

Excipients with known effects

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

There have been no interactions between flutamide and leuprorelin; nevertheless, in the combined treatment with flutamide and an LHRH agonist, the possible side effects of each medicinal product must be considered.

Increases in prothrombin time have been reported in patients receiving chronic treatment with oral anticoagulants (e.g. warfarin) following initiation of flutamide monotherapy. Therefore careful monitoring of prothrombin time is recommended and it may be necessary to adjust the dose of anticoagulant if Flutamide is administered concomitantly with oral anticoagulants.

Concomitant administration of other potentially hepatotoxic drugs should be undertaken only after careful assessment of the benefit and risks. Given the known potential liver and renal toxicities of the product, it is important to avoid excessive consumption of alcohol.

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

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Flutamide 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).

Flutamide is intended only for use in male patients. Contraceptive measures should be taken during treatment.

Flutamide may cause foetal harm when administered to a pregnant woman. In animal studies, the reproductive toxicity of flutamide was associated with the anti-androgenic activity of this agent. There was decreased 24-hour survival in the offspring of rats treated with flutamide at doses of 30, 100, or 200 mg/kg/day (approximately 3, 9, and 19 times the human dose) during pregnancy. A slight increase in minor variations in the development of the sternebra and vertebra was seen in foetuses of rats at the two higher doses. Feminisation of the males also occurred at the two higher dose levels. There was a decreased survival rate in the offspring of rabbits receiving the highest dose (15 mg/kg/day; equal to 1.4 times the human dose).

No studies have been conducted in pregnant or lactating women. Therefore, the possibility that flutamide may cause foetal harm if administered to a pregnant woman, or may be present in the breast milk of lactating women, must be considered.

No studies on effects on the ability to drive and use machines have been performed with flutamide. Possible undesirable effects such as fatigue, dizziness and confusion have been reported and may interfere with the ability to drive and use machines.

Monotherapy

The undesirable effects of flutamide most frequently reported are gynaecomastia and/or breast tenderness, sometimes accompanied by periods of galactorrhoea. These reactions often disappear with the suspension of the treatment or reduction of the dose.

It has been proven that flutamide has a low cardiovascular risk potential, significantly less than that of diethylstilboestrol.

Combined treatment

The undesirable effects most frequently reported during combined treatment of flutamide with an LHRH agonist were hot flushes, reduced libido, erectile dysfunction, diarrhoea, nausea and vomiting. With the exception of diarrhoea, these are known undesirable effects of LHRH agonists alone, with a similar frequency.

The high rate of occurrence of gynaecomastia observed with monotherapy with Flutamide decreased greatly in combined treatment. In clinical trials, no significant difference was observed in the rate of occurrence of gynaecomastia between the placebo group and the group treated with flutamide and LHRH agonists.

The following convention has been utilised for the frequency classification:

Very common - (≥1 in 10)
Common - (≥1 in 100 to <1 in 10)
Uncommon - (≥1 in 1,000 to <1 in 100)
Rare – (≥1 in 10,000 to <1 in 1,000)
Very rare - (<1 in 10,000)
Not known – (cannot be estimated from the available data)

* There have been a few cases reported of malignant breast neoplasms in male patients treated with flutamide. One of them consisted of the aggravation of a lump that had been detected previously, three or four months prior to commencing monotherapy with flutamide in a patient with benign prostatic hypertrophy. After the excision, a diagnosis was made of slightly differentiated ductal carcinoma. The other case consisted of gynaecomastia and a lump, observed, respectively, two to six months after the start of monotherapy with flutamide to treat an advanced prostate carcinoma. Nine months after the treatment began, the lump was removed and a moderately differentiated invasive ductal tumour was diagnosed in T4N0M0, G3 state.

The high incidence of gynaecomastia seen with flutamide monotherapy is generally reduced with combination therapy.

Micronodular alterations of the body of breast can uncommonly occur.

An increase in serum testosterone is initially possible during monotherapy with flutamide. In addition, hot flushes and changes in hair character can occur.

Following the marketing of flutamide, cases of acute renal failure, interstitial nephritis, and myocardial ischemia have been reported with frequency unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.go.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.