4.1. Therapeutic indications

Flutamide is indicated for the treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated. Flutamide may be used in combination with an LHRH agonist, both on commencement of treatment or as an adjunctive therapy in patients already receiving an LHRH agonist. Flutamide may also be used in surgically castrated patients.

4.2. Posology and method of administration

Posology

Adults and older people: One tablet three times daily at 8 hour intervals. When Flutamide is used as initial treatment with an LHRH agonist, a reduction in severity of the flare reaction may be achieved if treatment with Flutamide is initiated before the LHRH agonist. Consequently, it is recommended that treatment with Flutamide should commence simultaneously or at least 24 or more hours before the LHRH agonist.

The administration of Flutamide should begin 8 weeks prior to radiotherapy and continue for its duration, or for 12 weeks pre-prostatectomy.

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

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

Method of administration

For oral use.

The tablets are to be taken preferably after food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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'.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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)

SOC

Monotherapy

Combination therapy with LHRH analog

Infections and infestations

Rare

Herpes zoster

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Very rare

Neoplasm of the male breast*

Blood and lymphatic system disorders

Rare

Anaemia, leucopenia, thrombocytopenia

Very rare

Haemolytic anaemia, megalocytic anaemia, methaemoglobinaemia, sulfhaemoglobinaemia, macrocytic anaemia

Immune system disorders

Rare

Lupus-like syndrome

Metabolism and nutrition disorders

Common

Increased appetite

Rare

Anorexia

Anorexia

Very rare

Hyperglycaemia, aggravation of diabetes mellitus

Psychiatric disorders

Common

Insomnia

Rare

Anxiety, depression

Depression, anxiety

Nervous system disorders

Rare

Dizziness, headache

Numbness, confusion, nervousness, drowsiness

Eye disorders

Rare

Blurred vision

Cardiac disorders

Rare

Cardiovascular disorders

Not known

QT prolongation (see sections 4.4 and 4.5)

Vascular disorders

Very common

Hot flushes

Rare

Hot flushes, hypertension, lymphoedema

Hypertension

Not known

Thromboembolism

Respiratory, thoracic and mediastinal disorders

Rare

Interstitial pneumonitis, dyspnoea

Very rare

Cough

Pulmonary symptoms (e.g. dyspnoea), interstitial lung disease

Gastrointestinal disorders

Very common

Diarrhoea, nausea, vomiting

Common

Nausea, vomiting, diarrhoea

Rare

Non-specific abdominal disorders, constipation, ulcer-like pain, dyspepsia, colitis, upset stomach, heartburn

Non-specific abdominal disorders, abdominal pain

Hepatobiliary disorders

Common

Hepatitis

Uncommon

Hepatitis

Rare

Liver function test abnormalities (see section 4.4)

Hepatic dysfunction, jaundice

Very rare

Cholestatic jaundice, hepatic encephalopathy, liver cell necrosis, hepatotoxicity with fatal outcome

Skin and subcutaneous tissue disorders

Rare

Urticaria, pruritus, ecchymosis, alteration of the hair growth pattern and loss of hair (head)

Rash

Very rare

Photosensitivity reactions

Photosensitivity reactions, erythema, ulcers, bullous eruptions, epidermal necrolysis

Musculoskeletal and connective tissue disorders

Rare

Muscle cramps

Neuromuscular symptoms, reduced bone mineral density, osteoporotic disorders, arthralgia, myalgia

Renal and urinary disorders

Rare

Genitourinary tract symptoms, dysuria, changes in urinary frequency, change in urine colour to amber or yellow-green

Reproductive system and breast disorders

Very common

Gynaecomastia and/or breast pain, breast tenderness, galactorrhoea

Decreased libido, impotence

Uncommon

Gynaecomastia

Rare

Reversible increase of serum testosterone levels, reduced sperm counts, decreased libido

General disorders and administration site conditions

Common

Somnolence, tiredness

Rare

Oedema, asthenia, malaise, thirst, chest pain, hot flushes, weakness

Oedema, injection site irritation

Investigations

Common

Transient abnormal liver function

Changes in liver function

Rare

Elevated blood urea nitrogen (BUN) values, elevated serum creatinine values

* 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.

4.9. Overdose

Symptoms

In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia and/or lacrimation, anorexia, tranquilisation, emesis and methaemoglobinaemia.

Clinical trials have been carried out with flutamide at doses of up to 1500 mg per day for periods of up to 36 weeks without reports of severe undesirable effects. The undesirable effects reported were gynaecomastia, breast sensitivity and some increases in SGOT.

The acute toxic dose of flutamide in man has not been established. One patient survived after ingesting more than 5 g as a single dose, with no apparent adverse effects. Since flutamide is an anilide compound, it has the theoretic potential of producing methaemoglobinaemia. Accordingly, a patient with acute intoxication may be cyanotic.

Management

If vomiting does not occur spontaneously it should be induced, provided that the patient is alert. Gastric lavage may be considered. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. General supportive measures are appropriate, including frequent monitoring of vital signs and close observation of the patient. Since flutamide is highly protein bound, dialysis may not be of any use as treatment for overdose.