Document: spc-doc_PL 04569-0338 change

• spc-doc_PL 04569-0338
• spc-doc_PL 11311-0525

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Flutamide Tablets 250mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Flutamide Tablets contain Flutamide 250mg.

Amount of lactose per tablet: 221.7 mg For a full list of excipients see Section 6.1

3 PHARMACEUTICAL FORM

Tablets.

Yellow biconvex tablets marked ‘FT’ score ‘250’ on one side with a ‘G’ on the reverse.

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Flutamide Tablets 250mg are indicated for the treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated. Flutamide Tablets 250mg 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 Tablets 250mg may also be used in surgically castrated patients.

4.2 Posology and method of administration

Adults and the Elderly: One tablet three times daily. The tablets are to be taken preferably after meals. When Flutamide tablets are 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 at least three days before the LHRH agonist.

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 250 mg tablets should be administered with caution in patients with impaired renal function.

4.3 Contraindications

Flutamide Tablets 250mg are contraindicated in patients with known hypersensitivity to any of their components.

4.4 Special warnings and precautions for use

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.

Hepatic injury: 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. 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.

Liver function tests should be performed at the first sign or symptom of hepatic dysfunction (e.g., pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms). Flutamide-induced hepatotoxicity usually recovers with dose reduction or drug withdrawal, but fatalities have been reported (see section 4.8).

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

Flutamide 250 mg tablets should be administered with caution in patients with impaired renal function.

Periodic sperm counts should be considered in patients receiving chronic treatment with Flutamide who have not received medical or surgical castration. Flutamide administration tends to elevate plasma testosterone and oestradiol levels in such patients. This may be associated with fluid retention and therefore caution should be exercised in the use of Flutamide if cardiac disease is present.

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. 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.

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

Increases in prothrombin time have been reported in patients receiving chronic treatment with warfarin following initiation of Flutamide monotherapy. It may be necessary to adjust the dose of anticoagulant if Flutamide is administered concomitantly with warfarin.

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 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.

4.6 Pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

Possible undesirable effects such as tiredness and dizziness may interfere with the ability to drive and use machines.

4.8 Undesirable effects

Frequency classification:

Very common - >1 in 10 Common - >1 in 100 but <1 in 10 Uncommon - >1 in 1000 but <1 in 100 Rare - >1 in 10,000 but <1 in 1000 Very Rare - <1 in 10,000

Monotherapy

SOC	Frequency	Reactions
Infections and infestations	Rare	Herpes zoster
Neoplasms benign and malignant	Very rare	Malignant male breast neoplasms
Blood and lymphatic system disorder	Rare	Oedema, ecchymoses, lymphoedema
Immune system disorders	Rare	Lupus-like syndrome
Metabolism and nutrition disorders	Common	Increased appetite
	Rare	Anorexia
Psychiatric and Nervous system disorders	Common	Insomnia.
	Rare	Anxiety, depression, dizziness
Eye disorder	Rare	Blurred vision
Respiratory, Thoracic and Mediastinal disorders	Rare	Interstitial pneumonitis, dyspnoea
	Very rare	Cough
Cardiac and vascular disorders	Rare	Cardiovascular disorders, hypertension.
Gastrointestinal disorders	Common	Nausea, vomiting, diarrhoea,
	Rare	Constipation, ulcer-like pain, thirst, dyspepsia, colitis,upset stomach, heartburn
Hepato-biliary disorders	Rare	Hepatitis, liver function test abnormalities. See 4.4 Special warnings and precautions for use.
Skin and subcutaneous tissue disorders	Rare	Urticaria, pruritus, alteration of the hair growth pattern and loss of hair (head).
	Very rare	Photosensitivity
Musculoskeletal, Connective tissue and bone disorders	Rare	Muscle cramps
Renal and Urinary disorders	Very Rare	Acute renal failure

Reproductive system and breast disorders	Very common	Gynaecomastia, breast tenderness, galactorrhoea. (These reactions disappear upon discontinuation of treatment or dosage reduction).
	Rare	Reversible increase of serum testosterone levels. Reduced sperm counts, decreased libido.
General Disorders	Common	Somnolence, tiredness
	Rare	Asthenia, headache, dizziness, chest pain, malaise, hot flushes, weakness.
Investigations	Common	Transient abnormal liver function

Combination Therapy

SOC	Frequency	Reactions
Blood and lymphatic system disorders	Rare	Anaemia, leukopenia, thrombocytopenia, oedema.
	Very rare	Haemolytic anaemia, macrocytic anaemia, methemoglobinaemia, sulfhemoglbinaemia
Metabolism and nutrition disorders	Rare	Anorexia
	Very rare	Hyperglycemia, aggravation of diabetes mellitus
Reproductive system and breast disorders	Very common	Hot flushes, decreased libido, impotence.
	Rare	Gynaecomastia
Psychiatric and Nervous system disorders	Rare	Drowsiness, depression, confusion, anxiety, nervousness.
Cardiac and Vascular disorders	Very Rare	Pulmonary symptoms, such as dyspnoea and hypertension.
Respiratory, thoracic and mediastinal disorders	Very Rare	Interstitial lung disease
Gastrointestinal disorders	Very Common	Nausea, vomiting, diarrhoea
	Rare	Unspecified gastrointestinal disorders, abdominal pain.
Hepato-biliary disorders	Rare	Hepatitis, jaundice
	Very rare	Cholestatic jaundice, hepatic encephalopathy, hepatic necrosis, cases of severe hepatic injury with some fatal outcomes.
Skin and Subcutaneous tissue disorders	Rare	Rash
	Very rare	Photosensitivity, erythema, ulcerations, bullous eruptions, epidermal necrolysis
Musculoskeletal, Connective tissue and Bone disorders	Rare	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.
	Very Rare	Acute renal failure
General disorders	Rare	Injection site irritation
Investigations	Common	Changes in liver function
	Very rare	Elevated blood urea nitrogen (BUN), elevated serum creatinine

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

4.9 Overdose

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

The acute toxic dose of Flutamide in man has not been established. One patient survived after ingesting more than 5g 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. If vomiting does not occur spontaneously it should be induced, provided that the patient is alert. 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Anti-Androgens, ATC - Code L02 B B01

Flutamide is a non-steroidal, highly specific, orally active anti-androgenic agent. It has been demonstrated to reduce prostate and seminal vesicle weights in intact immature rats and to prevent androgen-stimulated hypertrophy of these organs in castrated immature rats. Prostate weights in dogs and baboons were also reduced by Flutamide treatment. The biological activity of oral Flutamide is attributable to its pharmacologically active metabolite, hydroxyflutamide, which is believed to exert an anti-androgenic effect directly on the target tissues, either by inhibiting androgen uptake or by blocking cytoplasmic and nuclear binding of androgen.

5.2 Pharmacokinetic properties

Flutamide is rapidly and extensively absorbed and almost completely metabolised following oral administration. The major metabolite is hydroxyflutamide, which has been demonstrated to possess potent antiandrogenic activity. The elimination half life in plasma is 5 to 6 hours for flutamide and its main metabolite hydroxyflutamide. The peak plasma concentration of hydroxyflutamide at steady state at the recommended therapeutic dose (250mg t.i.d.) is approximately 1700pg/L and the elimination half-life at steady-state is approximately 10 hours. The drug is excreted mainly in the urine, with 4.2% of the dose excreted in the faeces over 72 hours.

5.3 Preclinical safety data

The effects observed in oral repeat dose toxicology studies in the rat, dog and monkey were as expected for a potent anti-androgenic agent. Reductions in prostate gland and seminal vesicle weights were observed in all species and reduced testicular weights were observed in the rat and monkey. Histological changes characteristic of anti-androgenic activity were observed in all species and there was evidence of suppression of spermatogenesis.

The influence of Flutamide on fertility and the development of the progeny has beend studied in rats. Additional teratogenicity studies have been performed in rabbits. The effects were related to the antiandrogenic actions of Flutamide. These effects are not relevant to the clinical use of Flutamide in the treatment of prostate cancer.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose Lactose monohydrate Pre-gelatinised maize starch Sodium laurilsulfate Colloidal anhydrous silica Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Flutamide tablets are packaged either in PVC/aluminium blister packs or in polypropylene pots with polyethylene caps (with optional polyethylene ullage filler), containing 20, 21, 30 50, 60, 84, 100, 105, 250 or 10*21 tablets.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04569/0338

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 31/07/2006

10 DATE OF REVISION OF THE TEXT

30/09/2010