Document: spc-doc_PL 11311-0525 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 250mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 mg flutamide

Excipient with known effect: Each tablet contains 221.7 mg of lactose (as lactose monohydrate)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Yellowish, round biconvex tablets with score notch on one side.

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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 forms 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 tumours confined to the prostate (stage B2 or T2b) or extending beyond the capsule (stage C or T3-T4), with or without pelvic node involvement.

4.2 Posology and method of administration

Posology

One 250mg tablet 3 times daily at 8 hour intervals

When used as 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 one Flutamide tablet three times daily should be started at least three days before an 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. Flutamide should be started at least three days prior to initiation of the LHRH agonist. Administration of Flutamide 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.

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

Method of administration

Oral

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

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: Flutamide may be hepatotoxic, chronic flutamide therapy should be used with caution in patients with pre-existing hepatic dysfunction only after considering the benefits and potential risks. Liver function tests should be performed before treatment is started. Since transaminase abnormalities, cholestatic jaundice, hepatic necrosis, and hepatic encephalopathy have been reported with the use of flutamide, periodic liver function tests should be considered. 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 two to three 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, or if the serum transaminase values exceed two-to threefold normal values in patients without pathological findings. 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 oestradiol levels, fluid retention may occur. In severe cases this can lead to an increased risk of angina and heart failure, thus the drug should be used with caution in cardiovascular disease. Flutamide can exacerbate edema or ankle swelling in patients prone to these conditions.

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.

Flutamide is indicated for use only in male patients.

Contraceptive measures should be taken during treatment.

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

The tablets contain lactose. Patients with rare hereditary problems of galactose-intolerance, lactose-deficiency or glucose-galactose malabsorption should not take flutamide.

4.5 Interaction with other medicinal products and other forms of interaction

LHRH agonist

Interactions between flutamide and leuprolide have not occurred, however, in combination therapy of flutamide Tablets administered with an LHRH agonist, the possible adverse effects of each product must be considered.

Warfarin/oral anticoagulants

Increases in prothrombin time have been reported in patients receiving long-term warfarin/oral anticoagulants 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.

Steroids

Flutamide may delay the metabolism of steroids.

Hepatotoxic drugs

Concurrent administration of potentially hepatotoxic drugs should be undertaken after careful assessment of benefit and risks.

Alcohol

Given the known potential liver and renal toxicities of the product, excessive alcohol consumption should be avoided.

Theophylline

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

4.6 Fertility, pregnancy and lactation

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

Flutamide Tablets may cause fetal harm when administered to a pregnant woman. In animal studies, reproductive toxicity was related to the antiandrogenic activity of this compound (see 5.3). 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 fetuses of rats at the two higher doses. Feminization 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 Tablets may cause fetal 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 the effects on the ability to drive and use machines have been performed with Flutamide. However, possible adverse reactions such as fatigue, dizziness and confusion have been reported and may impair the ability to drive and use machines.

4.8 Undesirable effects

Monotherapy

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

Flutamide 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 Flutamide 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.

The high incidence of gynecomastia observed with flutamide Tablets monotherapy was markedly lower in combination therapy. In clinical trials, no significant difference in gynecomastia incidence was observed between the placebo- and the flutamide-LHRH agonist treatment groups.

Table 1. Treatment related undesirable effects

Very common 1/10); Common >1/100 to <1/10); Uncommon >1/1,000, to <1/100);

Rare >1/10,000, <1/1,000); Very rare (<1/10,000) and not known (cannot be estimated from the available data).

Italics Indicate post-marketing experience

BODY SYSTEM	Flutamide	Flutamide PLUS LHRH
Infections and infestations
Rare	Herpes zoster
Neoplasms benign and malignan (including cysts and polyps)
Very rare:	Neoplasm of the male breast*	Male breast neoplasm *
Blood and the lymphatic system disorders
Rare	ecchymoses, lymphedema	Anemia, leucopenia, thrombocytopenia
Very Rare:		Hemolytic anemia, macrocytic anemia/ megalocytic anemia, methemoglobinemia, sulfhemoglobinemia
Immune system disorders
Rare	Lupus-like syndrome
Metabolism and nutrition disordei
Common:	Increased appetite
Rare	Anorexia	Anorexia
Very rare		Hyperglycemia, aggravation of diabetes mellitus
Psychiatric disorders
Common	Insomnia
Rare	Anxiety, depression	Depression, anxiety
Nervous System Disorders

Rare	Dizziness, headache	Drowsiness, confusion, nervousness, numbness
Eye Disorders
Rare	Blurred vision
Vascular disorders
Very common		Hot flushes
Rare	Hot flushes	Hypertension
Not known		Thromboembolism
Respiratory, thoracic and mediastinal disorders
Very rare:		Lung symptoms (e.g. dyspnea), Interstitial lung disease
Gastrointestinal disorders
Very common		Diarrhea, nausea, vomiting
Common:	Diarrhea, nausea, vomiting
Rare:	Non-specific abdominal disorders , Upset stomach, ulcer-like pain, heartburn, constipation	Unspecified gastrointestinal/abdominal disorders
Hepato-biliary disorders
Common	Hepatitis
Uncommon		Hepatitis
Rare:		Hepatic dysfunction, Jaundice
Very rare:		Cholestatic jaundice, hepatic encephalopathy, hepatic necrosis, cases of death following severe hepatic injury/hepatotoxicity.
Skin and subcutaneous tissue disorders
Rare	Pruritus, ecchymoses	Rash
Very rare	Photosensitivity reactions	Photosensitivity reactions, erythema, ulcerations, bullous eruptions, epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders

Rare		Neuromuscular symptoms
Renal and urinary disorder
Rare		Genitourinary tract symptoms
Very rare:		Change in urine color to amber or yellow-green
Reproductive system and breast disorders
Very Common:	Gynecomastia and/or breast tenderness, galactorrhea	Decreased libido, impotence, hot flashes
Uncommon		Gynecomastia
Rare	Decreased libido Reduced sperm counts
General disorders and administration site conditions
Common:	Tiredness
Rare	Edema, weakness, malaise, thirst, chest pain	Edema, Injection site irritation
Investigations
Common:	Transient abnormal liver function
	Hepatitis
Rare		Changes in liver function, elevated blood urea nitrogen (BUN), Elevated serum creatinine

*Few reports of malignant male breast neoplasms in patients dosed with Flutamide have been reported. One involved aggravation of a pre-existing nodule which was first detected three or four months before initiation of Flutamide therapy in a patient with benign prostatic hypertrophy. After excision, this was diagnosed as a poorly differentiated ductal carcinoma.

The other report involved gynecomastia 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.

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.

Because flutamide is non-steroidal it shows a low potential for cardiovascular side effects.

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.gov.uk/yellowcard.

4.9 Overdose

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

Clinical trials have been conducted with flutamide Tablets in doses up to 1500 mg per day for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness and some increases in SGOT.

The single dose of Flutamide associated with symptoms of overdosage, or considered to be life-threatening, has not been established. One patient survived after taking more than 5g as a single dose - no adverse effects were observed.

Since flutamide is highly protein bound, dialysis may not be of any use as treatment for overdose. As in the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. General supportive care, including frequent monitoring of the vital signs and close observation of the patient, is indicated. Gastric lavage may be considered.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, ATC code: G03H A.

Flutamide is an anilide, nonsteroidal oral antiandrogen. In animal studies flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding in target tissues. When flutamide is given in combination with

surgical or medical castration, suppression of both testicular and adrenal

androgen activity is

achieved.

5.2 Pharmacokinetic properties

Absorption

Flutamide is well absorbed following oral ingestion.

Biotransformation

Studies with radiolabelled flutamide show rapid and extensive conversion to its metabolites which are detectable in plasma up to 8 hours post dosing.

Elimination

Approximately 45% of the administered dose is excreted in urine and 2% in faeces during the first two days.

Metabolism removes the radiolabel resulting in apparent slowing of excretion due to retention of the label as tritiated water. Thus excretion and metabolism is essentially complete within two days.

5.3 Preclinical safety data

Preclinical safety data: Animal studies to determine tolerance after repeated administration have been performed in monkeys for up to 6 weeks, in rats for up to 52 weeks and in dogs for up to 78 weeks. The daily administered oral doses were up to 90mg/kg in monkeys, up to 40mg/kg in dogs and up to 180mg/kg in rats, corresponding to 1.5 to 18 fold of the dose used in humans. In addition to weight loss and anorexia which occurred in all animal species, vomiting was observed in dogs and monkeys. All other clinical findings showed no abnormalities. The autopsy finding revealed a reduced size of the prostate, testicles and seminal vesicles with suppressed spermatogenesis which corresponded to the antiandrogenic effect of flutamide. In addition, an increase in the organ weight of the liver in rats and dogs, and increased transaminase levels in dogs were observed without corresponding morphological changes. In rats only, the occurrence of drug-related (but not dose-dependent) adenomas of testicular interstitial cells was observed.

This effect is related to the mechanism of action of flutamide and is species specific.

In a long-term study in rats, dose-related increases in mammary gland adenomas or carcinomas were observed.

Mutagenicity : In a range of screening tests flutamide did not show any mutagenic potential.

Reproduction toxicity : The influence of flutamide on fertility and the development of the progeny has been 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 prostate cancer.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Maize Starch

Microcrystalline Cellulose Sodium Lauryl Sulfate Colloidal anhydrous silica Magnesium Stearate

6.2 Incompatibilities

None known

6.3 Shelf life 5 years

6.4    Special precautions for storage

Do not store above 25°C. Store the tablets in the original package.

6.5    Nature and contents of container

PVC/aluminium blister strips in a cardboard carton 28, 56 and 84 tablets per pack

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.