Summary of product characteristics

Flutamide 250 mg tablets
Summary of Product Characteristics
SUMMARY OF PRODUCT CHARACTERISTICS
TRADE NAME OF THE MEDICINAL PRODUCT
QUALITATIVE AND QUANTITATIVE COMPOSITION
PHARMACEUTICAL FORM
CLINICAL PARTICULARS
Therapeutic indications
Advanced prostatic carcinoma, in which suppression of testosterone effects is
indicated.

Flutamide 250 mg tablets may be used as initial treatment in combination with LHRH
agonist, as adjunctive therapy in patients already on treatment with an LHRH agonist
and as therapy for patients who have been surgically castrated and for patients who
have not responded to other forms of hormonal manipulation or who have not
tolerated them.
Flutamide 250 mg tablets may be used in combination with LHRH agonists for the management of locally confined B2-C2 (T2b-T4) prostate carcinoma as initial therapy; bulky 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. Posology and method of administration
The recommended dosage is 250 mg three times daily, preferably after meals. Data in the literature show that the incidence and the severity of the LHRH agonist flare reaction may be reduced by initiating treatment with an antiandrogen before rather than concomitantly with the agonist. For this reason, when flutamide is used as initial treatment in combination with an LHRH agonist, administration should be started at least three days before the LHRH agonist at the dosage of 750 mg/day (1 tablet three times a day) and continued thereafter at the same dose. Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
Administration of Flutamide 250 mg tablets and the LHRH agonist should begin 8 weeks prior to radiation therapy and continue through the course of radiation therapy (usually approximately 8 weeks) i.e. a total of approximately 16 weeks. Dosage adjustment in renal or liver function: Flutamide may be hepatotoxic. In patients with impaired liver function, long-term treatment with flutamide should only be administered after careful assessment of the individual benefits and risks. Contra-indications
Flutamide is contraindicated in patients who are hypersensitive to flutamide or any component of this preparation. Special warnings and special precaution 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. 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. 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). If the patient has jaundice or laboratory evidence of liver injury, in the absence of biopsy-confirmed liver metastasis, flutamide therapy should be discontinued or the dosage reduced. 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 hepatoxicity occur. Patients should be informed that Flutamide 250 mg tablets and the drug used for medical castration should be administered concomitantly, and that they should not interrupt their dosing or stop taking these medications without consulting their physician. Monitoring of clinical response to Flutamide 250 mg tablets (both serum PSA levels and change in prostate volume) during the first months of treatment is recommended in previously untreated patients. In patients, who have not received medical or surgical castration, periodic sperm count determinations may be considered during long-term treatment. Flutamide administration tends to elevate plasma testosterone and oestradiol levels and may induce fluid retention in patients who have not been previously castrated; therefore caution is required in the presence of heart disease. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
Interaction with other medicaments and other forms of interaction
Avoid concomitant administration of potentially hepatotoxic drugs. Avoid excessive alcohol consumption. Interactions between flutamide and leuprolide have not been described. Increase in prothrombin time have been noted in patients receiving long term warfarin therapy after flutamide was initiated. Therefore close monitoring of prothrombin time is recommended and adjustment of the anticoagulant dose may be necessary when flutamide is administered concomitantly with warfarin. Pregnancy and lactation
Flutamide 250 mg tablets is not intended for use in women. No studies have been conducted in pregnant or lactating women. Therefore, the possibility that Flutamide tablets 250 mg may cause foetal harm if administered to a pregnant woman or may be present in the breast milk of a lactating woman, must be considered Effects on ability to drive and use machines
Patients should be advised that initial sedative effects, may interfere with driving and the operation of machinery. Undesirable effects
Adverse reactions to flutamide according to system organ class and frequency are
listed below.

System Organ Class
Frequency *
Undesirable effects
Methemoglobinemia Leucopenia Lymphoedema ** Thrombocytopenia # Ecchymoses Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
System Organ Class
Frequency *
Undesirable effects
Anorexia Upset stomach Ulcer-like pain Heartburn Constipation ** Cholestatic jaundice Hepatic encephalopathy Hepatic necrosis, which may be fatal Photosensitivity reactions including erythema, ulcerations, bullous eruptions and epidermal necrolysis Genitourinary symptoms Urea blood level increased Creatinine serum level increased Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
System Organ Class
Frequency *
Undesirable effects
Malaise
Chest pain
Tiredness
Injection site irritation
* Adverse drug reactions are ordered under headings of frequency by using the following rate scale: 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 including isolated reports) ** ADRs only during flutamide as monotherapy # ADRs only during flutamide + LHRH agonist Monotherapy: In clinical studies, the most frequently reported adverse reactions to Flutamide 250 mg tablets are gynecomastia and/or breast tenderness, sometimes accompanied by galactorrhea, and diarrhoea. Gynecomastia occurred in 9% of patients receiving flutamide together with medical castration. These reactions disappear upon discontinuation of treatment or reduction in dosage. Combination therapy: The high incidence of gynecomastia observed with flutamide monotherapy was reduced greatly in combination therapy. In clinical trials, no significant difference in gynecomastia incidence was observed between the placebo -and the flutamide- LHRH agonist treatment groups. Flutamide 250 mg tablets demonstrate a low potential for cardiovascular complications, and when compared to diethystilbestrol the cardiovascular toxicity has been shown to be significantly lower. 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 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. Overdose
In animal studies with flutamide alone, signs of overdose included hypoactivity, piloerection, slow respiration, ataxia, and/or lacrimation, anorexia, tranquilization, emesis, and methaemoglobinemia. Clinical trials have been conducted with flutamide in doses up to 1500 mg per days for periods up to 36 weeks with no serious adverse effects reported. Those adverse reactions reported included gynecomastia, breast tenderness and some increase in SGOT. The single dose of flutamide ordinarily associated with symptoms of overdose or considered to be life-threatening has not been established. Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
Since flutamide is highly protein bound, dialysis may not be of any use as treatment of overdosage. As in the management of overdosage with any drug, it should be born in mind that multiple agents may have been taken. If vomiting does not occur spontaneously, it should be induced if the patient is alert. Gastric lavage and general supportive care, including frequent monitoring of the vital signs and close observation of the patients, is indicated. One patient survived after taking more than 5g as a single dose - no adverse effects were observed. PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
In animal studies, flutamide demonstrates potent antiandrogenic effects. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. Most cases of advanced prostatic carcinoma are known to be androgen sensitive and respond to flutamide treatment. When flutamide is given in combination with surgical or medical castration, suppression of both testicular and adrenal androgen activities is achieved. Pharmacokinetic properties
Flutamide is well absorbed following oral ingestion Analysis of plasma, urine and faeces following a single oral 200 mg dose of tritium-labelled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. It is excreted mainly in the urine with only 4.2% of the dose excreted in the faeces over 72 hours. The composition of plasma radioactivity showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity one hour after administration. At least six metabolites have been identified in plasma. The major plasma metabolite is a biologically active 2-hydroxy flutamide which accounts for 23% of the plasma tritium one hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl) phenol. Following a single 250 mg oral dose to normal adult volunteers, low plasma levels of varying amounts of flutamide were detected. The biologically active metabolite 2-hydroxy flutamide reaches maximum plasma levels in about two hours, indicating that it is rapidly formed from flutamide. The plasma half-life for this metabolite is about 6 hours. Following multiple oral dosing of 250 mg three times daily in normal geriatric volunteers, flutamide and its active metabolite approached steady-state plasma levels (based on pharmacokinetic simulations) after the fourth flutamide dose. The half-life of the active metabolite in geriatric volunteers after a single flutamide dose is about 8 hours and at steady-state is 9.6 hours. Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
Flutamide, in vivo, at steady-state plasma concentrations of 24 to 78 ng/ml is 94% to 96% bound to plasma proteins. The active metabolite of flutamide, in vivo, at steady-state plasma concentrations of 1556 to 2284 ng/ml, is 92% to 94% bound to plasma proteins. In male rats neither flutamide nor any of its metabolites is preferentially accumulated in any tissue except the prostate after an oral 5 mg/kg dose of 14C-Flutamide. Total drug levels were highest 6 hours after drug administration in all tissues. Levels declined at roughly similar rates to low levels at 18 hours. The major metabolite was present at higher concentrations than flutamide in all tissues studied. Preclinical safety data
Acute toxicity studies in rats have shown that the LD50 of flutamide following oral administration is equivalent to 1078 mg/kg in males and to 787 mg/kg in females, whereas the LD50 p.o. in dogs is above 2.000 mg/kg. Treatment of rats and dogs for one year with doses up to 75 mg/kg (7.5 times the human dose) was not associated with any important effects other than those on the genital organs (atrophy of epididymides, seminal vesicles, prostate and the seminiferous tubules of the testes associated with reduced spermatogenesis, hyperplasia of the pituitary), closely related to the mechanism of action of the compound. Slight alterations of biochemical and haematological parameters returned to normal after discontinuation of treatment. Reproduction studies in adult male rats have demonstrated that the genital atrophy induced by flutamide diminishes fertility. Flutamide did not demonstrate DNA modifying activity in the AMES Salmonella/ microsome Mutagenesis Assay. Dominant lethal tests in rats were also negative. No carcinogenesis studies have been performed with flutamide. However, long term (1 year) treatment in toxicity studies, in rat and dogs, with doses up to 75 mg/kg/day was not associated with the development of tumours in dogs but and increased incidence of testicular follicular cell adenomas was observed in rats treated with doses equal to or greater than 7.5 mg/kg/day (7.5 times the human dose). PHARMACEUTICAL PARTICULARS
List of excipients
The inactive ingredients for Flutamide include: lactose monohydrate maize starch povidone crospovidone sodium laurilsulfate magnesium stearate hypromellose Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004 Flutamide 250 mg tablets
Summary of Product Characteristics
Incompatibilities
Shelf life
Special precautions for storage
Nature and contents of container
Al/PVDC green strips (blisters) of coated tablets. Blister strip of PVC 250 /PVDC 40 g - Aluminium 20 2 strips of 15 tablets are contained in an outer cardboard carton (30 tablets). 4 strips of 21 tablets are contained in an outer cardboard carton (84 tablets). Instructions for use/handling

ADMINISTRATIVE DATA

7.
MARKETING AUTHORIZATION HOLDER
MARKETING AUTHORIZATION NUMBER
DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION
DATE OF (PARTIAL) REVISION OF THE TEXT
Euro-SmPC (UK/H/0386/01/R/002) – currently approved, UK version – June 2004

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