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Product
Anti-cancer Products (Cytomid)
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Anti-cancer Products (Cytomid)
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Cytomid
Flutamide Tablets
COMPOSITION
Each uncoated tablet contains flutamide 250 mg.
DOSAGE FORM
CYTOMID is available as oral tablets
PHARMACOLOGY
Pharmacodynamics
Flutamide, an acetanilide is a nonsteroidal, orally active antiandrogen. It exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in target tissues or both. When flutamide is given in combination with surgical or medical castration, suppression of both testicular and adrenal androgen activity is achieved. Elevations of plasma testosterone and estradiol levels have been noted following flutamide administration.
Pharmacokinetics
Absorption : Flutamide is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide. Food has no effect on the bioavailability of flutamide.
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Distribution: Following a single 250 mg oral dose to normal adult volunteers, low plasma concentrations of flutamide were detected. The plasma half-life for the alpha-hydroxylated metabolite of flutamide is approximately 6 hours. 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.
Metabolism: The composition of plasma radioactivity, following a single 200 mg oral dose of tritium-labeled flutamide to normal adult volunteers, showed that flutamide is rapidly and extensively metabolized, with flutamide comprising only 2.5% of plasma radioactivity 1 hour after administration. At least six metabolites have been identified in plasma. The major plasma metabolite is a biologically active alpha-hydroxylated derivative which accounts for 23% of the plasma tritium 1 hour after drug administration. The major urinary metabolite is 2-amino-5-nitro-4-(trifluoromethyl)phenol.
Excretion: Flutamide and its metabolites are excreted mainly in the urine with only 4.2% of a single dose excreted in the feces over 72 hours.
INDICATIONS
CYTOMID is indicated in the treatment of advanced prostatic cancer (D2) as initial treatment in combination with a luteinizing hormone-releasing hormone (LHRH) agonist, as adjunctive therapy in patients already receiving LHRH agonist, in surgically castrated patients and in patients who have not responded or have become refractory to or who cannot tolerate other hormonal manipulation.
CYTOMID is also indicated in combination with LHRH agonists for the management of locally confined B2-C2 (T2b-T4) prostate carcinoma as initial therapy; bulky primary tumors confined to the prostate (stage B2 or T2b) or extending beyond the capsule (stage C or T3-T4), with or without pelvic node involvement.
DOSAGE AND ADMINISTRATION
The patient should not interrupt or alter the dosage regimen without consulting the clinician.
The recommended dosage is 250 mg three times daily at 8-hour intervals.
In combination with an LHRH agonist, it is recommended that CYTOMID therapy should be started 3 days prior to initiation of the LHRH agonist, to reduce the flare reaction. During radiation therapy, administration of both CYTOMID and LHRH agonist should begin 8 weeks prior and continue through the course of radiation (usually about 8 weeks), i.e. a total of about 16 weeks.
CONTRAINDICATIONS
Hypersensitivity to flutamide or any component of this preparation.
WARNINGS AND PRECAUTIONS
Drug interactions
On concomitant therapy with anticoagulants, adjustment of the initiating dose or maintenance anticoagulant dose may be necessary because increases in prothrombin time have been noted. Close monitoring of prothrombin time is recommended.
Avoid concomitant administration of potentially hepatotoxic drugs. Cases of increased theophylline plasma concentrations have been reported in patients receiving concomitant theophylline and flutamide. Theophylline is primarily metabolized by CYP 1A2 which is the primary enzyme responsible for the conversion of flutamide to its active agent 2-hydroxyflutamide.
General
In clinical trials, gynaecomastia occurred in 9% of patients receiving flutamide together with medical castration.
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 estradiol levels. Fluid retention may occur thus the drug should be used with caution in cardiac disease.
Renal impairment
Dose adjustment in patients with chronic renal insufficiency is not warranted .
Hepatic impairment
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.
Transaminase abnormalities, cholestatic jaundice, hepatic necrosis and hepatic encephalopathy have been reported with the use of flutamide. 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 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 in patients. Appropriate laboratory testing should be done monthly for the first 4 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, flutamide therapy should be discontinued or the dosage reduced.
Pregnancy
CYTOMID is indicated only for use in male patients. There is no data on pregnant women.
Lactation
CYTOMID is indicated only for use in male patients. There is no data on lactating women.
Paediatric use
Flutamide has not been studied in paediatric subjects .
UNDESIRABLE EFFECTS
Most frequent side-effects are gynaecomastia and breast tenderness, some times galactorrhoea. These disappear on stopping treatment.
Less frequent adverse reactions are diarrhoea, nausea, vomiting, insomnia, tiredness, transient abnormal liver function and hepatitis. Decreased libido, upset stomach, anorexia, ulcer-like pain, heartburn, constipation, oedema, ecchymosis, pruritus, lupus-like syndrome, headache, dizziness, weakness, malaise, blurred vision and reduced sperm counts have been reported rarely.
Rarely anaemia, leukopenia, anorexia, jaundice, hypertension, central nervous system adverse events and thrombocytopenia may be observed.
Additional adverse experiences: Very rarely, the following have been reported: haemolytic anaemia, methaemoglobinaemia, photosensitivity reactions, cholestatic jaundice, hepatic encephalopathy and hepatic necrosis. The hepatic conditions were usually reversible after stopping treatment.
OVERDOSAGE
The single dose of flutamide associated with symptoms of overdose or considered life threatening has not been established. Since flutamide is highly protein bound, dialysis may not be of any use as treatment for overdose. Gastric lavage may be considered.
PACKAGING INFORMATION
CYTOMID …........................ Strip of 10 tablets
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