Active ingredient: Bicalutamide Chemical name: (RS)-4'-Cyano-a", a", a',-trifluoro-3-(4-fluorophenylsulphonyl)-2-hydroxy-2- methylpropiono-m-toluidide. Structural formula: Molecular formula: C18H14F4N2O4S Molecular weight: 430.38 CAS Registry no. : 90357-06-5

DESCRIPTION

Bicalutamide is a fine white to off-white powder. At 37degC it is practically insoluble in water (4.6 mg/litre), acid (4.6 mg/litre at pH 1) and alkali (3.7 mg/litre at pH 8). In organic solvents it is slightly soluble in ethanol, sparingly soluble in methanol and freely soluble in acetone and tetrahydrofuran. Cosamide tablets are white film coated tablets containing 50 mg of the active ingredient bicalutamide. The tablets also contain the following excipients: lactose, povidone, sodium starch glycollate, magnesium stearate, and Opadry II white Y-30-18037.

PHARMACOLOGY

Bicalutamide is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. This inhibition impairs the growth and encourages apoptosis in androgen-dependent tumour cells and regression of prostatic tumours. In a subset of patients who experience disease progression while receiving bicalutamide, discontinuation of the drug may result in an ,,anti-androgen withdrawal syndrome", which manifests as a fall in prostate specific antigen (PSA) level. It is unknown whether this phenomenon translates to a prolongation of tumour response or survival. Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively in the (R)- enantiomer.

Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

Bicalutamide is highly protein bound (racemate 96%, R-enantiomer 99.6%). Steady state plasma concentrations of the (R)-enantiomer of approximately 9 ug per mL are observed during daily administration of bicalutamide 50 mg. At steady state the predominantly active (R)- enantiomer accounts for 99% of the total circulating enantiomers.

Bicalutamide undergoes stereospecific metabolism. Bicalutamide is extensively metabolised (via oxidation and glucuronidation). Its metabolites are eliminated via the kidneys and bile in approximately equal proportions. The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week. On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10 fold in plasma as a consequence of its long half-life. The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.

CLINICAL TRIALS

In a large multicentre, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomised to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with a Luteinising Hormone Releasing Hormone Agonist (LHRH Agonist) (either goserelin acetate implant or leuprorelin acetate depot). At the time of analysis, the median time of follow-up was 49 weeks. Bicalutamide/ LHRH agonist therapy was associated with a statistically significant (p = 0.005) improvement in time to treatment failure. Subjective responses, (including scores for pain, analgesic use and Eastern Oncology Cooperative Group (ECOG) performance status) assessed in patients with symptoms at entry were seen in 95 (52%) patients treated with bicalutamide and in 88 (54%) patients treated with flutamide, each in combination therapy with LHRH agonists. This small difference was not statistically significant between bicalutamide 50 mg combination therapy and flutamide combination therapy.

There is considerable debate regarding the relative merits of combination versus monotherapy in advanced prostate cancer, summarised by Dalesio et al 1995(1) in their meta-analysis of trials of maximal androgen blockade (MAB). This analysis showed no statistically significant reduction in the annual odds of death in favour of MAB. The meta-analysis included the effect of MAB only on mortality, and did not measure other end-points such as time to disease progression.

Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995; 346: 265-269.

CONTRAINDICATIONS

Cosamide is contraindicated in females and children. Known hypersensitivity to bicalutamide or any other constituents of the formulation. Co-administration of terfenadine, astemizole or cisapride with Cosamide is contraindicated (see PRECAUTIONS - Interactions with Other Medicines).

PRECAUTIONS

Bicalutamide is extensively metabolised in the liver. Data suggests that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, Cosamide should be used with caution in patients with moderate to severe hepatic impairment. Periodic liver function testing should be considered due to the possibility of hepatic changes. The majority of these changes occur within the first 6 months of bicalutamide therapy. Rare cases of death or hospitalisation due to severe liver injury have been observed with bicalutamide (see Adverse Effects). Cosamide therapy should be discontinued if at any time a patient develops jaundice or if serum ALT rises above two times the upper limit of normal. A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists. In patients with metastatic prostate cancer, treatment with bicalutamide monotherapy has been associated with reduced survival compared to castration. Cosamide should therefore not be used without concomitant LHRH agonist therapy in these patients.

Bicalutamide was inactive in in vitro tests for gene mutation and in in vitro and in vivo tests for clastogenicity. Two-year oral carcinogenicity studies were conducted in male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumour target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumours in male rats at all dose levels and uterine adenocarcinoma in female rats at 75 mg/kg/day (at these dose levels plasma (R)-bicalutamide concentrations were less than human therapeutic concentrations after the maximum recommended clinical dose of 150 mg). There is no evidence of Leydig cell hyperplasia in patients; uterine tumours are not relevant to the indicated patient population. A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 2 times human therapeutic concentrations after the maximum recommended clinical dose of 150 mg) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (less than the human therapeutic concentrations after the maximum recommended clinical dose of 150 mg) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man.

Administration of bicalutamide may lead to inhibition of spermatogenesis. The long- term effects of bicalutamide on male fertility have not been studied. In male rats dosed at 250 mg/kg/day (less than human therapeutic concentrations after the maximum recommended clinical dose of 150 mg), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.

Australian categorisation definition of Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Cosamide is contraindicated in females and must not be given to pregnant women.

Cosamide is contraindicated in females and must not be given to breast-feeding mothers.

Bicalutamide is extensively metabolised (via oxidation and glucuronidation) in the liver. Bicalutamide has shown no evidence of causing enzyme induction in humans during dosing at 50 mg daily in man. In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. The clinically or potentially significant drug interactions between bicalutamide and the following agents/drug classes, which are theoretical or have been observed, are described below. The drug/drug interactions described include both interactions mediated through effects on P450 metabolism and interactions mediated through other mechanisms.

: Although there is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide 50 mg and LHRH agonists at steady state, Cosamide 50 mg may prevent the harmful clinical consequences of flare associated with the start of LHRH agonist therapy.

: Bicalutamide is an inhibitor of CYP 3A4 and has been shown to increase plasma levels of midazolam by up to 80 %. Therefore, concomitant use of terfenadine, astemizole and cisapride is contraindicated. Caution should be exercised with other drugs metabolised by CYP 3A4, such as cyclosporin, calcium channel blockers, HIV antivirals, HMGCoA reductase inhibitors, carbamazepine, quinidine etc.

studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is therefore recommended that if Cosamide is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.

Caution should be exercised when prescribing Cosamide with other drugs which may inhibit drug oxidation eg. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of bicalutamide and an increase in adverse reactions.

During treatment with bicalutamide, somnolence has been reported. Those patients who experience this symptom should observe caution when driving or using machines.

ADVERSE EFFECTS

Bicalutamide 50 mg in general, has been well tolerated with few withdrawals due to adverse events. The pharmacological action of bicalutamide may give rise to certain expected effects. These include hot flushes, pruritus, breast tenderness and gynaecomastia which may be reduced by concomitant castration. Bicalutamide 50 mg may also be associated with the occurrence of diarrhoea, nausea, vomiting, asthenia and dry skin. Hepatic changes (elevated levels of transaminases, jaundice), rarely severe, have been observed in clinical trials with bicalutamide. The changes were frequently transient, resolving or improving with continued therapy or following cessation of therapy (see Precautions). Hypersensitivity reactions, including angioneurotic oedema and urticaria, and interstitial lung disease have been reported uncommonly. Hepatic failure has been rarely observed.

Clinical trial data - Combination therapy (with medical castration) in advanced prostate cancer

The following adverse experiences were reported in clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians, with a frequency of >=1%) during treatment with bicalutamide 50 mg plus an LHRH agonist. No causal relationship of these experiences to drug treatment has been made and some of the experiences reported are those that commonly occur in elderly patients.

Table 1: Bicalutamide Adverse Drug Reactions by Frequency and System Organ Class

Frequency	System Organ Class	Event
Very common (>= 10%)	Blood and lymphatic disorders Nervous system disorders Vascular disorders Gastrointestinal disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions	Anaemia Dizziness Hot flush Abdominal pain, constipation, nausea Haematuria Breast tenderness 1 , gynaecomastia 1 Asthenia, chest pain, oedema
Common (>= 1% - < 10%)	Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Gastrointestinal disorders Hepato-biliary disorders Cardiac disorders Skin and subcutaneous tissue disorders Reproductive system and breast disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Whole body Investigations	Decreased appetite, diabetes mellitus, hyperglycaemia, weight loss Decreased libido, depression Somnolence, insomnia Dyspepsia, flatulence, anorexia, dry mouth Hepatotoxicity, jaundice, hypertransaminasaemia 2 Myocardial infarction (fatal outcomes have been reported) 3 , cardiac failure 3 Alopecia, hirsutism/hair re-growth, rash, dry skin, pruritis, sweating Erectile dysfunction Nocturia Dyspnoea Headache, pain, pelvic pain, chills Weight increased
Uncommon (>= 0.1% - < 1%)	Immune system disorders Respiratory, thoracic and mediastinal disorders	Hypersensitivity reactions, angioedema and urticaria Intestinal lung disease (ILD) 4 - fatal outcomes have been reported
Rare (>= 0.01% - < 0.1%)	Hepato-biliary disorders	Hepatic failure 5 - fatal outcomes have been reported

May be reduced by concomitant castration

Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy

Observed in a pharmaco-epidemiology study of LHRH agonists and anti-androgens used in the treatment of prostate cancer. The risk appears to be increased when bicalutamide 50 mg was used in combination with LHRH agonists but no increase in risk was evident when bicalutamide 150 mg was used as a monotherapy to treat prostate cancer.

Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies

Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of hepatic failure in patients receiving treatment in the open-label bicalutamide arm of the 150 mg EPC studies

DOSAGE AND ADMINISTRATION

One tablet (50 mg) once a day. Treatment with Cosamide 50 mg should be started at the same time as treatment with a LHRH agonist.

No dosage adjustment is necessary for patients with mild hepatic impairment. Increased accumulation may occur in patients with moderate to severe hepatic impairment (see Precautions). In such cases, a lower or less frequent dose may be considered.

OVERDOSAGE

There is no human experience of overdosage. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since bicalutamide is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated. The physician should consider contacting the Poisons Information Centre on 131126 for advice on the treatment of overdosage.

PRESENTATION AND STORAGE CONDITIONS

bicalutamide 50mg tablets: white round, biconvex, film-coated tablets, with "BIC 50" on one side and "G" on the other; blister packs of 28, 30 *, 40 *, 90 * and 100 * tablets; bottles * of 28 *, 30 * and 100 * tablets.

POISON SCHEDULE OF THE MEDICINE

NAME AND ADDRESS OF THE SPONSOR

Level 1, 30 The Bond 30-34 Hickson Road Millers Point NSW 2000 ABN 93 002 359 739 www.alphapharm.com.au

DATE OF APPROVAL

Approved by the Therapeutic Goods Administration on 23 October 2007. Date of most recent amendment: 3 March 2011.

NAME OF THE MEDICINE