Chemical Name: (RS)-4'-Cyano-a',a',a',-trifluoro-3-(4-fluorophenylsulphonyl)-2- hydroxy-2-methylpropiono-m-toluidide. Structural Formula: CAS Number: 90357-06-5. Molecular formula: C18H14F4N2O4S Molecular weight: 430.38
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. COSUDEX 150 mg tablets are white film coated tablets containing 150 mg bicalutamide. Each tablet contains the following excipients: lactose, sodium starch glycollate, povidone, magnesium stearate, hypromellose, macrogol 300 and titanium dioxide.
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 anti-androgenic activity being almost exclusively in the (R)-enantiomer.
Absorption
COSUDEX is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
Distribution
Bicalutamide is highly protein bound (racemate 96%, R-enantiomer 99.6%). Steady state plasma concentrations of the (R)-enantiomer of approximately 22 mg per mL are observed during daily administration of COSUDEX 150 mg. At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
Metabolism and Elimination
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 COSUDEX, 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. In a clinical study the mean concentration of R-bicalutamide in semen of men receiving COSUDEX 150 mg was 4.9 mg/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 mg/kg. This is below that required to induce changes in offspring of laboratory animals.
The efficacy of COSUDEX 150 mg as a treatment for patients with locally advanced prostrate cancer (Stage T3 or T4 or N+) was demonstrated in a combined analysis of three placebo controlled double-blind studies. COSUDEX 150 mg was given as immediate hormonal therapy or as adjuvant therapy to radical prostatectomy or radiotherapy. The trials (0023, 0024 and 0025) were designed to allow data to be pooled and the primary endpoints were time to objective progression (TTP) and time to death (TTD: overall survival) on an intention-to-treat basis. In the first analysis the data did not demonstrate a beneficial effect of COSUDEX in the subgroup of patients with localised disease who received the drug as adjuvant therapy. Furthermore, for the subgroup of patients with localised disease who did not receive surgery or radiotherapy, a subsequent analysis after a median follow up of 7.4 years indicated that treatment with COSUDEX was associated with a trend towards an increased mortality risk compared to placebo (37.7% vs 32.9%); hazard ratio (HR) = 1.16 95% CI 0.99 to 1.37). These data indicate that COSUDEX should not be used for the treatment of disease, which remains localised to the prostate. In the subgroup of patients with locally advanced prostate cancer who did not receive treatment with radical prostatectomy or radiotherapy, immediate therapy with COSUDEX 150mg significantly reduced the risk of objective disease progression (Hazard Ratio (HR) = 0.60; 95% CI 0.49 to 0.73). A statistically significant reduction in the risk of objective disease progression was also seen in the subgroup of patients with locally advanced disease who received COSUDEX as adjuvant to radical prostatectomy or radiotherapy (HR = 0.69; 95% CI 0.58 to 0.82). No difference in survival was seen. A reduction in risk of objective disease progression was seen across most patients groups but was most evident in those at highest risk of disease progression. Therefore clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression may be to defer hormonal therapy until signs that the disease is progressing. Patients receiving COSUDEX were more likely to withdraw from treatment as the result of an adverse event (29.3% vs 10.0% for COSUDEX and placebo, respectively), whilst patients receiving placebo were more likely to withdraw treatment as a result of disease progression (5.5% vs 12.9% for COSUDEX and placebo, respectively).
In a combined analysis of two studies with 480 previously untreated patients with non-metastatic (M0) locally advanced prostate cancer and requiring immediate hormonal therapy, at 56% mortality, the hazard ratio for survival was 1.05 (CI 0.81 to 1.36, p=0.699) and for time to progression was 1.20 (CI 0.96 to 1.51, p=0.107) between COSUDEX 150 mg and castration (where a hazard ratio of 1 indicates identical efficacy and values <1 indicate an advantage for COSUDEX). Castration was either pharmacological or surgical. One of the studies showed an advantage for COSUDEX therapy, whereas the other showed an advantage for castration therapy. Equivalence of COSUDEX to castration could not be concluded.
In patients with locally advanced prostate cancer, COSUDEX 150 mg is indicated as adjuvant therapy to treatment of curative intent, or alone as immediate therapy in patients who are not receiving treatment of curative intent.
COSUDEX 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 COSUDEX is contraindicated (see Interactions with other medicines).
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, COSUDEX 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 COSUDEX therapy. Rare cases of death or hospitalisation due to severes liver injury have been observed with COSUDEX (see ADVERSE EFFECTS). COSUDEX 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 COSUDEX in combination with LHRH agonists.
In patients with prostate cancer localised to the prostate gland, treatment with bicalutamide 150 mg has been associated with increased mortality (in patients managed with watchful waiting) or lack of demonstrated benefit (in patients managed with prostatectomy or radiotherapy) - see CLINICAL TRIALS. COSUDEX 150 mg should therefore not be used in these patients.
In patients with metastatic prostate cancer, treatment with bicalutamide monotherapy has been associated with reduced survival compared to castration. COSUDEX 150 mg should therefore not be used 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.
COSUDEX is contraindicated in females and must not be given to pregnant women.
COSUDEX is contraindicated in females and must not be given to breast-feeding mothers.
COSUDEX is extensively metabolised (via oxidation and glucuronidation) in the liver. COSUDEX 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 COSUDEX 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.
Effects of bicalutamide on other medicines
Cytochrome P450:
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.
Demonstrated interactions
Warfarin: In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is therefore recommended that if COSUDEX is started in patients who are already receiving coumarin anticoagulants, prothrombin time should be closely monitored.
Theoretical interactions
Caution should be exercised when prescribing COSUDEX 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 COSUDEX, somnolence has been reported. Those patients who experience this symptom should observe caution when driving or using machines.
Clinical trial data
Unless specified, the following frequency categories were assigned based on the incidence of the adverse event in the 150mg arm of the combined Early Prostate Cancer studies (for COSUDEX monotherapy).
Table 1
| Frequency | System Organ Class | Event |
| Very common (>=10%) | Blood and lymphatic Skin and subcutaneous tissue disorders | anaemia rash |
| Frequency | System Organ Class | Event |
| Reproductive system and breast disorders General disorders and administration site conditions | breast tenderness 1 , gynaecomastia 1 asthenia | |
| Common (>=1% - <10%) | Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Vascular disorders Gastrointestinal disorders Hepato-biliary disorders Skin and subcutaneous tissue disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions Investigations | decreased appetite decreased libido, depression dizziness, somnolence hot flush abdominal pain, constipation, dyspepsia, flatulence, nausea hepatotoxicity, jaundice, hypertransaminasaemia 2 alopecia, hirsuitism/ hair re-growth, dry skin 3 , pruritis haematuria erectile dysfunction chest pain, oedema weight increased |
| Uncommon (>=0.1% - <1%) | Immune system disorders Respiratory, thoracic and mediastinal disorders | hypersensitivity, angioedema,and urticaria) interstitial lung disease (ILD) - fatal outcomes have been reported. |
| Rare (>=0.01% - <0.1%) | Hepato-biliary disorders | hepatic failure 5 - fatal outcomes have been reported. |
The majority of patients receiving COSUDEX 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients.
Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.
Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
Due to the coding conventions used in the EPC studies, adverse events of 'dry skin' were coded under the COSTART term of 'rash'. No separate frequency descriptor can therefore be determined for the 150 mg COSUDEX dose however the same frequency as the 50 mg dose is assumed.
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 COSUDEX arm of the 150 mg EPC studies.
In addition, heart failure was reported in clinical trials (as a possible adverse drug reaction in the opinion of investigating clinicians, with a frequency of >1%) during treatment with COSUDEX plus an LHRH analogue. There is no evidence of a causal relationship with drug treatment.
COSUDEX 150 mg monotherapy, either as immediate or adjuvant therapy in locally advanced prostate cancer: 150 mg once a day, for at least 2 years or until disease progression.
No dosage adjustment is necessary for patients with renal impairment.
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.
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.
COSUDEX 150 mg tablets, blister pack of 28 tablets. Round, biconvex, white film-coated tablet. An arrow logo is impressed on one side and 'Casodex 150' is impressed on the other side.
Store below 30degC.
Prescription only medicine (Schedule 4)
AstraZeneca Pty Ltd ABN 54 009 682 311 Alma Road NORTH RYDE NSW 2113
Date of approval: 01 July 2009 Date of most recent amendment: 19 February 2010
COSUDEX is a trademark of the AstraZeneca group of companies.
(c) AstraZeneca 2010