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.
4 years.
Not applicable.
Tablet Core
Lactose Monohydrate
Magnesium Stearate
Povidone
Carboxymethyl amidon sodium.
Film-coating material
Hypromellose
Macrogol 300
Titanium Dioxide
In this section, undesirable effects are defined as follows: Very common (> 1/10); common (> 1/100 to <1/10); uncommon (> 1/1,000 to ≤1/100); rare (> 1/10,000 to ≤1/1,000); very rare (≤ 1/10,000); not known (cannot be estimated from the available data).
Table 1 Frequency of Adverse Reactions
|
System Organ Class |
Frequency |
Event |
|
Blood and the lymphatic system disorders |
Common |
Anaemia |
|
Immune system disorders |
Uncommon |
Hypersensitivity, angioedema and urticaria |
|
Metabolism and nutrition disorders |
Common |
Decreased appetite |
|
Psychiatric disorders |
Common |
Decreased libido Depression |
|
Nervous system disorders |
Common |
Dizziness Somnolence |
|
Cardiac disorders |
Not known |
QT prolongation |
|
Vascular disorders |
Common |
Hot flush |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Interstitial lung diseasee (fatal outcomes have been reported). |
|
Gastrointestinal disorders |
Common |
Abdominal pain Constipation Dyspepsia Flatulence Nausea |
|
Hepato-biliary disorders |
Common |
Hepatotoxicity, jaundice, hypertransaminasaemiaa |
|
Rare |
Hepatic failured (fatal outcomes have been reported). | |
|
Skin and subcutaneous tissue disorders |
Very common |
Rash |
|
Common |
Alopecia Hirsutism/hair re-growth Dry skinc Pruritus | |
|
Rare |
Photosensitivity reaction | |
|
Renal and urinary disorders |
Common |
Haematuria |
|
Reproductive system and breast disorders |
Very common |
Gynaecomastia and breast tendernessb |
|
Common |
Erectile dysfunction | |
|
General disorders and administration site conditions |
Very common |
Asthenia |
|
Common |
Chest pain Oedema | |
|
Investigations |
Common |
Weight increased |
a. Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
b. The majority of patients receiving Casodex 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.
c. 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 Casodex dose however the same frequency as the 50 mg dose is assumed.
d. 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 Casodex arm of the 150 mg EPC studies.
e. 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.
Increased PT/INR: Accounts of coumarin anticoagulants interacting with Casodex have been reported in post-marketing surveillance.
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 website: www.mhra.gov.uk/yellowcard.
Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals. Target organ changes, including tumour induction (Leydig cells, thyroid, liver) in animals, are related to these activities. Enzyme induction has not been observed in man. Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all species examined. Reversal of testicular atrophy occurred 4 months after the completion of dosing in a 6-month rat study (at doses of approximately 0.6 times human therapeutic concentrations at the recommended dose of 150 mg). No recovery was observed at 24 weeks after the completion of dosing in a 12-month rat study (at doses of approximately 0.9 times human concentrations at the recommended human dose of 150 mg). Following 12 months of repeated dosing in dogs (at doses of approximately 3 times human therapeutic concentrations at the recommended human dose of 150 mg), the incidence of testicular atrophy was the same in dosed and control dogs after a 6-month recovery period. In a fertility study (at doses of approximately 0.6 times human therapeutic concentrations at the recommended human dose of 150 mg), male rats had an increased time to successful mating immediately after 11 weeks of dosing; reversal was observed after 7 weeks off-dose.
Pharmacotherapeutic group: Antiandrogen, ATC code L02 B B03
Mechanism of action
Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to the wild type or normal androgen receptor without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of Casodex can result in the 'antiandrogen withdrawal syndrome' in a subset of patients.
Clinical efficacy and safety
Casodex 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non-metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8113 patients, where Casodex was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 9.7 years median follow up, 36.6% and 38.17% of all Casodex and placebo-treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patient 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, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 9.7 years median follow up with 31.4% mortality (HR= 1.01; 95% CI 0.94 to 1.09). However, some trends were apparent in exploratory subgroup analyses.
Data on progression-free survival and overall survival over time based on Kaplan-Meier estimates for patients with locally advanced disease are summarised in the following tables:
Table 2 Proportion of locally advanced disease patients with disease progression over time by therapy sub-group
|
Analysis population |
Treatment Arm |
Events (%) at 3 years |
Events (%) at 5 years |
Events (%) at 7 years |
Events (%) at 10 years |
|
Watchful waiting (n=657) |
Casodex 150 mg |
19.7% |
36.3% |
52.1% |
73.2% |
|
placebo |
39.8% |
59.7% |
70.7% |
79.1% | |
|
Radiotherapy (n=305) |
Casodex 150 mg |
13.9% |
33.0% |
42.1% |
62.7% |
|
placebo |
30.7% |
49.4% |
58.6% |
72.2% | |
|
Radical prostatectomy (n=1719) |
Casodex 150 mg |
7.5% |
14.4% |
19.8% |
29.9% |
|
placebo |
11.7% |
19.4% |
23.2% |
30.9% |
Table 3 Overall survival in locally advanced disease by therapy sub-group
|
Analysis population |
Treatment Arm |
Events (%) at 3 years |
Events (%) at 5 years |
Events (%) at 7 years |
Events (%) at 10 years |
|
Watchful waiting (n=657) |
Casodex 150 mg |
14.2% |
29.4% |
42.2% |
65.0% |
|
placebo |
17.0% |
36.4% |
53.7% |
67.5% | |
|
Radiotherapy (n=305) |
Casodex 150 mg |
8.2% |
20.9% |
30.0% |
48.5% |
|
placebo |
12.6% |
23.1% |
38.1% |
53.3% | |
|
Radical prostatectomy (n=1719) |
Casodex 150 mg |
4.6% |
10.0% |
14.6% |
22.4% |
|
placebo |
4.2% |
8.7% |
12.6% |
20.2% |
For patients with localised disease receiving Casodex alone, there was no significant difference in progression free survival. There was no significant difference in overall survival in patients with localised disease who received Casodex as adjuvant therapy, following radiotherapy (HR=0.98; 95% CI 0.80 to 1.20) or radical prostatectomy (HR=1.03; 95% CI 0.85 to 1.25). In patients with localised disease, who would otherwise have been managed by watchful waiting, there was also a trend toward decreased survival compared with placebo patients (HR=1.15; 95% CI 1.00 to 1.32). In view of this, the benefit-risk profile for the use of Casodex is not considered favourable in patients with localised disease.
In a separate programme, the efficacy of Casodex 150 mg for the treatment of patients with locally advanced non-metastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of 2 studies with 480 previously untreated patients with non-metastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Casodex and castration in survival (hazard ratio = 1.05 [CI 0.81 to 1.36]); however, equivalence of the two treatments could not be concluded statistically.
In a combined analysis of 2 studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, Casodex 150 mg was demonstrated to be less effective than castration in survival time (hazard ratio = 1.30 [CI 1.04 to 1.65]), with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.
Bicalutamide is a racemate with its antiandrogen activity being almost exclusively in the R-enantiomer.
Paediatric population
No studies have been conducted in paediatric patients.
Absorption
Bicalutamide 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%) and extensively metabolised (oxidation and glucuronidation); its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
Biotransformation
The (S)-enantiomer is rapidly cleared relative to (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.
On daily administration of Casodex 150 mg, the (R)-enantiomer accumulates about 10-fold in plasma as a consequence of its long half-life.
Steady state plasma concentrations of the (R)-enantiomer, of approximately 22 microgram/ml are observed during daily administration of Casodex 150 mg. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
Elimination
In a clinical study, the mean concentration of R-bicalutamide in semen of men receiving Casodex 150 mg was 4.9 microgram/ml. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 microgram/kg. This is below that required to induce changes in offspring of laboratory animals.
Special Populations
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.
12th February 2018
AstraZeneca UK Ltd.,
600 Capability Green,
Luton, LU1 3LU, UK.
Do not store above 30°C.
PVC/Aluminium foil blister pack comprising strips of 5, 10 and 14 tablets to give pack sizes of 10, 20, 30, 40, 50, 80, 90, 100, 200 or 14, 28, 56, 84, 140 and 280 tablets.
Not all pack sizes may be marketed.
PL 17901/0006
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Date of first authorisation: 18th June 2000
Date of latest renewal: 16th June 2004
