Casodex

Overdose

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.

Shelf life

4 years.

Casodex price

Average cost of Casodex 50 mg per unit in online pharmacies is from 1.48$ to 15.32$, per pack from 58$ to 1070$.

Incompatibilities

Not applicable.

List of excipients

Tablet Core

Lactose Monohydrate

Magnesium Stearate

Povidone

Carboxymethyl amidon sodium.

Film-coating material

Hypromellose

Macrogol 300

Titanium Dioxide

Undesirable effects

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.

Preclinical safety data

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

Pharmacodynamic properties

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.

Pharmacokinetic properties

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.

Date of revision of the text

12th February 2018

Marketing authorisation holder

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

Special precautions for storage

Do not store above 30°C.

Nature and contents of container

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.

Marketing authorisation number(s)

PL 17901/0006

Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18th June 2000

Date of latest renewal: 16th June 2004