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CASODEX 150 MG FILM-COATED TABLETS

Active substance(s): BICALUTAMIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Casodex® 150 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 150 mg bicalutamide (INN).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
White.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Casodex 150 mg is indicated either alone or as adjuvant to radical
prostatectomy or radiotherapy in patients with locally advanced prostate
cancer at high risk for disease progression (see section 5.1).
Casodex 150 mg is also indicated for the management of patients with locally
advanced, non-metastatic prostate cancer for whom surgical castration or other
medical intervention is not considered appropriate or acceptable.

4.2

Posology and method of administration
Posology
Adult males including the elderly: The dosage is one 150 mg tablet to be taken
orally once a day.
Casodex 150 mg should be taken continuously for at least 2 years or until
disease progression.
Special populations

Renal impairment: No dosage adjustment is necessary for patients with renal
impairment.
Hepatic 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 section 4.4).
Paediatric population
Casodex is contraindicated for use in children (see section 4.3).
4.3

Contraindications
Casodex 150 mg is contraindicated in females and children (see section 4.6).
Casodex 150 mg must not be given to any patient who has shown a
hypersensitivity reaction to the active substance or to any of the excipients
listed in section 6.1.
Co-administration of terfenadine, astemizole or cisapride with Casodex is
contraindicated (see section 4.5).

4.4

Special warnings and precautions for use
Initiation of treatment should be under the direct supervision of a specialist.
Bicalutamide is extensively metabolised in the liver. Data suggest that its
elimination may be slower in subjects with severe hepatic impairment and this
could lead to increased accumulation of bicalutamide. Therefore, Casodex
150 mg 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 changes are expected to occur within the first
6 months of Casodex therapy.
Severe hepatic changes and hepatic failure have been observed rarely with
Casodex 150 mg, and fatal outcomes have been reported (see section 4.8).
Casodex 150 mg therapy should be discontinued if changes are severe.
For patients who have an objective progression of disease together with
elevated PSA, cessation of Casodex therapy should be considered.
Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4), as such,
caution should be exercised when co-administered with drugs metabolised
predominantly by CYP 3A4 (see sections 4.3 and 4.5).

In rare cases, photosensitivity reactions have been reported for patients taking
Casodex 150 mg. Patients should be advised to avoid direct exposure to
excessive sunlight or UV-light while on Casodex 150 mg and the use of
sunscreens may be considered. In cases where the photosensitivity reaction is
more persistent and/or severe, an appropriate symptomatic treatment should be
initiated.
Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this
medicine.
Androgen deprivation therapy may prolong the QT interval.
In patients with a history of or risk factors for QT prolongation and in patients
receiving concomitant medicinal products that might prolong the QT interval
(see section 4.5) physicians should assess the benefit risk ratio including the
potential for Torsade de pointes prior to initiating Casodex.
4.5

Interaction with other medicinal products and other forms of interaction
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. Although
clinical studies using antipyrine as a marker of cytochrome P450 (CYP)
activity showed no evidence of a drug interaction potential with Casodex,
mean midazolam exposure (AUC) was increased by up to 80%, after
co-administration of Casodex for 28 days. For drugs with a narrow therapeutic
index such an increase could be of relevance. As such, concomitant use of
terfenadine, astemizole and cisapride is contraindicated (see section 4.3) and
caution should be exercised with the co-administration of Casodex with
compounds such as ciclosporin and calcium channel blockers. Dosage
reduction may be required for these drugs particularly if there is evidence of
enhanced or adverse drug effect. For ciclosporin, it is recommended that
plasma concentrations and clinical condition are closely monitored following
initiation or cessation of Casodex therapy.
Caution should be exercised when prescribing Casodex with other drugs which
may inhibit drug oxidation e.g. cimetidine and ketoconazole. In theory, this
could result in increased plasma concentrations of bicalutamide which
theoretically could lead to an increase in side effects.
In vitro studies have shown that bicalutamide can displace the coumarin
anticoagulant, warfarin, from its protein binding sites. It is therefore
recommended that if Casodex 150 mg is started in patients who are already
receiving coumarin anticoagulants, prothrombin time should be closely
monitored.
Since androgen deprivation treatment may prolong the QT interval, the
concomitant use of Casodex with medicinal products known to prolong the QT
interval or medicinal products able to induce Torsade de pointes such as class
IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol,

dofetilide, ibutilide) antiarrhythmic medicinal products, methadone,
moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section
4.4).
Paediatric population
Interaction studies have only been performed in adults.
4.6

Fertility, pregnancy and lactation
Pregnancy
Bicalutamide is contraindicated in females and must not be given to pregnant
women.
Breast-feeding
Bicalutamide is contraindicated during breast-feeding.
Fertility
Reversible impairment of male fertility has been observed in animal studies
(see section 5.3). A period of subfertility or infertility should be assumed in
man.

4.7.

Effects on ability to drive and use machines
Casodex is unlikely to impair the ability of patients to drive or operate
machinery. However, it should be noted that occasionally somnolence may
occur. Any affected patients should exercise caution.

4.8

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
Immune system disorders

Common

Anaemia

Uncommon
Common

Hypersensitivity,
angioedema and urticaria
Decreased appetite

Common

Decreased libido

Metabolism and nutrition
disorders
Psychiatric disorders

Depression
Nervous system disorders

Common

Dizziness
Somnolence

Cardiac disorders

Not known

QT prolongation (see
sections 4.4 and 4.5)

Vascular disorders

Common

Hot flush

Respiratory, thoracic and
mediastinal disorders

Uncommon

Gastrointestinal disorders

Common

Interstitial lung diseasee
(fatal outcomes have been
reported).
Abdominal pain
Constipation
Dyspepsia
Flatulence
Nausea

Hepato-biliary disorders

Common
Rare

Hepatotoxicity, jaundice,
hypertransaminasaemiaa
Hepatic failured (fatal
outcomes have been
reported).

Very common

Rash

Common

Alopecia
Hirsutism/hair re-growth
Dry skinc
Pruritis

Rare
Renal and urinary disorders Common

Photosensitivity reaction
Haematuria

Reproductive system and
breast disorders

Gynaecomastia and breast
tendernessb
Erectile dysfunction
Asthenia

Skin and subcutaneous
tissue disorders

General disorders and
administration site
conditions

Investigations
a.

Very common
Common
Very common

Common

Chest pain
Oedema

Common

Weight increased

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.

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.
4.9

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.

5

PHARMACOLOGICAL PROPERTIES

5.1

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 (%) Events (%)
at 5 years
at 7 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%

Events (%)
at 10 years

Table 3 Overall survival in locally advanced disease by therapy sub-group
Analysis
population

Treatment
Arm

Events (%)
at 3 years

Events (%) Events (%)
at 5 years
at 7 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

Casodex 150 mg

8.2%

20.9%

30.0%

48.5%

Events (%)
at 10 years

(n=305)

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 (see sections 4.3
and 4.6).
5.2

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.

5.3

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 and none of these findings is
considered to have relevance to the treatment of patients with prostate cancer.
Atrophy of seminiferous tubules is a predicted class effect with antiandrogens
and has been observed for all species examined. Full reversal of testicular
atrophy was 24 weeks after a 12-month repeated dose toxicity study in rats,
although functional reversal was evident in reproduction studies 7 weeks after
the end of an 11 week dosing period. A period of subfertility or infertility
should be assumed in man.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet Core

Lactose Monohydrate
Magnesium Stearate
Povidone
Carboxymethyl amidon sodium.
Film-coating material
Hypromellose
Macrogol 300
Titanium Dioxide
6.2

Incompatibilities
Not applicable.

6.3

Shelf life
4 years.

6.4

Special precautions for storage
Do not store above 30oC.

6.5

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.

6.6

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.

7.

MARKETING AUTHORISATION HOLDER
AstraZeneca UK Limited,

600 Capability Green,
Luton,
LU1 3LU, UK

8.

MARKETING AUTHORISATION NUMBER(S)
PL 17901/0006

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/08/2010

10

DATE OF REVISION OF THE TEXT
11/09/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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