Included as part of the "PRECAUTIONS" Section
Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported
post-marketing in association with the use of CASODEX. Hepatotoxicity in these reports generally
occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes
leading to drug discontinuation occurred in approximately 1% of CASODEX patients in controlled
Serum transaminase levels should be measured prior to starting treatment with CASODEX, at regular
intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs
suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like”
symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in
particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their
ALT rises above two times the upper limit of normal, CASODEX should be immediately discontinued
with close follow-up of liver function.
Gynecomastia And Breast Pain
In clinical trials with CASODEX 150 mg as a single agent for prostate cancer, gynecomastia and breast
pain have been reported in up to 38% and 39% of patients, respectively.
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may
manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should
therefore be given to monitoring blood glucose in patients receiving CASODEX in combination with
Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient’s
response. If PSA levels rise during CASODEX therapy, the patient should be evaluated for clinical
progression. For patients who have objective progression of disease together with an elevated PSA, a
treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Dose And Schedule
Inform patients that therapy with CASODEX and the LHRH analog should be started
at the same time and that they should not interrupt or stop taking these medications without consulting
their healthcare provider [see DOSAGE AND ADMINISTRATION].
Inform patients that CASODEX can cause hepatitis, which may result in hepatic failure and
death. Advise patients that liver function tests should be monitored regularly during treatment and to
report signs and symptoms of hepatitis [see WARNINGS AND PRECAUTIONS].
Inform patients that diabetes or loss of glycemic control in patients with pre-existing
diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given
to monitoring blood glucose in patients receiving CASODEX in combination with LHRH agonists [see WARNINGS AND PRECAUTIONS].
During treatment with CASODEX, somnolence has been reported. Advise patients who
experience this symptom to observe caution when driving or operating machines [see ADVERSE REACTIONS].
Inform patients that cases of photosensitivity have been reported during treatment with
CASODEX and that they should avoid direct exposure to excessive sunlight or UV-light exposure.
Consideration should be given to the use of sunscreen [see ADVERSE REACTIONS].
Contraception And Fertility
Advise male patients with female partners of reproductive potential to use
effective contraception during treatment and for 130 days after the last dose of CASODEX therapy.
Advise male patients that CASODEX may impair fertility [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of
5, 15, or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were
attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell
tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is
approximately 0.7 times the human exposure at the recommended dose) and uterine adenocarcinoma in
female rats at 75 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose).
There is no evidence of Leydig cell hyperplasia in patients; uterine tumors 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 4 times the human exposure at the recommended dose) and an increased
incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 0.7 times
the human exposure at the recommended dose) 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. There
were no tumorigenic effects suggestive of genotoxic carcinogenesis.
A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E.
coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow
cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.
In repeat-dose toxicology studies, atrophy of seminiferous tubules of the testes has been observed for all
species examined, which is a predicted class effect with antiandrogens. In the 6- and 12-month rat study,
testicular atrophy was seen at approximately 2 times the human exposure at the recommended dose. In
the 12- month dog study, the incidence of testicular atrophy was seen at approximately 7 times the human
exposure at the recommended dose. In male rats administered 250 mg/kg/day (approximately 2 times
human exposure at the recommended dose), 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.
Female rats dosed at 1, 10 and 250 mg/kg/day (less than to 2 times the human exposure at the
recommended dose) had increased estrous cycle irregularity but there was no effect on fertility.
In a peri- and post-natal development study, female offspring of rats receiving doses of 10 mg/kg/day
(approximately 0.7 times the human exposure at the recommended clinical dose) and above had reduced
pregnancy rates. Administration of bicalutamide to pregnant females resulted in feminization of the male
offspring leading to hypospadias at doses of 10 mg/kg/day (approximately 0.7 times the human exposure
at the recommended dose) and above. Affected male offspring were also impotent.
Use In Specific Populations
CASODEX is contraindicated for use in pregnant women because it can cause fetal harm. CASODEX is
not indicated for use in females. There are no human data on the use of CASODEX in pregnant women.
In animal reproduction studies, oral administration of bicalutamide to pregnant rats during organogenesis
caused abnormal development of reproductive organs in male fetuses at exposures approximately 0.7 to 2
times the human exposure at the recommended dose (see Data).
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from
gestation days 6-15, male fetuses had reduced anogenital distance at doses of 10 mg/kg/day and above
(approximately 0.7 to 2 times the human exposure at the recommended dose).
In a pre- and post-natal development study, female rats were dosed from gestation day 7-16 and allowed
to litter and rear their offspring to weaning. Male offspring of rats
receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose)
and above, were observed to have reduced anogenital distance.
In a peri- and post-natal development study, female rats were dosed from gestation day 16 to lactation day
22 and allowed to litter and rear their offspring to weaning. Survival and weights of offspring during
lactation were reduced for litters from maternal rats receiving doses of 250 mg/kg/day (approximately 2
times the human exposure at the recommended dose). Male offspring of rats receiving doses of 10
mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above, were
observed to have reduced anogenital distance, smaller secondary sex organs, cryptorchidism and
hypospadias resulting in an inability to mate and impregnate their female partners. Female offspring of
rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended
dose) and above had reduced pregnancy rates.
CASODEX is not indicated for use in pregnant women. There is no information available on the presence
of bicalutamide in human milk, or on the effects on the breastfed infant or on milk production.
Bicalutamide has been detected in rat milk.
Females And Males Of Reproductive Potential
Antiandrogen therapy may cause morphological changes in spermatozoa [see Nonclinical Toxicology
]. Based on findings in animal reproduction studies and its mechanism of action, advise male
patients with female partners of reproductive potential to use effective contraception during treatment and
for 130 days after the final dose of CASODEX [see Pregnancy and CLINICAL PHARMACOLOGY].
Based on animal studies, CASODEX can lead to inhibition of spermatogenesis and may impair fertility in
males of reproductive potential. The long-term effects of CASODEX on male fertility have not been
studied [see Nonclinical Toxicology].
The safety and effectiveness of CASODEX in pediatric patients have not been established.
CASODEX (bicalutamide) orodispersible tablet was studied in combination with ARIMIDEX
(anastrozole) orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the
efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin independent
precocious puberty in boys with familial male-limited precocious puberty, also known as
testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥2 years and a diagnosis of
testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular
enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of
gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical
causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of
combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed,
an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and
received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months
and received treatment subsequently. Mean ± SD characteristics at baseline were as follows:
chronological age: 3.9±1.9 years; bone age 8.8±2.5; bone age/chronological age ratio: 2.06±0.51; growth
rate (cm/yr): 10.81±4.22; growth rate standard deviation score (SDS): 0.41±1.36.
The starting CASODEX dose was 12.5 mg. CASODEX was titrated in each patient until steady-state
R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5-15 mcg/mL,
which is the range of therapeutic concentrations achieved in adults with prostate cancer following the
administration of the currently approved CASODEX dose of 50 mg. The starting daily dose of
anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at
steady-state a serum estradiol concentration of <10 pmol/L (2.7 pg/mL). The following ascending doses
were used for CASODEX: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two
ascending doses: 0.5 mg and 1 mg. At the end of the titration phase, 1 patient was on 12.5 mg
CASODEX, 8 patients were on 50 mg CASODEX, and 4 patients were on 100 mg CASODEX;
10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of
patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with
once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by
The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of
treatment, relative to the growth rate during the ≥6 months prior to entering the study. Pre-study growth
rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced
during treatment. During CASODEX/ARIMIDEX treatment the mean growth rate (cm/yr) decreased by
1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (–1.2
to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for the overall population and for
subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone,
anastrozole or other aromatase inhibitors.
Table 2. Growth Rates
||Change from pre-study to 12
||% patients with
|Growth rate (cm/yr)
|Growth rate (SD
|NPT 4 (n=7)
1. Change compared to pre-study growth rate.
2. PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other
3. Median calculated as midpoint of 3rd and 4th ranked observations.
4. NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole, or other
Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from
a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification
(9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at
an estradiol concentration below the level of quantification.
There were no deaths, serious adverse events, or discontinuations due to adverse events during the study.
Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The
most frequently reported (>3 patients) adverse events were gynecomastia (7/14, 50%), central precocious
puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%), and upper
respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by
investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast
tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase
[ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain
(1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrozole by
investigators. For the patient who developed elevated ALT and AST, the elevation was <3X ULN, and
returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.
In two studies in patients given 50 or 150 mg daily, no significant relationship between age and
steady-state levels of total bicalutamide or the active R-enantiomer has been shown.
CASODEX should be used with caution in patients with moderate-to-severe hepatic impairment.
CASODEX is extensively metabolized by the liver. Limited data in subjects with severe hepatic
impairment suggest that excretion of CASODEX may be delayed and could lead to further accumulation.
Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see WARNINGS AND PRECAUTIONS].
No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was
noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the
half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and
impaired patients, respectively) in patients with severe liver disease (n=4).
Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of
total bicalutamide or the active R-enantiomer.