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CASODEX®
(bicalutamide)
TABLETS
DESCRIPTION
CASODEX® (bicalutamide) Tablets for oral administration contain 50 mg of bicalutamide, a
non-steroidal antiandrogen with no other known endocrine activity. The chemical name is
propanamide, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-
methyl-,(+-). The structural and empirical formulas are:

Bicalutamide has a molecular weight of 430.37. The pKa' is approximately 12. Bicalutamide is
a fine white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000
mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and
soluble in acetone and tetrahydrofuran.
CASODEX is a racemate with its antiandrogenic activity being almost exclusively exhibited by
the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.
The inactive ingredients of CASODEX Tablets are lactose, magnesium stearate, hypromellose,
polyethylene glycol, polyvidone, sodium starch glycollate, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
CASODEX is a non-steroidal antiandrogen. It competitively inhibits the action of androgens by
binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be
androgen sensitive and responds to treatment that counteracts the effect of androgen and/or
removes the source of androgen.
When CASODEX is combined with luteinizing hormone-releasing hormone (LHRH) analogue
therapy, the suppression of serum testosterone induced by the LHRH analogue is not affected.
However, in clinical trials with CASODEX as a single agent for prostate cancer, rises in serum
testosterone and estradiol have been noted.
In a subset of patients who have been treated with CASODEX and an LHRH agonist, and who
discontinue CASODEX therapy due to progressive advanced prostate cancer, a reduction in
Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal
phenomenon) may be observed.
Pharmacokinetics
Absorption:
Bicalutamide is well-absorbed following oral administration, although the absolute
bioavailability is unknown. Co-administration of bicalutamide with food has no clinically
significant effect on rate or extent of absorption.
Distribution:
Bicalutamide is highly protein-bound (96%). See Drug-Drug Interactions below.
Metabolism/Elimination:
Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized
primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is
predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent
and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly
cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total
steady-state plasma levels.
Special Populations:
Geriatric:
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.
Hepatic Insufficiency:
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 Insufficiency:
Renal impairment (as measured by creatinine clearance) had no significant effect on the
elimination of total bicalutamide or the active R-enantiomer.
Women, Pediatrics
Bicalutamide has not been studied in women or pediatric subjects.
Drug-Drug Interactions:
Clinical studies have not shown any drug interactions between bicalutamide and LHRH
analogues (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic
enzymes.


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. Clinical studies have shown that with co-
administration of CASODEX, mean midazolam (a CYP 3A4 substrate) levels may be increased
1.5 fold (for Cmax) and 1.9 fold (for AUC). Hence, caution should be exercised when
CASODEX is co-administered with CYP 3A4 substrates.
In vitro protein-binding studies have shown that bicalutamide can displace coumarin
anticoagulants from binding sites. Prothrombin times should be closely monitored in patients
already receiving coumarin anticoagulants who are started on CASODEX.
Pharmacokinetics of the active enantiomer of CASODEX in normal males and patients with
prostate cancer are presented in Table 1.
Table 1
Normal Males (n=30)
Patients with Prostate Cancer (n=40)

Clinical Studies
In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated
advanced prostate cancer were randomized to receive CASODEX 50 mg once daily (404
patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH
analogues (either goserelin acetate implant or leuprolide acetate depot).
In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%)
patients treated with CASODEX-LHRH analogue therapy and 235 (57.5%) patients treated with
flutamide-LHRH analogue therapy had died. There was no significant difference in survival
between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87
(95% confidence interval 0.72 to 1.05).
Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups.
There was no significant difference in time to objective tumor progression between treatment
groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone
metastases or the worsening of any existing bone metastases on bone scan attributable to
metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal
metastases. The hazard ratio for time to progression of CASODEX plus LHRH analogue to that
of flutamide plus LHRH analogue was 0.93 (95% confidence interval, 0.79 to 1.10).
Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment
Quality of life was assessed with self-administered patient questionnaires on pain, social
functioning, emotional well-being, vitality, activity limitation, bed disability, overall health,
physical capacity, general symptoms, and treatment related symptoms. Assessment of the
Quality of Life questionnaires did not indicate consistent significant differences between the two
treatment groups.
INDICATIONS AND USAGE
CASODEX is indicated for use in combination therapy with a luteinizing hormone-releasing
hormone (LHRH) analogue for the treatment of Stage D2 metastatic carcinoma of the prostate.

CONTRAINDICATIONS
CASODEX is contraindicated in any patient who has shown a hypersensitivity reaction to the
drug or any of the tablet’s components.
CASODEX has no indication for women, and should not be used in this population, particularly
for non-serious or non-life threatening conditions. Further, CASODEX should not be used by
women who are or may become pregnant. If this drug is used during pregnancy, or if the patient
becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to
the fetus. CASODEX may cause fetal harm when administered to pregnant women. The male
offspring of rats receiving doses of 10 mg/kg/day (plasma drug concentrations in rats equal to
approximately 2/3 human therapeutic concentrations*) and above were observed to have reduced
anogenital distance and hypospadias in reproductive toxicology studies. These pharmacological
effects have been observed with other antiandrogens. No other teratogenic effects were observed
in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 human therapeutic
concentrations*) or rats receiving doses up to 250 mg/kg/day (approximately 2 times human
therapeutic concentrations*).
*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
WARNINGS
Hepatitis:
Rare cases of death or hospitalization due to severe liver injury 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 clinical trials.
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.
PRECAUTIONS
General:
1. 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). 2. In clinical trials with CASODEX as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively. 3. 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 analogue, may be considered.
Information for Patients:
Patients should be informed that therapy with CASODEX and the LHRH analogue should be
initiated concomitantly, and that they should not interrupt or stop taking these medications
without consulting their physician. Treatment with CASODEX should be started at the same
time as treatment with an LHRH analogue.
Drug Interactions:
In vitro studies have shown CASODEX can displace coumarin anticoagulants, such as warfarin,
from their protein-binding sites. It is recommended that if CASODEX is started in patients
already receiving coumarin anticoagulants, prothrombin times should be closely monitored and
adjustment of the anticoagulant dose may be necessary (see CLINICAL PHARMACOLOGY,
Drug-Drug Interactions).
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 2/3 human therapeutic
concentrations*) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1
1/2 times the human therapeutic concentrations*). 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 human therapeutic concentrations*) and an increased
incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately
2/3 human therapeutic concentrations*) 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 CASODEX does not have genotoxic activity.
Administration of CASODEX may lead to inhibition of spermatogenesis. The long-term effects
of CASODEX on male fertility have not been studied.
In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations*),
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.
No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times
human therapeutic concentrations, respectively*) or their female offspring were observed.
Administration of bicalutamide to pregnant females resulted in feminization of the male
offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.
*Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
Pregnancy:
Pregnancy Category X:
(See CONTRAINDICATIONS.)
Nursing Mothers:
CASODEX is not indicated for use in women. It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, caution should be exercised
when CASODEX is administered to a nursing woman.
Pediatric Use:
Safety and effectiveness of CASODEX in pediatric patients have not been established.
ADVERSE REACTIONS
In patients with advanced prostate cancer treated with CASODEX in combination with an LHRH
analogue, the most frequent adverse experience was hot flashes (53%).
In the multicenter, double-blind, controlled clinical trial comparing CASODEX 50 mg once daily
with flutamide 250 mg three times a day, each in combination with an LHRH analogue, the
following adverse experiences with an incidence of 5% or greater, regardless of causality, have
been reported.
Table 2 Incidence of Adverse Events (≥ 5% in Either Treatment Group) Regardless of
Causality
Body System
Body as a Whole
Cardiovscular
Digestive
Hemic and
Lymphatic
Anemia††
Metabolic and
Nutritional
Peripheral Edema
Muscoloskeletal
Nervous System
Respiratory
System
Dyspnea
Appendages
Rash
Urogenital
†Increased liver enzyme test includes increases in AST, ALT or both. ††Anemia includes anemia, hypochronic- and iron deficiency anemia.
Other adverse experiences (greater than or equal to 2%, but less than 5%) reported in the
CASODEX-LHRH analogue treatment group are listed below by body system and are in order of
decreasing frequency within each body system regardless of causality.
Body as a Whole: Neoplasm; Neck pain; Fever; Chills; Sepsis; Hernia; Cyst
Cardiovascular: Angina pectoris; Congestive heart failure; Myocardial infarct; Heart arrest;
Coronary artery disorder; Syncope
Digestive: Melena; Rectal hemorrhage; Dry mouth; Dysphagia; Gastrointestinal disorder;
Periodontal abscess; Gastrointestinal carcinoma
Metabolic and Nutritional: Edema; Bun increased; Creatinine increased; Dehydration; Gout;
Hypercholesteremia
Musculoskeletal: Myalgia; Leg cramps
Nervous: Hypertonia; Confusion; Somnolence; Libido decreased; Neuropathy; Nervousness
Respiratory: Lung disorder; Asthma; Epistaxis; Sinusitis
Skin and Appendages: Dry skin; Alopecia; Pruritus; Herpes zoster; Skin carcinoma; Skin
disorder
Special Senses: Cataract specified
Urogenital: Dysuria; Urinary urgency; Hydronephrosis; Urinary tract disorder
Abnormal Laboratory Test Values:
Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and
decreased hemoglobin and white cell count have been reported in both CASODEX-LHRH
analogue treated and flutamide-LHRH analogue treated patients.
Postmarketing Experience:
Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria, and
uncommon cases of interstitial lung disease, including interstitial pneumonitis and pulmonary
fibrosis, have been reported with CASODEX.
OVERDOSAGE
Long-term clinical trials have been conducted with dosages up to 200 mg of CASODEX daily
and these dosages have been well tolerated. A single dose of CASODEX that results in
symptoms of an overdose considered to be life-threatening has not been established.
There is no specific antidote; treatment of an overdose should be symptomatic.
In the management of an overdose with CASODEX, vomiting may be induced if the patient is
alert. It should be remembered that, in this patient population, multiple drugs may have been
taken. Dialysis is not likely to be helpful since CASODEX is highly protein bound and is
extensively metabolized. General supportive care, including frequent monitoring of vital signs
and close observation of the patient, is indicated.
DOSAGE AND ADMINISTRATION
The recommended dose for CASODEX therapy in combination with an LHRH analogue is one
50 mg tablet once daily (morning or evening), with or without food. It is recommended that
CASODEX be taken at the same time each day. Treatment with CASODEX should be started at
the same time as treatment with an LHRH analogue.
Dosage Adjustment in Renal Impairment:
No dosage adjustment is necessary for patients with renal impairment (see CLINICAL
PHARMACOLOGY, Special Populations, Renal Insufficiency).
Dosage Adjustment in Hepatic Impairment:
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment.
Although there is a 76% (5.9 and 10.4 days for normal and impaired patients, respectively)
increase in the half-life of the active enantiomer of bicalutamide in patients with severe liver
impairment (n=4), no dosage adjustment is necessary (see CLINICAL PHARMACOLOGY,
Special Populations, Hepatic Impairment, PRECAUTIONS and WARNINGS sections).
HOW SUPPLIED
50 mg Tablets:
(NDC 0310-0705) White, film-coated tablets (identified on one side with "CDX50" and on the
reverse with the "CASODEX logo") are supplied in unit dose blisters of 30 tablets per carton
(0310-0705-39), bottles of 30 tablets (0310-0705-30) and bottles of 100 tablets (0310-0705-10).
Store at controlled room temperature, 20°-25°C (68°-77°F).
AstraZeneca
Manufactured for
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: IPR Pharmaceuticals Inc.
Carolina, PR 00984
Made in USA
Rev 10-25-04

Source: http://cbrc.kaust.edu.sa/ddpc/DRUGBANK_DATA/DB01128/DB01128_2005-05-01.pdf