Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Bicalutamide is a nonsteroidal antiandrogen devoid of other endocrine activity which competes with androgen for the binding of androgen receptors.1 It does not suppress androgen production and may increase serum androgen concentrations.2 Bicalutamide is a racemate with the R-isomer primarily responsible for the antiandrogenic activity. Prostate cancer is mostly androgen-dependent and can be treated with surgical or chemical castration. To date, antiandrogen monotherapy has not consistently been shown to be equivalent to castration,3-5 although it may be considered for patients who want to maintain sexual potency.2,6 Antiandrogens are often used in combination with luteinizing hormone releasing hormone agonists (LHRHa), either for 2-4 weeks at the initiation of LHRHa to prevent or minimize temporary worsening of symptoms ("flare" reaction),1or sometimes to inhibit the effects of testicular and adrenal androgens (maximum androgen blockade).3 Antiandrogen withdrawal may lead to a paradoxical decrease in serum prostate-specific antigen level in some patients.7 In animal studies, bicalutamide has a fourfold greater affinity for the prostate androgen receptor than 2-hydroxyflutamide, the active metabolite of flutamide.8 Bicalutamide and flutamide are not completely cross-resistant.6

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindicated 10

Bicalutamide 150 mg 14,15

should NOT be administered to patients with localized disease who would otherwise undergo watchful waiting as treatment at this dose is associated with increased mortality.

Hepatic impairment: 10

Use with caution in patients with moderate to severe hepatic impairment. Metabolism may be delayed, resulting in prolonged elimination half-life and increased risk of toxicity.

Cardiac disease: 10

Use with caution in patients with cardiac disease. Elevated plasma testosterone and estradiol levels may occur, and could cause fluid retention.

Carcinogenicity: 2,10

Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation tests, and not clastogenic in mammalian in vitro and in vivo chromosome tests.10

Fertility: 1

Pregnancy: FDA Pregnancy Category X.1 Studies in animals or human beings have shown fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Breastfeeding .

SIDE EFFECTS:

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Side effects and incidences were those of bicalutamide when used with LHRHa unless marked with asterisk ( *) when it is used as monotherapy 150 mg PO daily
blood/bone marrow febrile neutropenia	anemia (7%)			D
blood/bone marrow febrile neutropenia	neutropenia (1-5%)		E
cardiovascular (general)	hypertension (5%)			D
cardiovascular (general)	peripheral edema (8%)			D
constitutional symptoms	fatigue (15%)		E	D
	sweating (6%)		E	D
	weight gain (1-5%)			D
	weight loss (4%)			D
dermatology/skin	alopecia (1-5%)		E	D
dermatology/skin	rash (6%)		E	D
endocrine	breast tenderness (4%; 39% *) 2		E	D

ORGAN SITE	SIDE EFFECT	ONSET
Dose-limiting side effects are bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Side effects and incidences were those of bicalutamide when used with LHRHa unless marked with asterisk ( *) when it is used as monotherapy 150 mg PO daily
	gynecomastia (6%; 38% *) 2		E	D
	hot flashes (51%; 12% *) 2		E	D
gastrointestinal	emetogenic potential: nonemetogenic
	anorexia (1-5%)		E
	constipation (17%)		E
	diarrhea (10%)		E
	dry mouth (1-5%)		E
	dyspepsia (1-5%)		E
	flatulence (5%)		E
	nausea (11%)		E
	vomiting (3%)		E
hepatic	increased bilirubin levels (1-5%)		E	D
hepatic	increased transaminase levels (6%)		E	D
infection	infection (10%)		E	D
infection	urinary tract infection (6%)		E	D
metabolic/laboratory	increased BUN (1-5%)		E	D
metabolic/laboratory	hyperglycemia (5%)		E
neurology	dizziness (7%)		E
	insomnia (5%)		E
	neuropathy, sensory (6%)		E
	somnolence (1-5%)		E
pain	abdominal pain (8%)		E
	back pain (15%)		E
	bone pain (4%)		E
	chest pain (6%)		E
	headache (4%)		E
	pain (27%)		E
	pelvic pain (13%)		E
pulmonary	dyspnea (7%)		E	D
pulmonary	pulmonary infiltrates and eosinophilia (rare) 16,17			D	L
renal/genitourinary	increased creatinine (1-5%)		E	D
	hematuria (7%)		E
	nocturia (9%)		E
	urinary incontinence (2%)		E
sexual/reproductive function	impotence (5%)		E	D
	decreased libido (1-5%)		E	D
	reduced sperm count 1		E
syndromes	flu-like symptoms (4%)		E

Adapted from reference 12 unless specified otherwise.

Diarrhea 8

is less common with bicalutamide (10%) than with flutamide (24%). Withdrawal from clinical trials because of diarrhea was also less common with bicalutamide (0.5%) than with flutamide (6%).

Fatigue: 2

Bicalutamide monotherapy causes a slightly higher incidence of fatigue than surgical castration.

Gynecomastia and breast tenderness:

Gynecomastia is more common with bicalutamide 150 mg monotherapy (38%) than combination therapy with LHRHa (6%). Breast tenderness is also more common with monotherapy

(39%) than combination therapy (4%).2 Gynecomastia and breast tenderness are related to the unopposed action of circulating estrogen during monotherapy, in contrast to the reduced circulating levels of testosterone and estrogen during combination therapy.3 Hot flashes are less common with monotherapy (12%) than combination therapy with LHRHa (51%),2 probably due to the hormonal changes described above.3

Erectile function 18

is not significantly altered with bicalutamide monotherapy.

Skin changes 3

are uncommon (less than 5%) and due to reduced androgenic stimulation of sebaceous gland (eg, dry skin, pruritus and rash).

Dose-related side effects: 2,19

No dose-related increase in adverse events was reported over the range of 50 to 200 mg daily doses.

Decreased bone mineral density 20

has been seen with castration but not with bicalutamide. Thus, patients treated with bicalutamide monotherapy may be at less risk for osteoporotic fractures compared with castrated patients.

INTERACTIONS:

There is no evidence of cytochrome P450 induction in patients receiving a daily dose of 150 mg.

SUPPLY AND STORAGE:

Oral: 14,15

AstraZeneca Pharma and Novopharm Limited supply bicalutamide as 50 mg film-coated tablets. Select non- medicinal ingredients: lactose. Store at room temperature.

DOSAGE GUIDELINES:

Oral: 50 mg PO once daily.14,15 BCCA usual dose noted in bold, italics Administer with food or on an empty stomach.10

Elimination may be slower in patients with severe hepatic impairment, leading to accumulation of bicalutamide. Use with caution in patients with moderate to severe hepatic impairment.10

dialysis is not likely to remove significant quantities from the body because of

REFERENCES:

Interpatient variability	wide range of interpatient variability 9
Oral Absorption	Extensively absorbed and unaffected by food. 10 Absolute bioavailability is not known. 11
	time to peak plasma concentration	up to 48 h, 12 approaching steady state at one month 9
Distribution	no information found
	cross blood brain barrier?	no information found
	volume of distribution	no information found
	plasma protein binding	96%
Metabolism	Extensive, hepatic; R-isomer oxidized to an inactive metabolite for further glucuronidation 1
	active metabolite(s)	none
	inactive metabolite(s)	hydroxybicalutamide, glucuronide conjugate 11
Excretion	urinary and fecal excretion
	urine	36% over 9 days
	feces	43% over 9 days
	terminal half life	one week for R-isomer
	clearance	no information found
Gender	no information found
Elderly	no clinically significant difference
Children	no information found
Ethnicity	no information found

AGENT	EFFECT	MECHANISM	MANAGEMENT
warfarin 10	increased risk of bleeding	displacement of warfarin from protein binding sites	monitor INR when bicalutamide is being started or discontinued

SYNONYM(S):

COMMON TRADE NAME(S):

CLASSIFICATION: