Casodex®

Bicalutamide

Nonsteroidal Antiandrogen

AstraZeneca

http://www.astrazeneca-us.com/default.asp

Casodex Monograph PDF download here.

 

CPS:PIS_m111200

Date of Preparation: February 10, 2000

Date of Revision: April 7, 2004

 

 

Pharmacology

CASODEX (bicalutamide) is a nonsteroidal antiandrogen, devoid of other endocrine activity. Bicalutamide competitively inhibits the action of androgens by binding to cytosol androgen receptors in target tissue. This inhibition results in regression of prostatic tumors. CASODEX is a racemate and the (R)-enantiomer is primarily responsible for the antiandrogenic activity of CASODEX.

 

Pharmacokinetics

The absorption, distribution, metabolism and excretion of bicalutamide has been investigated after administration of a single 50 mg oral dose to volunteers. The results indicated that the dose was extensively absorbed and was excreted almost equally in urine (36%) and feces (43%) over a 9-day collection period. There is no evidence of any clinically significant effect of food on bioavailability. Steady-state plasma concentrations of the (R)-enantiomer of approximately 9 µg/mL are observed during daily administration of 50 mg doses of CASODEX. At steady state, the active (R)-enantiomer accounts for 99% of the circulating plasma bicalutamide concentration. Bicalutamide is highly protein bound (racemate 96%, R-enantiomer 99.6%). On daily administration, the (R)-enantiomer accumulates about 10-fold in plasma, consistent with an elimination half-life of approximately 1 week. The (S)-enantiomer is very rapidly cleared relative to the (R)-enantiomer. The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. Patients with severe hepatic impairment eliminate the (R)-enantiomer from plasma more slowly. Bicalutamide is extensively metabolized via both oxidation and glucuronidation with approximately equal renal and biliary elimination of the metabolites.

Clinical Experience

In a large multicentre, 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) 3 times a day, each in combination with luteinizing hormone-releasing hormone (LHRH) analogues (either goserelin acetate implant or leuprolide acetate depot). At a median follow-up of 49 weeks, CASODEX-LHRH analogue therapy was associated with a statistically significant (p=0.005) improvement in time to treatment failure. With a longer follow-up (median 95 weeks), improvement in time to treatment failure was no longer statistically significant (p=0.10). At the same timepoint, 130 (32%) patients treated with CASODEX-LHRH analogue therapy and 145 (35%) patients treated with flutamide-LHRH analogue therapy had died. Subjective responses, (including scores for pain, analgesic use and Eastern Oncology Cooperative Group (ECOG) performance status) assessed in patients with symptoms at entry were seen in 95 (52%) patients treated with CASODEX and in 88 (54%) patients treated with flutamide, each in combination therapy with LHRH analogues. This small difference was not statistically significant between CASODEX 50 mg combination therapy and flutamide combination therapy.

    

 

Indications

CASODEX (bicalutamide) 50 mg is indicated for use in combination therapy with either an LHRH analogue or surgical castration in the treatment of metastatic (Stage D2) prostate cancer.

 

Contraindications

CASODEX (bicalutamide) is contraindicated in the following:

•  Patients with localized prostate cancer otherwise undergoing watchful waiting (see Warnings).

•  Patients with hypersensitivity to the drug or any of its components.

•  Women: The safety and effectiveness of CASODEX in women has not been studied.

•  Children: The safety and effectiveness of CASODEX in children has not been studied.

 

 

Warnings

Evidence from a large on-going clinical study demonstrates that at 5.4 year median follow-up, the use of CASODEX 150 mg as immediate therapy for the treatment of localized prostate cancer in patients otherwise undergoing watchful waiting is associated with increased mortality. In the absence of factors suggesting high risk of disease progression, it is recommended that clinicians do not administer CASODEX 150 mg in patients with localized prostate cancer. Health Canada previously assessed CASODEX 150 mg versus castration in the locally advanced patient population and found level 1 scientific evidence (one of the 2 randomized clinical trials) of increased mortality in CASODEX 150 mg treated patients.

     Patients taking CASODEX 50 mg per day for the treatment of metastatic prostate cancer are not affected by this new information.

     In some patients with metastatic prostate cancer, anti-androgens (steroidal and non-steroidal), may promote, rather than inhibit, the growth of prostate cancer. A decrease in PSA and/or clinical improvement following discontinuation of antiandrogens has been reported. It is recommended that patients prescribed an antiandrogen, who have PSA progression, should have the antiandrogen discontinued immediately and be monitored for 6 - 8 weeks for a withdrawal response prior to any decision to proceed with other prostate cancer therapy.

 

Precautions

Localized Prostate Cancer Patients

It is recommended that CASODEX 150 mg is not administered to patients with localized disease who would otherwise undergo watchful waiting.

 

Children

The safety and effectiveness of CASODEX in children has not been established.

 

Pregnancy

CASODEX is contraindicated in females. CASODEX may cause fetal harm when administered to pregnant women. The male offspring of rats (but not rabbits) receiving doses of 10 mg/kg/day 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) or rats (receiving doses up to 250 mg/kg/day).

 

Lactation

See Pregnancy.

Patients with Hepatic Impairment

CASODEX is extensively metabolized in the liver. Data suggest that CASODEX's elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of CASODEX. Therefore, CASODEX should be used with caution in patients with moderate to severe hepatic impairment.

     Severe hepatic changes have been observed rarely with CASODEX. CASODEX therapy should be discontinued if changes are severe.

Gynecomastia, Breast Pain

Gynecomastia has been reported in patients receiving CASODEX. For metastatic (M1) patients receiving CASODEX 50 mg, concomitant surgical or medical castration may reduce the effects of gynecomastia.

 

Drug Interactions

Clinical studies with CASODEX have not demonstrated any drug/drug interactions with LHRH analogues.

     In vitro studies have shown that the R-enantiomer is an inhibitor of CYP3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Although in vitro studies have suggested the potential for CASODEX to inhibit cytochrome 3A4, a number of clinical studies show the magnitude of any inhibition is unlikely to be of clinical significance for the majority of substances which are metabolised by cytochrome P450. Nevertheless, such an increase in AUC could be of clinical relevance for drugs with a narrow therapeutic index (e.g. cyclosporin).

     In vitro studies have shown that CASODEX can displace the coumarin anticoagulant, warfarin, from its protein binding sites. It is recommended that if CASODEX is started in patients who are already receiving coumarin anticoagulants prothrombin time should be closely monitored and adjustment of the anticoagulant dose may be necessary.

Laboratory Tests

Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring patients' responses.

     Since transaminase abnormalities and jaundice, rarely severe, have been reported with the use of CASODEX, periodic liver function tests should be considered. If clinically indicated, discontinuation of therapy should be considered. Abnormalities are usually reversible upon discontinuation.

     Since CASODEX may elevate plasma testosterone and oestradiol levels, fluid retention could occur. Accordingly, CASODEX should be used with caution in those patients with cardiac disease.

 

Adverse Effects

CASODEX in Metastatic Patients: CASODEX (bicalutamide), in general has been well tolerated with few withdrawals due to adverse events (see  Table 1).

CPS:Casodex_t1Click here for Table 1

Table 1: CASODEX

Frequency of Adverse Reactions

 

Frequency	System Organ Class	Event
Very Common (≥ 10%)	Reproductive system and breast disorders	Breast tendernessa
		Gynecomastiaa
	General disorders	Hot flushesa
Common (≥ 1% and <10%)	Gastrointestinal disorders	Diarrhea
		Nausea
	Hepatobiliary disorders	Hepatic changes (elevated levels of transaminases, jaundice)b
	General disorders	Asthenia
		Pruritus
Uncommon (≥ 0.1% and <1%)	Immune system disorders	Hypersensitivity reactions, including angioneurotic oedema and urticaria
	Respiratory, thoracic and mediastinal disorders	Interstitial lung disease
Rare (≥ 0.01% and <0.1%)	Gastrointestinal disorders	Vomiting
	Skin and subcutaneous tissue disorders	Dry skin

 

 ^a May be reduced by concomitant castration.

 ^b Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.

 

 

     In patients with advanced prostate cancer, treated with CASODEX 50 mg in combination with an LHRH analogue, the most frequent adverse experience was hot flashes (49%).

     Diarrhea was the adverse event most frequently leading to treatment withdrawal with 6% of patients treated with flutamide-LHRH analogue and 0.5% of patients treated with CASODEX-LHRH analogue withdrawing.

     In the multicentre, double-blind controlled clinical trial comparing CASODEX 50 mg once daily with flutamide 250 mg 3 times a day, each in combination with an LHRH analogue, the following adverse experiences with an incidence of more than 5%, regardless of causality have been reported. See  Table 2.

CPS:Casodex_t2Click here for Table 2

Table 2: CASODEX

Incidence of Adverse Events (≥ 5% in Either Treatment Group) Regardless of Causality

 

Adverse Event	Treatment Group Number of Patients (%)
	CASODEX 50 mg Plus LHRH Analogue (N=401)		Flutamide Plus LHRH Analogue (N=407)
Hot flashes	196	(49)	202	(50)
Pain (general)	109	(27)	93	(23)
Constipation	67	(17)	50	(12)
Back pain	62	(15)	68	(17)
Asthenia	60	(15)	69	(17)
Pelvic pain	52	(13)	46	(11)
Nausea	44	(11)	45	(11)
Infection	41	(10)	35	(9)
Diarrhea	40	(10)	98	(24)
Nocturia	35	(9)	43	(11)
Peripheral edema	34	(8)	28	(7)
Abdominal pain	33	(8)	31	(8)
Dizziness	30	(7)	27	(7)
Dyspnea	30	(7)	24	(6)
Hematuria	30	(7)	20	(5)
Anemiaa	29	(7)	35	(9)
Urinary tract infection	26	(6)	24	(6)
Increased liver enzyme testb	25	(6)	40	(10)
Rash	25	(6)	20	(5)
Paresthesia	24	(6)	27	(7)
Chest pain	24	(6)	20	(5)
Sweating	23	(6)	18	(4)
Flatulence	22	(5)	16	(4)
Hypertension	21	(5)	18	(4)
Impotence	20	(5)	29	(7)
Hyperglycemia	20	(5)	16	(4)
Insomnia	19	(5)	30	(7)
Gynecomastia	19	(5)	23	(6)
Bone pain	18	(4)	26	(6)
Headache	17	(4)	20	(5)
Flu syndrome	16	(4)	20	(5)
Weight loss	16	(4)	20	(5)
Vomiting	12	(3)	20	(5)
Urinary incontinence	9	(2)	20	(5)

 

 ^a Anemia includes anemia, hypochromic- and iron-deficiency anemia.

 ^b Increased liver enzyme test includes increases in ALT, AST or both.

 

 

     In addition, the following adverse experiences were reported in clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians) with a frequency of ≥ 1% during treatment with CASODEX 50 mg plus an LHRH analogue. No causal relationship of these experiences to drug treatment has been made and some of the experiences reported are those that commonly occur in elderly patients.

 

Cardiovascular

heart failure.

 

Gastrointestinal

anorexia, dry mouth, dyspepsia, constipation, flatulence.

 

Central Nervous System

dizziness, insomnia, somnolence, decreased libido.

 

Respiratory

dyspnea.

 

Urogenital

impotence, nocturia.

 

Hematological

anemia.

 

Skin and Appendages

alopecia, rash, sweating, hirsutism.

 

Metabolic and Nutritional

hyperglycemia, edema, weight gain, weight loss, diabetes mellitus.

 

Whole Body

abdominal pain, chest pain, headache, pain, pelvic pain, chills.

Abnormal Laboratory Test Values

Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, creatinine and decreased hemoglobin and white cell count have been reported in both CASODEX-LHRH analogue treated and flutamide-LHRH analogue treated patients. Increased liver enzyme tests and decreases in hemoglobin were reported less frequent