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

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. 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.

Gynaecomastia 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 gynaecomastia.

CASODEX is extensively metabolized in the liver. Data suggests 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 and hepatic failure have been observed rarely with CASODEX. CASODEX therapy should be discontinued if changes are severe.

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).

The safety and effectiveness of CASODEX (non-steroidal antiandrogen) in children has not been established.

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

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 estradiol levels, fluid retention could occur. Accordingly, CASODEX should be used with caution in those patients with cardiac disease.

CASODEX (bicalutamide), in general has been well tolerated with few withdrawals due to adverse events.

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 flushes
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
	Hepatobiliary Disorders	Hepatic failure

^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 flushes (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 three 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.

Table 2: CASODEX

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

^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:

heart failure.

anorexia, dry mouth, dyspepsia, constipation, flatulence.

dizziness, insomnia, somnolence, decreased libido.

dyspnoea.

impotence, nocturia.

anemia.

alopecia, rash, sweating, hirsutism.

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

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

Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, creatinine and decreased haemoglobin 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 haemoglobin were reported less frequently with CASODEX-LHRH analogue therapy. Other changes were reported with similar incidence in both treatment groups.

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

In vitro studies have shown that the R-enantiomer is an inhibitor of CYP 3A4, 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.

Interactions with food have not been established.

Interactions with herbal products have not been established.

Interactions with laboratory tests have not been established.

The recommended dose for CASODEX (bicalutamide) therapy in combination with an LHRH analogue or surgical castration is one 50 mg tablet once daily with or without food. CASODEX treatment should be started at the same time as treatment with an LHRH analogue or after surgical castration.

No dosage adjustment is necessary for patients with renal or mild hepatic impairment. Increased accumulation may occur in patients with moderate to severe hepatic impairment (see Warnings and Precautions).