Casodex 50 mg

Interactions with herbal products have not been established.

Interactions with food have not been established.

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 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).

melena, rectal hemorrhage, dry mouth, dysphagia, gastrointestinal disorder, periodontal abscess, gastrointestinal carcinoma, rectal disorder, intestinal obstruction, gastritis.

The following adverse reactions have been identified during post-approval use of CASODEX:

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.

In patients with advanced prostate cancer, treated 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 most frequent adverse experiences were hot flushes (53%), asthenia (22%), constipation (22%), nausea (14%), peripheral edema (13%), haematuria (12%), abdominal pain (11%), dizziness (10%), gynecomastia (9%), rash (9%), chest pain (8%), impotence (7%), flatulence (7%), dyspepsia (7%), anorexia (6%), breast tenderness (6%), weight gain (5%), depression (4%), dry skin (4%), alopecia (4%), pruritis (3%), somnolence (3%), decreased libido (2%), hirsuitism (2%), and hypersensitivity reactions (including angioneurotic edema and urticaria) (1%).

Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy.

Hepatic failure (see Warnings and Precautions) and interstitial lung disease have been observed in post-marketed data.

CASODEX (bicalutamide), in general has been well tolerated with few withdrawals due to adverse events. The most common adverse events leading to withdrawal of study medication were abnormal liver function tests (1.5%), hot flushes (1.0%), and nausea and vomiting (0.7%).

After a 160 week follow-up, there were 213/401 deaths in the CASODEX-LHRH arm and 235/407 deaths in the flutamide-LHRH arm of the trial. There were 30 vs. 18 deaths due to adverse events in the two arms respectively and in both arms, the most common causes of death due to adverse events were attributed to the cardiovascular system (see Cardiovascular under the Clinical Trial Adverse Drug Reactions sub-section below).

cataract, abnormal vision, conjunctivitis.

dry skin, alopecia, pruritus, herpes zoster, skin carcinoma, skin disorder, skin hypertrophy, hirsutism, skin ulcer.

interstitial lung disease.

diabetes mellitus.

leg cramps, bone disorders, myalgia.

In addition, the following adverse experiences were reported by investigators within the same clinical trials (as possible adverse drug reactions in the opinion of investigating clinicians) with a frequency of less than 5%, during treatment with CASODEX 50 mg plus an LHRH analogue. No causal relationship of these experiences to drug treatment has been made.

dysuria, urinary urgency, hydronephrosis, urinary tract disorder, bladder stenosis, kidney calculus, prostatic disorder, balanitis.

hepatic failure.

lung disorder, asthma, epistaxis, sinusitis, pleural effusion, voice alteration.

hypertonia, confusion, somnolence, decreased libido, neuropathy, nervousness.

edema, BUN increased, creatinine increased, dehydration, gout, hypercholesteremia, hypoglycemia, hypercalcemia.

hypersensitivity reactions, including angioneurotic oedema and urticaria.

ecchymosis, thrombocytopenia.

neoplasm, neck pain, fever, chills, sepsis, hernia, cyst, injection site reaction, allergic reaction, neck rigidity, face edema.

In the pivotal trial of 813 patients comparing CASODEX 50 mg once daily with Flutamide 250 mg three times a day, each in combination with an LHRH analogue, an imbalance of deaths related to cardiovascular adverse events was noted (CASODEX-LHRH therapy: 18 deaths; Flutamide-LHRH therapy: 9 deaths) however, there is difficulty in interpreting this imbalance as the exposure was longer on the CASODEX-LHRH arm by a mean of 13 weeks. Other cardiovascular-related experiences reported include angina pectoris, congestive heart failure, myocardial infarction, heart arrest, coronary artery disorder, syncope, atrial fibrillation, cerebrovascular accident, deep thrombophlebitis, arrhythmia, bradycardia, cerebral ischemia, hemorrhage.

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

CASODEX is extensively metabolized in the liver. Data suggests that the elimination of CASODEX 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 (bicalutamide) 150 mg is not to be administered.

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. 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.

During treatment with CASODEX, somnolence has been reported and those patients who experience this symptom should observe caution when driving or using machines.

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.

A reduction in glucose tolerance has been observed in males receiving CASODEX in combination with LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving CASODEX in combination with LHRH agonists.

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.

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.

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.

The pharmacokinetics of the (R)-enantiomer are unaffected by mild to moderate hepatic impairment. Patients with severe hepatic impairment eliminate the (R)-enantiomer from plasma more slowly.

The pharmacokinetics of the (R)-enantiomer are unaffected by age.

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 faeces (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 one week. The (S)-enantiomer is very rapidly cleared relative to the (R)-enantiomer. Bicalutamide is extensively metabolized via both oxidation and glucuronidation with approximately equal renal and biliary elimination of the metabolites.

CASODEX (bicalutamide) is a non-steroidal 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 tumours. CASODEX is a racemate and the (R)-enantiomer is primarily responsible for the antiandrogenic activity of CASODEX.

The pharmacokinetics of the (R)-enantiomer are unaffected by renal impairment.

The pharmacokinetics of the (R)-enantiomer are unaffected by age.