11. CASODEX ® (bicalutamide) tablets contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor 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. chem

1. CASODEX 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D 2 metastatic carcinoma of the prostate. CASODEX 150 mg daily is not approved for use alone or with other treatments . • CASODEX 50 mg is an androgen receptor inhibitor indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D 2 metastatic carcinoma of the prostate. • CASODEX 150 mg daily is not approved for use alone or with other treatments.

3. CASODEX ® (bicalutamide) 50 mg tablets for oral administration. 50 mg tablets

2. The recommended dose for CASODEX therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening). 2.1. Recommended Dose and Schedule The recommended dose for CASODEX therapy in combination with an LHRH analog 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 analog. If a dose of CASODEX is missed, take the next dose at the scheduled time. Do not take the missed dose and do not double the next dose. 2.2. Dosage Adjustment in Renal Impairment No dosage adjustment is necessary for patients with renal impairment . 2.3. Dosage Adjustment in Hepatic Impairment No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary .

5. • Severe hepatic injury and fatal hepatic failure have been observed. Monitor serum transaminase levels prior to starting treatment with CASODEX, at regular intervals for the first four months of treatment and periodically thereafter, and for symptoms or signs suggestive of hepatic dysfunction. Use CASODEX with caution in patients with hepatic impairment. • Hemorrhage with Concomitant Use of Coumarin Anticoagulant. Closely monitor the Prothrombin Time (PT) and International Normalized Ratio (INR), and adjust the anticoagulant dose as needed. • Gynecomastia and breast pain have been reported during treatment with CASODEX 150 mg when used as a single agent. • CASODEX is used in combination with an LHRH agonist. LHRH agonists have been shown to cause a reduction in glucose tolerance in males. Consideration should be given to monitoring blood glucose in patients receiving CASODEX in combination with LHRH agonists. • Monitoring Prostate Specific Antigen (PSA) is recommended. Evaluate for clinical progression if PSA increases. 5.1. Hepatitis Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported postmarketing 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. 5.2. Hemorrhage with Concomitant Use of Coumarin Anticoagulant In the postmarketing setting, there have been reports of excessive prolongation of the prothrombin time (PT) and International Normalized Ratio (INR) days to weeks after the introduction of CASODEX in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Closely monitor the PT/INR, and adjust the anticoagulant dose as needed . 5.3. Gynecomastia and Breast Pain In clinical trials with CASODEX 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively. 5.4. Glucose Tolerance A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic 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. 5.5. Laboratory Tests 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 analog, may be considered.

7. Clinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (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 C max ) 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. PT/INR should be closely monitored in patients concomitantly receiving coumarin anticoagulants and CASODEX. Adjustment of the anticoagulant dose may be necessary . • R-bicalutamide is an inhibitor of CYP 3A4; therefore, caution should be used when CASODEX is co-administered with CYP 3A4 substrates. • PT/INR should be closely monitored in patients already receiving coumarin anticoagulants who are started on CASODEX.