text: Bicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n = 4).
  Long-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.There is no specific antidote; treatment of an overdose should be symptomatic.In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
  Bicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen.When bicalutamide is combined with luteinizing hormone-releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.
  AbsorptionBicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Coadministration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.DistributionBicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].Metabolism/EliminationBicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.Table 3ParameterMeanStandard DeviationNormal Males (n = 30)Apparent Oral Clearance (L/hr)0.3200.103Single Dose Peak Concentration (mcg/mL)0.7680.178Single Dose Time to Peak Concentration (hours)31.314.6Half-life (days)5.82.29Patients with Prostate Cancer (n = 40) Css (mcg/mL)8.9393.504
  Two-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic concentrations*
  ) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations*
  ). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations*