Included as part of the PRECAUTIONS section.
Rare cases of death or hospitalization due to severe liver injury have been reported post-marketing in association with the use of CASODEX (bicalutamide). 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 (bicalutamide) patients in controlled clinical trials.
Serum transaminase levels should be measured prior to starting treatment with CASODEX (bicalutamide), 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 (bicalutamide) should be immediately discontinued with close follow-up of liver function.
Gynecomastia and Breast Pain
In clinical trials with CASODEX (bicalutamide) 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.
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 (bicalutamide) in combination with LHRH agonists.
Regular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient's response. If PSA levels rise during CASODEX (bicalutamide) 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.
Patient Counseling Information
Patients should be informed that therapy with CASODEX (bicalutamide) and the LHRH analog should be started at the same time and that they should not interrupt or stop taking these medications without consulting their physician.
During treatment with CASODEX (bicalutamide), somnolence has been reported, and those patients who experience this symptom should observe caution when driving or operating machines.
Patients should be informed that diabetes, or loss of glycemic control in patients with pre-existing diabetes has been reported during treatment with LHRH agonists. Consideration should therefore be given to monitoring blood glucose in patients receiving CASODEX (bicalutamide) in combination with LHRH agonists.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.
A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E. coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that CASODEX (bicalutamide) does not have genotoxic activity.
Administration of CASODEX (bicalutamide) may lead to inhibition of spermatogenesis. The long-term effects of CASODEX (bicalutamide) on male fertility have not been studied.
In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week therapy period of dosing.
No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times human therapeutic concentrations, respectively) or their female offspring were observed. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.
Use In Specific Populations
PREGNANCY CATEGORY X [see CONTRAINDICATIONS]. Based on its mechanism of action, CASODEX (bicalutamide) may cause fetal harm when administered to a pregnant woman. CASODEX (bicalutamide) is contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
While there are no human data on the use of CASODEX (bicalutamide) in pregnancy and CASODEX (bicalutamide) is not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.
In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. 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 (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).
CASODEX (bicalutamide) is not indicated for use in women.
The safety and effectiveness of CASODEX (bicalutamide) in pediatric patients have not been established.
CASODEX (bicalutamide) orodispersible tablet was studied in combination with ARIMIDEX (anastrozole) orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥ 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean ± SD characteristics at baseline were as follows: chronological age: 3.9 ± 1.9 years; bone age 8.8 ± 2.5; bone age/chronological age ratio: 2.06 ± 0.51; growth rate (cm/yr): 10.81 ± 4.22; growth rate standard deviation score (SDS): 0.41 ± 1.36.
The starting CASODEX (bicalutamide) dose was 12.5 mg. CASODEX (bicalutamide) was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5-15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved CASODEX (bicalutamide) dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of < 10 pmol/L (2.7 pg/mL). The following ascending doses were used for CASODEX (bicalutamide) : 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase 1 patient was on 12.5 mg CASODEX (bicalutamide), 8 patients were on 50 mg CASODEX (bicalutamide), and 4 patients were on 100 mg CASODEX (bicalutamide) ; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.
The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the ≥ 6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During CASODEX (bicalutamide) /ARIMIDEX treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (–1.2 to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.
Table 2. Growth rates
2 PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors
3 NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
4 Median calculated as midpoint of 3rd and 4th ranked observations
Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.
There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported ( > 3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%) and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrazole by investigators. For the patient who developed elevated ALT and AST, the elevation was < 3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.
In two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.
CASODEX (bicalutamide) should be used with caution in patients with moderate-to-severe hepatic impairment. CASODEX (bicalutamide) is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of CASODEX (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].
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).
Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.
Bicalutamide has not been studied in women.
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