Bicalutamide (Page 3 of 4)

13. NONCLINICAL TOXICOLOGY

13.1. 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 1) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations 1). 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 1) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations 1) 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 Bicalutamide Tablets, USP does not have genotoxic activity.

Administration of Bicalutamide Tablets, USP may lead to inhibition of spermatogenesis. The long-term effects of Bicalutamide Tablets, USP on male fertility have not been studied.

In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations 1), 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 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 1) 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.


1
Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.

14. CLINICAL STUDIES

14.1. Bicalutamide Tablets, USP 50 mg Daily in Combination with an LHRH-A

In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive Bicalutamide Tablets, USP 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).

In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with Bicalutamide Tablets, USP -LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).

Figure 1 — The Kaplan-Meier probability of death for both antiandrogen treatment groups.

Figure
(click image for full-size original)

There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2).

Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of Bicalutamide Tablets, USP plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).

Figure 2 — Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.

Figure
(click image for full-size original)

Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.

14.2 Safety Data from Clinical Studies using Bicalutamide Tablets, USP 150 mg

Bicalutamide Tablets, USP 150 mg are not approved for use either alone or with other treatments.

Two identical multicenter, randomized, open-label trials comparing Bicalutamide Tablets, USP 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.

Monotherapy — M1 Group

Bicalutamide Tablets, USP 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that Bicalutamide Tablets, USP treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the Bicalutamide Tablets, USP treated group compared to that in the castrated group, respectively.

Locally Advanced (T3-4, NX, MO) Group

Bicalutamide Tablets, USP 150 mg daily are not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the Bicalutamide Tablets, USP group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the Bicalutamide Tablets, USP group.

In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for Bicalutamide Tablets, USP 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing Bicalutamide Tablets, USP 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.

Bicalutamide Tablets, USP 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the Bicalutamide Tablets, USP arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the Bicalutamide Tablets, USP treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).

16. HOW SUPPLIED/STORAGE AND HANDLING

Bicalutamide Tablets, USP, 50 mg are white, round, biconvex, film-coated tablets with “BCM 50” debossed on one side. They are supplied as follows:

NDC 67253-191-03, Bottles of 30
NDC 67253-191-10, Bottles of 100

16.1. Storage and Handling

Store at controlled room temperature, 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). See USP Controlled Room Temperature.

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