Bicalutamide (Page 3 of 5)

8.5 Geriatric Use

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.

8.6 Hepatic Impairment

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).

8.7 Renal Impairment

Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.

10 OVERDOSAGE

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.

11 DESCRIPTION

Bicalutamide tablets, USP 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-(trifluoromethy])phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and molecular formulas are:

Bicalutamide Tablets, USP
(click image for full-size original)

Bicalutamide, USP has a molecular weight of 430.37. The pKa’ is approximately 12. Bicalutamide is a 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.

Bicalutamide 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 bicalutamide tablets are lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, sodium starch glycolate (type A), talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 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.

12.3 Pharmacokinetics

Absorption

Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.

Distribution

Bicalutamide is highly protein-bound (96%) [see DRUG INTERACTIONS ( 7)].

Metabolism/Elimination

Bicalutamide 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.

Parameter Mean Standard Deviation
Normal Males (n=30)
Apparent Oral Clearance (L/hr) 0.320 0.103
Single Dose Peak Concentration (mcg/mL) 0.768 0.178
Single Dose Time to Peak 31.3 14.6
Concentration (hours)
Half-life (days) 5.8 2.29
Patients with Prostate Cancer (n=40)
C ss (mcg/mL) 8.939 3.504

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 0.7 times the human exposure at the recommended dose) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1.5 times the human exposure at the recommended dose). 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 the human exposure at the recommended dose) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) 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 does not have genotoxic activity.

In repeat-dose toxicology studies, atrophy of seminiferous tubules of the testes has been observed for all species examined, which is a predicted class effect with antiandrogens. In the 6-and 12-month rat study, testicular atrophy was seen at approximately 2 times the human exposure at the recommended dose. In the 12-month dog study, the incidence of testicular atrophy was seen at approximately 7 times the human exposure at the recommended dose. In male rats administered 250 mg/kg/day (approximately 2 times human exposure at the recommended dose), 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.

Female rats dosed at 1, 10 and 250 mg/kg/day (less than to 2 times the human exposure at the recommended dose) had increased estrous cycle irregularity but there was no effect on fertility.

In a peri-and post-natal development study, female offspring of rats receiving doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended clinical dose) and above had reduced pregnancy rates. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at doses of 10 mg/kg/day (approximately 0.7 times the human exposure at the recommended dose) and above. Affected male offspring were also impotent.

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