terone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
Elimination
The mean half-life of abiraterone in plasma is approximately 15 hours based on data from healthy subjects. Following oral administration of 14C-abiraterone acetate 1,000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Patients with hepatic impairment
The pharmacokinetics of abiraterone acetate was examined in subjects with pre-existing mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) and in healthy control subjects. Systemic exposure to abiraterone after a single oral 1,000 mg dose increased by approximately 11% and 260% in subjects with mild and moderate pre-existing hepatic impairment, respectively. The mean half-life of abiraterone is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. No dose adjustment is necessary for patients with pre-existing mild hepatic impairment. ZYTIGA should not be used in patients with pre-existing moderate or severe hepatic impairment (see section 4.2).
For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see sections 4.2 and 4.4).
Patients with renal impairment
The pharmacokinetics of abiraterone acetate was compared in patients with end-stage renal disease on a stable haemodialysis schedule versus matched control subjects with normal renal function. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis. Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction (see section 4.2). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.
5.3 Preclinical safety data
Developmental or reproductive toxicology studies were not conducted with abiraterone acetate; however, in all animal toxicity studies, circulating testosterone levels were significantly reduced. As a result, reduction in organ weights and morphological and/or histopathological changes in the reproductive organs, and the adrenal, pituitary and mammary glands were observed. All changes showed complete or partial reversibility. The changes in the reproductive organs and androgen-sensitive organs are consistent with the pharmacology of abiraterone. All treatment-related hormonal changes reversed or were shown to be resolving after a 4-week recovery period. ZYTIGA is contraindicated in pregnancy (see section 4.3).
Aside from reproductive organ changes seen in all animal toxicology studies, non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Carcinogenicity s
