nificantly reduced and plasma half-life prolonged compared tohealthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted [see Use inSpecific Populations (8.7)]. No pharmacokinetic data are available for patients with severe hepaticimpairment (Child-Pugh C).
Drug Interactions
Pharmacokinetic studies eva luating changes in systemic levels of colchicine when co-administered withCYP3A4 and P-gp inhibitors in healthy subjects have been conducted with GOLPERBA. Carvedilol20 to 40 mg QD (considered a P-gp inhibitor), amlodipine 5 to 10 mg QD (considered a weak inhibitor ofCYP3A4) and ciprofloxacin 500 mg BID (considered a moderate CYP3A4 inhibitor) did not cause anysignificant changes in colchicine systemic levels. Co-administration with posaconazole 300 mg QD
(considered a strong CYP3A4 inhibitor) increased AUC by approximately 3-fold.
These results should not be extrapolated to other inhibitors as colchicine is known to be a substrate forCYP3A4 and P-gp, and case reports of colchicine toxicity associated with the co-administration of CYP3A4and P-gp inhibitors (i.e., clarithromycin) have been published.
Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a dualinhibitor of CYP3A4 and P-gp. Toxicities have also been reported when colchicine is administered withinhibitors of CYP3A4 that may not be potent inhibitors of P-gp (e.g., grapefruit juice), or inhibitors of P-gpthat may not be potent inhibitors of CYP3A4 (e.g., cyclosporine). If treatment with a P-gp and CYP3A4inhibitor is required in patients with normal renal and hepatic function, the patients’ dose of colchicine mayneed to be reduced or interrupted.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine toproduce aneuploid cells (cells with an unequal number of chromosomes), colchicine presents a theoreticalincreased risk of malignancy.
Mutagenesis
Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomalaberration assay in cultured human white blood cells, colchicine treatment resulted in the formation ofmicronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process ofmitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, althoughmicronuclei are formed.
Impairment of Fertility
There were no studies conducted of the effects of GLOPERBA on fertility. Published nonclinical studieshave demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis.
Published colchicine reproductive studies have reported abnormal sperm morphology and reduced spermcounts in males and interference with sperm penetration, second meiotic division and normal cleavage infemales.
14 CLINICAL STUDIES
The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature.
Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis ofgout flares in patients with gout initiating treatment with urate-lowering therapy. In both trials, treatment withcolchicine decreased the frequency of gout flares.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
GLOPERBA (colchi |
