eraction studies have not been conducted with the other common medications used concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g. theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.
There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Carcinogenesis, Mutagenesis, Impairment of Fertility: In a two year rat carcinogenicity study a higher incidence of uterine adenocarcinoma, relative to controls, was observed in females receiving 30mg/kg/day (at least 174 times human AUC exposure after a 1mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3mg/kg/day and above, and in females receiving 10mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1mg twice daily dose). Anagrelide hydrochloride was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y, TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (1,440 mg/m2 /day, 195 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male rats. However, in female rats, at oral doses of 60 mg/kg/day (360 mg/m2 /day, 49 times the recommended maximum human dose based on body surface area) or higher, it disrupted implantation when administered in early pregnancy and retarded or blocked parturition when administered in late pregnancy.
Pregnancy: Pregnancy Category C.
(i) Teratogenic Effects
Teratology studies have been performed in pregnant rats at oral doses up to 900 mg/kg/day (5,400 mg/m2 /day, 730 times the recommended maximum human dose based on body surface area) and in pregnant rabbits at oral doses up to 20 mg/kg/day (240 mg/m2 /day, 32 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to anagrelide hydrochloride.
(ii) Nonteratogenic Effects
A fertility and reproductive performance study performed in female rats revealed that anagrelide hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2 /day, 49 times the recommended maximum human dose based on body surface area) or higher disrupted implantation and exerted adverse effect on embryo/fetal survival.
A perinatal and postnatal study performed in female rats revealed that anagrelide hydrochloride at oral doses of 60 mg/kg/day (360 mg/m2 /day, 49 times the recommended maximum human dose based on body surface area) or higher produced delay or blockage of parturition, deaths of nondelivering pregnant dams a |
