Brands, Medical Use, Clinical Data
- Fibrinolytic Agents
- Platelet Aggregation Inhibitors
- Capsules (0.5 mg or 1 mg)
Brands / Synonyms
Agrylin; Anagrelide HCL; Anagrelide, Hydrochloride
For the treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.
Anagrelide is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It works by inhibiting the maturation of megakaryocytes into platelets. The exact mechanism of action is unclear, although it is known to be a potent (IC50 = 36nM) inhibitor of phosphodiesterase-III.
Mechanism of Action
The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Anagrelide inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count.
There are no reports of overdosage with anagrelide, however thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Single oral doses of anagrelide at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
Biotrnasformation / Drug Metabolism
Extensive, with < 1% recovered unchanged in the urine. Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2).
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is increased
8-fold in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has
not been studied.
Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products
have been conducted. In vivo interaction studies in humans have demonstrated that digoxin and warfarin do
not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
Although additional drug interaction studies have not been conducted, the most common medications used
concomitantly with anagrelide in clinical trials were aspirin, acetaminophen, furosemide, iron, ranitidine,
hydroxyurea, and allopurinol. There is no clinical evidence to suggest that anagrelide interacts with any of these
An in vivo interaction study in humans demonstrated that a single 1mg dose of anagrelide administered
concomitantly with a single 900 mg dose of aspirin was generally well tolerated. There was no effect on bleeding
time, PT or aPTT. No clinically relevant pharmacokinetic interactions between anagrelide and acetylsalicylic acid
were observed. In that same study, aspirin alone produced a marked inhibition in platelet aggregation ex vivo.
Anagrelide alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet
aggregation by aspirin.
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 coadministered medicinal products sharing that clearance mechanism e.g.
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.