Anagrelide (Page 3 of 4)

8.6 Hepatic Impairment

Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8- fold in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and Administration (2.3)]. Use of anagrelide in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions (5.1)].


At higher than recommended doses, this medicine has been shown to cause hypotension. There have been postmarketing case reports of intentional overdose with anagrelide hydrochloride. Reported symptoms include sinus tachycardia and vomiting. Symptoms resolved with supportive management. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.

In case of overdosage, stop anagrelide dosing and monitor platelet countsfor thrombocytopenia and observe for possible complications such as bleeding. Consider resumption of anagrelide dosing once the platelet count returns to the normal range.


Anagrelide hydrochloride, USP is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5 dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate and it has the following structural formula:


C10 H7 Cl2 N3 O·HCl·H2 O M.W. 310.56

Anagrelide hydrochloride, USP is a white to off white powder that is practically insoluble in water and slightly soluble in dimethyl sulfoxide and very slightly soluble in dimethylformamide.

Each Anagrelide Capsule USP, for oral administration, contains either 0.5 mg or 1 mg of anagrelide as anagrelide hydrochloride, USP and has the following inactive ingredients: black iron oxide, gelatin, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, hydroxylpropyl cellulose, propylene glycol, shellac and titanium dioxide, potassium hydroxide.


12.1 Mechanism of Action

The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture studies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 required for megakaryocytopoiesis, ultimately leading to reduced platelet production.

12.2 Pharmacodynamics

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. The active metabolite, 3-hydroxy anagrelide, has similar potency and efficacy to that of anagrelide in the platelet lowering effect; however, exposure (measured by plasma AUC) to 3-hydroxy anagrelide is approximately 2-fold higher compared to anagrelide. Anagrelide and 3-hydroxy anagrelide inhibit cyclic AMP phosphodiesterase 3 (PDE3) and 3-hydroxy anagrelide is approximately forty times more potent than anagrelide (IC50S = 0.9 and 36 nM, respectively). PDE3 inhibition does not alter platelet production. PDE3 inhibitors, as a class can inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those typically required to reduce platelet count. PDE3 inhibitors have cardiovascular (CV) effects including vasodilation, positive inotropy and chronotropy.

Cardiac Electrophysiology

The effect of anagrelide dose (0.5 mg and 2.5 mg single doses) on the heart rate and QTc interval prolongation potential was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in 60 healthy adult men and women.

A dose-related increase in heart rate was observed, with the maximum increase occurring around the time of maximal drug concentration (0.5 to 4 hours). The maximum change in mean heart rate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and +29.1 bpm for 2.5 mg.

Dose-related increase in mean QTc was observed. The maximum mean (95% upper confidence bound) change in QTcI (individual subject correction) from placebo after baseline-correction was 7.0 (9.8) ms and 13.0 (15.7) ms following anagrelide doses of 0.5 mg and 2.5 mg, respectively.

12.3 Pharmacokinetics

Dose proportionality has been found in the dose range 0.5 mg to 2.5 mg.


Following oral administration of anagrelide, at least 70% is absorbed from the gastrointestinal tract. In fasted subjects, anagrelide peak plasma concentrations occur within about 1 hour after administration.

Pharmacokinetic data obtained from healthy volunteers comparing the pharmacokinetics of anagrelide in the fed and fasted states showed that administration of a 1 mg dose of anagrelide with food decreased the Cmax by 14%, but increased the AUC by 20%. Food decreased the Cmax of the active metabolite 3- hydroxy-anagrelide by 29%, although it had no effect on the AUC.


Anagrelide is primarily metabolized by CYP1A2 to the active metabolite, 3-hydroxy-anagrelide, which is subsequently metabolized by CYP1A2 to the inactive metabolite, RL603. Less than 1% of the administered dose is recovered in the urine as anagrelide, and approximately 3% and 16 to 20% of the administered dose is recovered as 3-hydroxy-anagrelide and RL603, respectively.


Anagrelide and 3-hydroxy-anagrelide are eliminated with plasma half-lives of approximately 1.5 and 2.5 hours, respectively. Anagrelide and 3-hydroxy-anagrelide do not accumulate in plasma when the clinical dose regimens are administered.

Drug Interactions

Aspirin: In two pharmacodynamic interaction studies in healthy subjects, co-administration of single-dose anagrelide 1 mg and aspirin 900 mg or repeat-dose anagrelide 1 mg once daily and aspirin 75 mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1 mg and aspirin 900 mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Digoxin or warfarin: In vivo interaction studies in humans have demonstrated that anagrelide does not affect the pharmacokinetic properties of digoxin or warfarin, nor does digoxin or warfarin affect the pharmacokinetic properties of anagrelide.

Specific Populations

Pediatric: Dose-normalized Cmax and AUC of anagrelide were higher in children and adolescents (age range 7 through 16 years) with essential thrombocythemia, by 17% and 56%, respectively, than in adult patients (19 through 57 years).

Geriatric: Cmax and AUC of anagrelide were 36% and 61% higher, respectively, in elderly patients (age range 65 through 75 years), than in younger adults (age range 22 through 50 years), but Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower, respectively, in the elderly patients.

Renal Impairment: Pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with severe renal impairment (creatinine clearance <30 mL/min) showed no significant effects on pharmacokinetics of anagrelide.

Hepatic Impairment: A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment (Child-Pugh score 7 to 9 showed a 2-fold increase in mean anagrelide Cmax and an 8-fold increase in total exposure (AUC) to anagrelide compared with healthy subjects. Additionally, subjects with moderate hepatic impairment showed 24% lower mean 3-hydroxy anagrelide Cmax and 77% higher mean 3-hydroxy anagrelide AUC compared to healthy subjects.


13.1 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 30 mg/kg/day (at least 174 times human AUC exposure after a 1 mg twice daily dose). Adrenal phaeochromocytomas were increased relative to controls in males receiving 3 mg/kg/day and above, and in females receiving 10 mg/kg/day and above (at least 10 and 18 times respectively human AUC exposure after a 1 mg twice daily dose).

Anagrelide hydrochloride was not mutagenic in the bacterial mutagenesis (Ames) assay or the mouse lymphoma cell (L5178Y, TK+/-) forward mutation assay, and was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or the in vivo mouse micronucleus test.

Anagrelide hydrochloride at oral doses up to 240 mg/kg/day (233 times the recommended human dose of 10 mg/day based on body surface area) had no effect on fertility and reproductive function of male rats. However, in fertility studies in female rats, oral doses of 30 mg/kg/day (29 times the recommended maximum human dose based on body surface area) or higher resulted in increased pre- and post-implantation loss and a decrease in the number of live embryos.

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