Anagrelide Hydrochloride

ANAGRELIDE HYDROCHLORIDE — anagrelide hydrochloride capsule
Physicians Total Care, Inc.


Anagrelide hydrochloride is an off white powder that is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and in dimethylformamide. Anagrelide hydrochloride is a platelet-reducing agent with a chemical name of 6,7-dichloro-1,5-dihydroimidazo[2,1-b] quinazolin-2(3H)-one monohydrochloride monohydrate, and it has the following structural formula:

Structural Formula
(click image for full-size original)

C10 H7 Cl2 N3 O·HCl·H2 O M.W. 310.55

Each anagrelide hydrochloride capsule, for oral administration, contains either 0.5 mg or 1 mg of anagrelide base (as anagrelide hydrochloride) and has the following inactive ingredients: black iron oxide, crospovidone, D&C yellow #10 aluminum lake, FD&C blue #1/brilliant blue aluminum lake, FD&C blue #2/indigo carmine aluminum lake, FD&C red #40/allura red aluminum lake, gelatin, lactose anhydrous, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, shellac glaze and titanium dioxide.


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 In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte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.

Following oral administration of 14 C-anagrelide in people, more than 70% of radioactivity was recovered in urine. Based on limited data, there appears to be a trend toward dose linearity between doses of 0.5 mg and 2 mg. At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours. The available plasma concentration time data at steady state in patients showed that anagrelide does not accumulate in plasma after repeated administration.

Two major metabolites have been identified (RL603 and 3-hydroxy anagrelide).

There were no apparent differences between patient groups (pediatric versus adult patients) for tmax and for t1/2 for anagrelide, 3-hydroxy anagrelide, or RL603.

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%.

Pharmacokinetic (PK) data from pediatric (age range 7 to 14 years) and adult (age range 16 to 86 years) patients with thrombocythemia secondary to a myeloproliferative disorder (MPD), indicate that dose- and body weight-normalized exposure, Cmax and AUCτ, of anagrelide were lower in the pediatric patients compared to the adult patients (Cmax 48%, AUCτ 55%).

Pharmacokinetic data from fasting elderly patients with ET (age range 65 to 75 years) compared to fasting adult patients (age range 22 to 50 years) indicate that the Cmax and AUC of anagrelide were 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active metabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients.

A 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 the pharmacokinetics of anagrelide.

A pharmacokinetic study at a single dose of 1 mg anagrelide in subjects with moderate hepatic impairment showed an 8 fold increase in total exposure (AUC) to anagrelide.


A total of 942 patients with myeloproliferative disorders including 551 patients with Essential Thrombocythemia (ET), 117 patients with Polycythemia Vera (PV), 178 patients with Chronic Myelogenous Leukemia (CML), and 96 patients with other myeloproliferative disorders (OMPD), were treated with anagrelide in three clinical trials. Patients with OMPD included 87 patients who had Myeloid Metaplasia with Myelofibrosis (MMM), and 9 patients who had unknown myeloproliferative disorders.

Clinical Studies

Patients with ET, PV, CML, or MMM were diagnosed based on the following criteria:


  • Platelet count ≥ 900,000/µL on two determinations
  • Profound megakaryocytic hyperplasia in bone marrow
  • Absence of Philadelphia chromosome
  • Normal red cell mass
  • Normal serum iron and ferritin and normal marrow iron stores


  • Persistent granulocyte count ≥ 50,000/µL without evidence of infection
  • Absolute basophil count ≥ 100/µL
  • Evidence for hyperplasia of the granulocytic line in the bone marrow
  • Philadelphia chromosome is present
  • Leukocyte alkaline phosphatase ≤ lower limit of the laboratory normal range


  • A1 Increased red cell mass
  • A2 Normal arterial oxygen saturation
  • A3 Splenomegaly
  • B1 Platelet count ≥ 400,000/µL, in absence of iron deficiency or bleeding
  • B2 Leukocytosis (≥ 12,000/µL, in the absence of infection)
  • B3 Elevated leukocyte alkaline phosphatase
  • B4 Elevated Serum B12

Diagnosis positive if A1, A2, and A3 present; or, if no splenomegaly, diagnosis is positive if A1 and A2 are present with any two of B1, B2, or B3.


  • Myelofibrotic (hypocellular, fibrotic) bone marrow
  • Prominent megakaryocytic metaplasia in bone marrow
  • Splenomegaly
  • Moderate to severe normo-chromic normocytic anemia
  • White cell count may be variable; (80,000 to 100,000/µL)
  • Increased platelet count
  • Variable red cell mass; teardrop poikilocytes
  • Normal to high leukocyte alkaline phosphatase
  • Absence of Philadelphia chromosome

Patients were enrolled in clinical trials if their platelet count was ≥ 900,000/µL on two occasions or ≥ 650,000/µL on two occasions with documentation of symptoms associated with thrombocythemia. The mean duration of anagrelide therapy for ET, PV, CML, and OMPD patients was 65, 67, 40, and 44 weeks, respectively; 23% of patients received treatment for 2 years. Patients were treated with anagrelide starting at doses of 0.5 to 2 mg every 6 hours. The dose was increased if the platelet count was still high, but to no more than 12 mg each day. Efficacy was defined as reduction of platelet count to or near physiologic levels (150,000 to 400,000/µL). The criteria for defining subjects as “responders” were reduction in platelets for at least 4 weeks to ≤600,000/µL, or by at least 50% from baseline value. Subjects treated for less than 4 weeks were not considered evaluable. The results are depicted graphically below:

Graph 1
(click image for full-size original)

* x103 /µL

** Nine hundred and forty-two subjects with myeloproliferative disorders were enrolled in three research studies. Of these, 923 had platelet counts over the duration of the studies.

Time on Treatment
Weeks Years
Baseline 4 12 24 48 2 3 4
Mean* 1131 683 575 526 484 460 437 457
N 923 ** 868 814 662 530 407 207 55

Anagrelide was effective in phlebotomized patients as well as in patients treated with other concomitant therapies including hydroxyurea, aspirin, interferon, radioactive phosphorus, and alkylating agents.

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