Anagrelide (Monograph)

Brand name: Agrylin
Drug class: Platelet-reducing Agents
VA class: BL400
Chemical name: 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate
CAS number: 58579-51-4; 68475-42-3

Introduction

Platelet-reducing agent; imidazoquinazoline derivative.^{1 4 5 7 9 10 11 12 14 15 16 17 18 22 23 24 26 31 32}

Uses for Anagrelide

Thrombocythemia

Reduction of elevated platelet counts and associated risk of thromboembolic and hemorrhagic events in patients with thrombocythemia secondary to essential thrombocythemia (ET) and other myeloproliferative disorders.^{1 3 7 13 14 15 17 18 23} Has been designated an orphan drug by FDA for the treatment of ET.²

Management of ET generally based on a risk-stratification approach.^{3 7 11 14 16 19 20 22 25 27 31 32} Treatment with a cytoreductive agent (e.g., anagrelide, hydroxyurea) usually reserved for patients at high risk (i.e., age >60 years, previous history of thrombosis, and/or platelet count ≥1,500,000/mm³) of developing thromboembolic and/or hemorrhagic complications.^{3 7 9 11 12 13 14 16 20 25 31 32} Some clinicians also recommend cytoreductive therapy in intermediate-risk ET patients (e.g., 40–60 years of age, platelet count >1,000,000/mm³, and cardiovascular risk factor [smoking, arterial hypertension, hypercholesterolemia, or diabetes mellitus] or familial thrombophilia).^{27 31 32}

Hydroxyurea (often combined with low-dose aspirin) generally considered drug of choice in high-risk patients with ET because of proven efficacy and infrequent acute toxicity.^{3 6 7 11 14 17 20 21 22 25 27 30 32} However, because of potential leukemogenic effects with hydroxyurea when used long term or sequentially with other cytotoxic drugs,^{3 5 7} anagrelide or interferon alfa suggested as alternative therapy in high-risk patients, particularly younger patients (<40–60 years of age), and in those who do not respond to or cannot tolerate hydroxyurea.^{3 5 7 9 17 22 24 25 27 31 32} Consider cautious use of low-dose aspirin concomitantly with anagrelide based on relative risks of thrombosis and arterial hemorrhage in individual patients.^{3 5 6 11 27 31 32} (See Specific Drugs or Foods under Interactions.)

Related/similar drugs

Agrylin

Anagrelide Dosage and Administration

General

• Initiate therapy under close supervision of a clinician.¹

• Monitor platelet counts every 2 days for 1 week following initiation of therapy, then at least weekly thereafter until maintenance dosage established.^{1 23}

Administration

Oral Administration

Administer orally without regard to meals.¹

Dosage

Available as anagrelide hydrochloride; dosage expressed in terms of anagrelide.¹

Pediatric Patients

Thrombocythemia

Oral

Children and adolescents 7–14 years of age: Initially, 0.5 mg daily.¹ Initial dosages up to 0.5 mg 4 times daily have been used.¹

Maintain initial dosage for ≥1 week, then adjust to lowest effective dosage that will maintain platelet counts <600,000/mm³ or ideally within normal range.^{1 17} Usual maintenance dosage is 1.5–3 mg daily.^{1 17 18}

Increase dosage by ≤0.5 mg daily in any 1-week period.^{1 17}

Continue therapy indefinitely if adequate response achieved.^{17 23}

Adults

Thrombocythemia

Oral

Initially, 0.5 mg 4 times daily or 1 mg twice daily recommended by manufacturer.¹ Lower dosages (e.g., 0.5 mg twice daily) have been used and may improve tolerability.⁵

Maintain initial dosage for ≥1 week, then adjust to lowest effective dosage that will maintain platelet counts <600,000/mm³ or ideally within normal range (e.g., 150,000–400,000/mm³).^{1 17} Usual maintenance dosage is 1.5–3 mg daily.^{1 13 17 22}

Increase dosage by ≤0.5 mg daily in any 1-week period.^{1 17 22}

Continue therapy indefinitely if adequate response achieved.^{17 23}

Prescribing Limits

Pediatric Patients

Thrombocythemia

Oral

Children and adolescents 7–14 years of age: Maximum 10 mg daily or 2.5 mg as a single dose.¹

Adults

Thrombocythemia

Oral

Maximum 10 mg daily or 2.5 mg as a single dose.¹

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment, reduce initial dosage to 0.5 mg daily and maintain for ≥1 week.¹ Increase dosage by ≤0.5 mg daily in any 1-week period.¹ (See Hepatic Impairment under Cautions.)

Contraindicated in severe hepatic impairment.¹

Renal Impairment

Dosage adjustment not required in patients with renal impairment.¹

Cautions for Anagrelide

Contraindications

Severe hepatic impairment.¹

Warnings/Precautions

Warnings

Cardiovascular Effects

Adverse cardiovascular effects (e.g., vasodilation, tachycardia, palpitations, edema, CHF) reported with usual dosages of anagrelide, including rare cases of sudden death.^{1 5 16 17 18 26} Assess risk versus benefits of therapy.^{1 16 17} Use with caution, if at all, in patients with known or suspected cardiovascular disease.^{1 5 13 15 16 17 18 22 23 24} Evaluate cardiac status prior to and during therapy.^{1 5 13 16 17} Consider reduced dosages.⁵ Some clinicians recommend immediate discontinuance of therapy if any evidence of cardiac dysfunction occurs.^{5 26}

Temporary decreases in BP reported, usually during treatment initiation; BP appears to normalize during maintenance therapy.^{5 9 17 23 24}

General Precautions

Laboratory Monitoring

Monitor CBCs, liver function tests, and renal function tests while platelet counts are being decreased, usually during first 2 weeks of therapy.¹

To assess response to therapy and prevent thrombocytopenia, monitor platelet counts every 2 days for first week of therapy, then at least weekly thereafter until maintenance dosage achieved.^{1 23}

Rebound Thrombocythemia

A rapid (e.g., within 4 days) increase in platelet count generally is observed when anagrelide is discontinued or interrupted.^{1 5 16 17 18 23} Continue treatment indefinitely (if adequate response achieved) to prevent rebound thrombocythemia.^{17 23}

Anemia

Decreases in hemoglobin and hematocrit (anemia) reported, usually with long-term use.^{1 5 9 10 12 13 16 17 18 24 27}

Bleeding Tendency

Concomitant use with aspirin may increase bleeding tendency.^{3 5 6 9} (See Specific Drugs and Foods under Interactions.) Use caution with such combined therapy.^{3 5 6} Some clinicians suggest that aspirin not be used concomitantly with anagrelide in patients with history of bleeding.³

Renal Effects

Renal impairment reported in a few patients following treatment with anagrelide; most patients had preexisting renal impairment.^{1 17 23} Monitor renal function while platelet counts are being decreased.¹

Fetal/Neonatal Morbidity

Safety of use during pregnancy not established; embryotoxicity and fetotoxicity demonstrated in animals.¹ Generally not recommended in pregnant women unless potential benefits outweigh possible risks to fetus.^{1 5 11 16 22} Women of childbearing potential should avoid pregnancy and use contraception during therapy.^{1 5}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether anagrelide is distributed into human milk.¹ Discontinue nursing or drug because of potential risk in nursing infants.^{1 5}

Pediatric Use

Evaluated in a limited number of children and adolescents 7–14 years of age with thrombocythemia secondary to myeloproliferative disorders;^{1 28 29} preliminary data suggest no overall differences in dosage or adverse effects relative to adults.¹

Geriatric Use

Response in patients ≥65 years of age does not appear to differ from that in younger adults.¹ Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function.^{1 5 16 22}

Hepatic Impairment

Extensively metabolized in liver; possible increased systemic exposure to anagrelide in patients with hepatic impairment.^{1 9} (See Elimination: Special Populations, under Pharmacokinetics.)

Weigh risks of therapy against potential benefits in patients with mild to moderate hepatic impairment.¹ Reduce dosage and carefully monitor for adverse cardiovascular effects or other manifestations of toxicity.^{1 17 22 23} (See Hepatic Impairment under Dosage and Administration and see Cardiovascular Effects under Cautions.)

Contraindicated in patients with severe hepatic impairment.¹

Renal Impairment

Closely monitor patients with known or suspected renal impairment for cardiovascular effects or other manifestations of toxicity.^{1 17 23}

Common Adverse Effects

Headache,^{1 3 5 7 9 10 16 17 18 23 24} palpitations,^{1 3 5 7 9 10 16 17 18 23 24} diarrhea,^{1 3 5 7 9 10 17 18 23 24} asthenia,^{1 9 23} edema,^{1 5 9 10 16 17 18 23 24} nausea,^{1 7 9 18 23 24} abdominal pain,^{1 9 17 18 23 24} dizziness,^{1 9 16 18 23 24} pain,^{1 9} dyspnea,^{1 9} flatulence,^{1 9 18} vomiting,^{1 9 23} fever,^{1 9} peripheral edema,^{1 9} rash,^{1 9} chest pain,^{1 23} anorexia,^{1 9} tachycardia,^{1 7 9 16 18 23 24} pharyngitis,^{1 9} malaise,^{1 9 23} cough,^{1 9} paresthesia,^{1 9} back pain,¹ pruritus,^{1 9} dyspepsia.^{1 9}

Drug Interactions

Metabolized partially by CYP1A2; inhibits CYP1A2 to a limited extent.¹

Inhibits phosphodiesterase (PDE) type 3.^{1 4 5 9 10 11 16 18 22 23}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: Potential pharmacokinetic interaction (decreased clearance of anagrelide).^{1 9 22}

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 substrates: Potential pharmacokinetic interaction (decreased clearance of substrate).^{1 22}

Specific Drugs or Foods

Anagrelide Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration. ⁹

Following oral administration, peak plasma concentrations attained within 1–2 hours.^{5 9 22 23 24}

No evidence of drug accumulation following multiple dosing.^{1 9 29}

Onset

Platelet counts usually begin to decrease within 7–14 days.^{1 5 9 10 17 22} Complete response (e.g., platelet count ≤600,000/mm³) generally achieved within 4–12 weeks.¹

Food

Food decreases peak plasma concentrations by 14% and increases AUC by 20%; not clinically important.^{1 5 9}

Special Populations

In children and adolescents 7–14 years of age, AUC and peak plasma anagrelide concentrations lower than those in adults 16–86 years of age.¹

Distribution

Extent

Distributes extensively into large peripheral compartment.²⁴

Crosses placenta.⁵

Elimination

Metabolism

Extensively metabolized in liver to at least 4 metabolites, including an active hydroxylated derivative (3-hydroxyanagrelide).^{1 4 5 9 16 17 22 23 24}

Undergoes first-pass metabolism by CYP1A2 to 3-hydroxyanagrelide.⁹

Elimination Route

Excreted principally in urine as metabolites (>70%) and unchanged drug (<1%).^{5 9 16 17 22 23 24} Approximately 10% excreted in feces through bile.^{5 24}

Half-life

Anagrelide: Approximately 1.3 hours after a single 0.5-mg dose under fasting conditions.^{1 17 29}

3-Hydroxyanagrelide: Approximately 3 hours.²⁹

Special Populations

Systemic exposure increased eightfold in patients with moderate hepatic impairment compared with that in healthy individuals.^{1 9}

Severe renal impairment (Cl_cr <30 mL/minute) does not appear to affect pharmacokinetics of anagrelide.^{1 9}

Possible decreased clearance and prolonged half-life in geriatric patients.⁵

Stability

Storage

Oral

Tablets

25°C in light-resistant container; may be exposed to 15–30°C.¹

Actions

• Exact mechanism of action not fully elucidated;^{1 4 9 12 17 22 23} thought to reduce platelet counts in a dose-related manner by selectively inhibiting megakaryocyte maturation during postmitotic stage of development.^{1 4 6 9 10 12 13 14 15 16 17 18 19 22 23 23 24} Reduces size and ploidy of megakaryocytes, but does not appear to affect platelet function or bleeding time.^{1 5 9 15 16 17 19 22 24 23}

• Acts selectively on megakaryocytes with minimal or no effect on other blood-cell precursors.^{3 4 5 11 13 14 17 18 23 24} Current data suggest no long-term leukemogenicity.^{3 5 17 23}

• Inhibits phospholipase A₂ and phosphodiesterase (PDE) type 3 activity in platelets; results in increased concentrations of cyclic adenosine monophosphate (cAMP).^{1 4 5 9 10 11 16 18 22 23 24 29} Such increases in cAMP may produce an anti-aggregating effect on platelets at dosages substantially higher than those required to cause thrombocytopenia.^{1 3 4 5 6 8 9 11 15 16 17 18 23 24}

• Exerts positive inotropic and vasodilatory effects through inhibition of cAMP PDE type 3 in myocardium;^{5 9 11 16 17 18 22 23 24 26} such actions may result in adverse cardiovascular effects.^{9 10 16 17 23 26}

Advice to Patients

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. ¹ Advise women of childbearing potential to avoid pregnancy and use effective contraception while taking anagrelide.¹ If pregnancy occurs, apprise patient of potential risk to fetus.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., liver disease).¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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