Anagrelide hydrochloride

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
Brands: Agrylin

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 hydrochloride

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.)

Anagrelide hydrochloride 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 hydrochloride

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}

Interactions for Anagrelide hydrochloride

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

Drug or Food	Interaction	Comments
Aspirin	No clinically important interaction observed in vivo;1 however, potential for increased risk of bleeding due to additive platelet inhibition3 5 9 10 11 14 22 27	Use concomitantly with caution, considering individual risks of thrombosis and bleeding; carefully monitor for bleeding3 5 11 27
Digoxin	Pharmacokinetic interaction unlikely1 9 22
Fluvoxamine	Possible decreased clearance of anagrelide1 9 22
Grapefruit juice	Possible decreased clearance of anagrelide 9 22
Omeprazole	Possible decreased clerance of anagrelide 22
PDE type 3 inhibitors (e.g., amrinone, cilostazol, milrinone)	Possible additive pharmacologic effects1 9 22	Use with caution22
Sucralfate	Possible decreased absorption of anagrelide1
Theophylline	Possible decreased clearance of theophylline 1 9 22
Warfarin	Pharmacokinetic interaction unlikely1 9 22

Anagrelide hydrochloride 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

ActionsActions

• 
  

  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.

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

Anagrelide Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	0.5 mg (of anagrelide)*	Agrylin	Shire
			Anagrelide Hydrochloride Capsules	Barr, Mylan, Sandoz, Teva
		1 mg (of anagrelide)*	Agrylin	Shire
			Anagrelide Hydrochloride Capsules	Barr, Mylan, Sandoz, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Agrylin 0.5MG Capsules (SHIRE US INC.): 50/$329.97 or 150/$970.02

Agrylin 1MG Capsules (SHIRE US INC.): 50/$545.99 or 150/$1621.95

Anagrelide HCl 0.5MG Capsules (IVAX PHARMACEUTICALS INC.): 30/$79.98 or 90/$235.97

Anagrelide HCl 1MG Capsules (IVAX PHARMACEUTICALS INC.): 50/$109.99 or 150/$310.02

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 01, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Shire. Agrylin (anagrelide hydrochloride) capsules prescribing information. Wayne, PA; 2004 Dec.

2. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site. Accessed 2007 Nov 30.

3. Steurer M, Gastl G, Jedrzejczak WW et al. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer. 2004; 101:2239-46. [PubMed 15476273]

4. Wang G, Franklin R, Hong Y et al. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol. 2005; 146:324-32. [PubMed 16041400]

5. Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opin Pharmacother. 2004; 5:1781-98. [PubMed 15264993]

6. Harrison CN, Campbell PJ, Buck G et al for the United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005; 353:33-45. [PubMed 16000354]

7. Penninga EI, Bjerrum OW. Polycythaemia vera and essential thrombocythaemia: current treatment strategies. Drugs. 2006; 66:2173-87. [PubMed 17137402]

8. Petrides PE. Anagrelide: What was new in 2004 and 2005? Semin Thromb Hemost. 2006; 32:399-408.

9. Wagstaff AJ, Keating GM. Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs. 2006; 66:111-31. [PubMed 16398570]

10. Birgegard G. Anagrelide treatment in myeloproliferative disorders. Semin Thromb Hemost. 2006; 32:260-6. [PubMed 16673280]

11. Campbell PJ, Green AR. Management of polycythemia vera and essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2005; 201-8.

12. Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood. 2001; 97:863-6. [PubMed 11159509]

13. Mazzucconi MG, Redi R, Bernasconi S et al. A long-term study of young patients with essential thrombocythemia treated with anagrelide. Haematologica. 2004; 89:1306-13. [PubMed 15531452]

14. Barbui T, Finazzi G. When and how to treat essential thrombocythemia. N Engl J Med. 2005; 353:85-6. [PubMed 16000360]

15. Laguna MS, Kornblihtt LI, Marta RF et al. Effectiveness of anagrelide in the treatment of symptomatic patients with essential thrombocythemia. Clin Appl Thromb Hemost. 2000; 6:157-61. [PubMed 10898276]

16. Brooks WG, Stanley DD, Goode JV. Role of anagrelide in the treatment of thrombocytosis. Ann Pharmacother. 1999; 33:1116-8. [PubMed 10534225]

17. Oertel MD. Anagrelide, a selective thrombocytopenic agent. Am J HealthSyst Pharm. 1998; 55:1979-86.

18. Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med. 1992; 92:69-76. [PubMed 1731512]

19. Thiele J, Kvasnicka HM, Schmitt-Graeff A. Effects of anagrelide on megakaryopoiesis and platelet production. Semin Thromb Hemost. 2006; 32:352-61. [PubMed 16810611]

20. Tefferi A. Essential thrombocythemia: scientific advances and current practice. Curr Opin Hematol. 2006; 13:93-8. [PubMed 16456375]

21. American Society of Hematology. Old treatment remains best option for patients with blood disorder [Abstract 6]. Washington, DC; 2004 Dec 5. Press release.

22. Harrison CN. Anagrelide for control of thrombocytosis due to myeloproliferative disorders. Future Oncol. 2005; 1:609-18. [PubMed 16556037]

23. Pescatore SL, Lindley C. Anagrelide: a novel agent for the treatment of myeloproliferative disorders. Expert Opin Pharmacother. 2000; 1:537-46. [PubMed 11249536]

24. Spencer CM, Brogden RN. Anagrelide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs. 1994; 47:809-22. [PubMed 7520859]

25. Finazzi G, Barbui T. Expertise-based management in essential thrombocythemia and polycythemia vera. Cancer J. 2007; 13:372-6. [PubMed 18032974]

26. Engel PJ, Johnson H, Baughman RP et al. High-output heart failure associated with anagrelide therapy for essential thrombocytosis. Ann Intern Med. 2005; 143:311-3. [PubMed 16103481]

27. Gisslinger H. Update on diagnosis and management of essential thrombocythemia. Semin Thromb Hemost. 2006; 32:430-6. [PubMed 16810619]

28. Chintagumpala MM, Kennedy LL, Steuber CP. Treatment of essential thrombocythemia with anagrelide. J Pediatr. 1995; 127:495-8. [PubMed 7658287]

29. Shire, Wayne, PA: Personal communication.

30. Barosi G, Besses C, Birgegard G et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia. 2007; 21:277-80. [PubMed 17251900]

31. Briere JB. Essential thrombocythemia. Orphanet J Rare Dis.. 2007; 2:3. Available from website. Accessed 2008 Jan 2.

32. Barbui T, Barosi G, Grossi A et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004; 89:215-32. [PubMed 15003898]

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