Anagrelide

Special Alerts

Anagrelide - Contraindications and Warnings Regarding Hepatic Impairment

A "Dear Healthcare Professional" letter has been distributed by Shire US Inc, the distributor of Agrylin® (anagrelide). In conjunction with the Food and Drug Administration (FDA), the prescribing information has been updated to acknowledge significant pharmacokinetic alterations observed in patients with hepatic impairment. Severe hepatic impairment is now labeled as a contraindication for use. In addition, the warnings section notes the need for dosage reduction (coupled with close monitoring for cardiovascular events) in patients with moderate hepatic impairment.

Additional information is available at http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Agrylin, last accessed February 14, 2005.

Pronunciation

(an AG gre lide)

U.S. Brand Names

Agrylin®

Synonyms

1370-999-397; Anagrelide Hydrochloride; BL4162A; 6,7-Dichloro-1,5-Dihydroimidazo [2,1b] quinazolin-2(3H)-one Monohydrochloride

Generic Available

Canadian Brand Names

Agrylin®

Use

Treatment of essential thrombocythemia (ET) and thrombocythemia associated with chronic myelogenous leukemia (CML), polycythemia vera, and other myeloproliferative disorders

Pregnancy Risk Factor

Pregnancy Implications

Teratogenic effects were not observed in animal studies; however, decreased pup survival was noted. Use of anagrelide during pregnancy is limited. The manufacturer recommends effective contraception in women of childbearing potential. Use during pregnancy only if potential benefit to mother outweighs possible risk to the fetus.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to anagrelide or any component of the formulation; severe hepatic impairment

Warnings/Precautions

Use caution in patients with known or suspected heart disease; palpitations, orthostatic hypotension, and congestive heart failure have been reported. Thrombocytopenia appears to be the main dose-limiting side effect. Use caution in patients with renal dysfunction (serum creatinine

2 mg/dL) or hepatic dysfunction (measures of liver function >1.5 times ULN).

Adverse Reactions

>10%:

Cardiovascular: Palpitations (27%), edema (other than peripheral: 21%),

Central nervous system: Headache (44%), dizziness (15%), pain (15%),

Gastrointestinal: Diarrhea (26%), nausea (17%), abdominal pain (16%)

Neuromuscular & skeletal: Weakness (23%)

Respiratory: Dyspnea (12%)

1% to 10%:

Cardiovascular: Angina, arrhythmias, cardiovascular disease, chest pain (8%), CHF, hypertension, orthostatic hypotension, peripheral edema (9%), syncope, tachycardia (7%), thrombosis, vasodilatation

Central nervous system: Amnesia, chills, confusion, depression, fever (9%), insomnia, malaise (6%), migraine, nervousness, somnolence

Dermatologic: Alopecia, photosensitivity, pruritus (6%), rash (8%), urticaria

Endocrine & skeletal: Dehydration

Gastrointestinal: Anorexia (8%), aphthous stomatitis, constipation, dyspepsia (5%), eructation, flatulence (10%), gastritis, GI distress, GI hemorrhage, melena, vomiting (10%)

Hematologic: Anemia, ecchymosis, hemorrhage, lymphadenoma, thrombocytopenia

Hepatic: Liver enzymes increased

Neuromuscular & skeletal: Arthralgia, back pain (6%), leg cramps, myalgia, paresthesia (6%)

Ocular: Amblyopia, diplopia , tinnitus, visual field abnormality

Renal: Dysuria, hematuria, renal failure

Respiratory: Asthma, bronchitis, cough (6%), epistaxis, pharyngitis (7%), pneumonia, rhinitis, sinusitis

Miscellaneous: Flu-like syndrome

Frequency not defined: Atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete heart block, gastric/duodenal ulceration, leukocyte count increased, MI, pancreatitis, pericarditis, pericardial effusion, pleural effusion, pulmonary fibrosis, pulmonary infiltrates, pulmonary hypertension, seizure

Overdosage/Toxicology

Single oral doses of anagrelide at 2500, 1500, and 200 mg/kg in mice, rats, and monkeys, respectively, were not lethal. Symptoms of acute toxicity include decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys. There are no reports of human overdosage with anagrelide. Platelet reduction from anagrelide therapy is dose-related; therefore, thrombocytopenia, which can potentially cause bleeding, is expected from overdosage.

Should overdosage occur, cardiac and central nervous system toxicity can also be expected. In the case of overdosage, close clinical supervision of the patient is required; this especially includes monitoring of the platelet count for thrombocytopenia. Dosage should be decreased or stopped, as appropriate, until the platelet count returns to within the normal range.

Drug Interactions

Substrate of CYP1A2 (minor)

Drotrecogin alfa: Antiplatelet agents may enhance the adverse/toxic effects of drotrecogin alfa.

NSAIDs: Concurrent use may enhance the adverse/toxic effects of antiplatelet agents.

Salicylates: Concurrent use may enhance the adverse/toxic effects of antiplatelet agents.

Treprostinil: Concurrent use may enhance the adverse/toxic effects of antiplatelet agents.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS adverse effects).

Food: No clinically significant effect on absorption.

Mechanism of Action

Anagrelide appears to inhibit cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. It also causes a dose-related reduction in platelet production, which results from decreased megakaryocyte hypermaturation. The drug disrupts the postmitotic phase of maturation.

Pharmacodynamics/Kinetics

Duration: 6-24 hours

Metabolism: Hepatic

Half-life elimination, plasma: 1.3 hours

Time to peak, serum: 1 hour

Excretion: Urine (<1% as unchanged drug)

Dosage

Note: Maintain for

1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/

L ideally to the normal range; the dose must not be increased by >0.5 mg/day in any 1 week; maximum dose: 10 mg/day or 2.5 mg/dose

Oral:

Children: Initial: 0.5 mg/day (range: 0.5 mg 1-4 times/day)

Adults: 0.5 mg 4 times/day or 1 mg twice daily

Elderly: There are no special requirements for dosing in the elderly

Dosage adjustment in hepatic impairment:

Moderate impairment: Initial: 0.5 mg once daily; maintain for 1 week with careful monitoring of cardiovascular status

Severe impairment: Contraindicated

Monitoring Parameters

Anagrelide therapy requires close supervision of the patient. Because of the positive inotropic effects and side effects of anagrelide, a pretreatment cardiovascular examination is recommended along with careful monitoring during treatment; while the platelet count is being lowered (usually during the first 2 weeks of treatment), blood counts (hemoglobin, white blood cells), liver function test (AST, ALT) and renal function (serum creatinine, BUN) should be monitored. Platelet counts should be performed every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached.

Reference Range

Thrombocythemia: 60-300 ng/mL

Patient Education

Before using this drug, tell your physician your entire medical history, including any allergies (especially drug allergies), heart, kidney, or liver disease. Limit alcohol intake, as it may aggravate side effects. To avoid dizziness and lightheadedness when rising from a seated or lying position, get up slowly. This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your physician. It is not known whether this drug is excreted into breast milk. It is recommended to discontinue the drug or not to breast-feed, taking into account the risk to the infant. Tell your physician and pharmacist of all nonprescription and prescription medications you may use, especially sucralfate. Do not share this medication with others. Laboratory tests will be done to monitor the effectiveness and possible side effects of this drug.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May impair ability to concentrate and produce bad dreams

Mental Health: Effects on Psychiatric Treatment

May cause hypotension which may be exacerbated by psychotropics; may cause heart block; use caution with TCAs

Oncology: Emetic Potential

Low (10% to 30%)

Dosage Forms

Capsule: 0.5 mg, 1 mg

References

Anagrelide Study Group, "Anagrelide, a Therapy for Thrombocythemic States: Experience in 577 Patients," Am J Med , 1992, 92:69-76.

Brooks WG, Stanley DD, and Goode JV, "Role of Anagrelide in the Treatment of Thrombocytosis," Ann Pharmacother , 1999, 33(10):1116-8, 1121.

Doubek M, Brychtova Y, Doubek R, et al, "Anagrelide Therapy in Pregnancy: Report of a Case of Essential Thrombocythemia," Ann Hematol , 2004, 83(11):726-7.

Pescatore SL and Lindley C, "Anagrelide: A Novel Agent for the Treatment of Myeloproliferative Disorders," Expert Opin Pharmacothet , 2000, 1(3):537-46.

Petitt RM, Silverstein MN, and Petrone ME, "Anagrelide for Control of Thrombocythemia in Polycythemia and Other Myeloproliferative Disorders," Semin Hematol , 1997, 34(1):51-4.

Spencer CM and Brogden RN, "Anagrelide. A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in the Treatment of Thrombocythaemia," Drugs , 1994, 47(5):809-22.

International Brand Names

Agrylin® (AU, CA, IL, ZA); Thromboreductin® (AT); Xagrid® (CH)

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