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.

>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

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.

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: Avoid ethanol (may increase CNS adverse effects).

Food: No clinically significant effect on absorption.

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)

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

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.

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