General Articles

Anagrelide

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Anagrelide may be confused with anastrozole

U.S. BRAND NAMES — Agrylin®

PHARMACOLOGIC CATEGORY
Phospholipase A2 Inhibitor

DOSING: ADULTS — Thrombocythemia: Oral: Initial: 0.5 mg 4 times/day or 1 mg twice daily (most patients will experience adequate response at dose ranges of 1.5-3 mg/day)

Note: Maintain initial dose for ≥ 1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/µl>0.5 mg/day in any 1 week; maximum dose: 10 mg/day or 2.5 mg/dose

DOSING: PEDIATRIC — Thrombocythemia: Oral: Initial: 0.5 mg/day (range: 0.5 mg 1-4 times/day); see “Note” in adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT — No adjustment required in renal insufficiency.

DOSING: HEPATIC IMPAIRMENT
Moderate impairment: Initial: 0.5 mg once daily; maintain for at least 1 week with careful monitoring of cardiovascular status; the dose must not be increased by >0.5 mg/day in any 1 week.

Severe impairment: Contraindicated

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg

DOSAGE FORMS: CONCISE
Capsule: 0.5 mg, 1 mg
Agrylin®: 0.5 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — May be administered without regard to food.

USE — Treatment of thrombocythemia associated with myeloproliferative disorders (eg, chronic myelogenous leukemia, essential thrombocythemia, polycythemia vera, myeloid metaplasia with myelofibrosis, or other myeloproliferative disorder)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Palpitation (26%), edema (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: Peripheral edema (9%), chest pain (8%), tachycardia (8%), angina, arrhythmia, HF, hypertension, postural hypotension, syncope, thrombosis, vasodilatation
Central nervous system: Fever (9%), malaise (6%), amnesia, chills, confusion, depression, insomnia, migraine, nervousness, somnolence
Dermatologic: Rash (8%), pruritus (6%), alopecia, bruising, photosensitivity, urticaria
Endocrine & skeletal: Dehydration
Gastrointestinal: Flatulence (10%), vomiting (10%), anorexia (8%), dyspepsia (5%), aphthous stomatitis, constipation, eructation, gastritis, GI distress, GI hemorrhage, melena
Genitourinary: Dysuria
Hematologic: Thrombocytopenia (9%; grades 3/4: 5%), anemia, hemorrhage
Hepatic: Liver enzymes increased
Neuromuscular & skeletal: Back pain (6%), paresthesia (6%), arthralgia, leg cramps, myalgia
Ocular: Amblyopia, diplopia, visual field abnormality
Otic: Tinnitus
Renal: Renal abnormality (1% to <5%), renal failure (1%), hematuria
Respiratory: Pharyngitis (7%), cough (6%), asthma, bronchitis, epistaxis, pneumonia, rhinitis, sinusitis
Miscellaneous: Flu-like syndrome, lymphadenopathy

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Frequency not defined: Atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete heart block, deep vein thrombosis, gastric/duodenal ulceration; interstitial lung disease (allergic alveolitis, eosinophilic pneumonia, interstitial pneumonitis); leukocyte count increased, MI, myelofibrosis, pancreatitis, pericarditis, pericardial effusion, pleural effusion, polycythemia, pulmonary fibrosis, pulmonary hypertension, pulmonary infiltrates, seizure, stroke, transient ischemic attack

CONTRAINDICATIONS — Severe hepatic impairment

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Pulmonary disorders: Interstitial lung disease (including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis) has been associated with use. Onset is from 1 week to several years, usually presenting with progressive dyspnea with lung infiltrations; symptoms usually improve after discontinuation. Renal abnormalities: Renal abnormalities (including renal failure) have been observed with anagrelide use; may be associated with pre-existing renal impairment, although dosage adjustment due to renal insufficiency was not required. Monitor closely in patients with renal insufficiency.

Disease-related concerns: Cardiovascular disease: Use with caution in patients with known or suspected heart disease; tachycardia, orthostatic hypotension, and heart failure have been reported. Pretreatment cardiovascular evaluation and careful monitoring during treatment is recommended. Hepatic impairment: Use with caution in patients with mild-to-moderate hepatic impairment; dosage reduction and careful cardiovascular monitoring are required for moderate impairment; use is contraindicated in severe hepatic impairment.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor)

DRUG INTERACTIONS
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Antiplatelet Agents. Risk C: Monitor therapy

Drotrecogin Alfa: Antiplatelet Agents may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

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Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Antiplatelet Agents. Bleeding may occur. Risk D: Consider therapy modification

Ibritumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy

Omega-3-Acid Ethyl Esters: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Antiplatelet Agents. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy

Salicylates: Antiplatelet Agents may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: May increase CNS adverse effects.

Food: No clinically significant effect on absorption.

Herb/Nutraceutical: Avoid herbs with anticoagulant/antiplatelet properties (alfalfa, anise, bilberry, bladderwrack, bromelain, cat’s
claw, celery, chamomile, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng [American], ginseng [Panax], ginseng [Siberian], grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, SAMe [S-adenosylmethionine], sweet clover, turmeric, white willow); may enhance the adverse effect of antiplatelets agents.

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PREGNANCY RISK FACTOR — C (show table)

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

DIETARY CONSIDERATIONS — May be taken without regard to food.

PRICING — (data from drugstore.com)
Capsules (Agrylin)
0.5 mg (50): $270.99
1 mg (50): $546.00

Capsules (Anagrelide HCl)
0.5 mg (30): $79.55
1 mg (50): $100.00

MONITORING PARAMETERS — Platelet count (every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached); CBC with differential, ALT, AST, BUN, and serum creatinine (monitor closely during first weeks of treatment); blood pressure; cardiovascular exam (pretreatment; monitor during therapy). Monitor for thrombosis or bleeding.

CANADIAN BRAND NAMES — Agrylin®; Dom-Anagrelide; Mylan-Anagrelide; PHL-Anagrelide; PMS-Anagrelide; Sandoz-Anagrelide

INTERNATIONAL BRAND NAMES — Agrelid (AR); Agrylin (AU, HK, ID, IL, KP, PH, TW); Thromboreductin (HK, ID, MY); Xagrid (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PT, RU, SE, TR)

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 (disrupts the postmitotic phase of maturation).

PHARMACODYNAMICS / KINETICS
Onset of action: Initial: Within 7-14 days; complete response (platelets ≤ 600,000/mm3): 4-12 weeks

Duration: 6-24 hours; upon discontinuation, platelet count begins to rise within 4 days

Metabolism: Hepatic; to RL603 and 3-hydroxy anagrelide

Half-life elimination, plasma: 1.3 hours

Time to peak, serum: 1 hour

Excretion: Urine (<1% as unchanged drug)

August 2010
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