Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

ANAGRELIDE

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Anagrelide is a platelet-reducing agent.

Specific Substances

    1) BL-4162A
    2) BL-4162a
    3) BMY-26538-01
    4) 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one hydrochloride
    5) CAS 68475-42-3 (anagrelide)
    6) CAS 58579-51-4 (anagrelide hydrochloride)
    7) CAS 823178-43-4 (anagrelide hydrochloride monohydrate)
    1.2.1) MOLECULAR FORMULA
    1) ANAGRELIDE HYDROCHLORIDE: C10H7Cl2N3OHCl.H2O

Available Forms Sources

    A) FORMS
    1) Anagrelide is available in the United States as 0.5 mg and 1 mg capsules (Prod Info AGRYLIN(R) oral capsules, 2014a; Prod Info anagrelide HCl oral capsules, 2014).
    B) USES
    1) Anagrelide is used to treat patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events (Prod Info AGRYLIN(R) oral capsules, 2014a).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Anagrelide is used to treat patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.
    B) PHARMACOLOGY: The exact mechanism is unknown. It's postulated that anagrelide reduces platelet production by decreasing megakaryocyte hypermaturation (size and ploidy and disrupting or preventing full megakaryocyte maturation). Anagrelide inhibits platelet aggregation by inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity with subsequent increases in cAMP levels in the platelets.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse events following therapeutic administration, at an incidence of at least 5% during clinical trials, are headache, diarrhea, abdominal pain, nausea, vomiting, asthenia, edema, palpitations, dizziness, chest pain, dyspnea, cough, flatulence, fever, rash, anorexia, tachycardia, paresthesia, back pain, pruritus, and dyspepsia.
    2) INFREQUENT: Adverse effects that were reported less frequently include: congestive heart failure, cardiomyopathy, vasodilatation, postural hypotension, QT interval prolongation, constipation, gastrointestinal hemorrhage, gastritis, anemia, thrombocytopenia, ecchymosis, elevated liver enzymes, arthralgia, myalgia, confusion, somnolence, insomnia, epistaxis, pneumonia, alopecia, diplopia, tinnitus, hematuria, and renal failure.
    3) RARE: Torsades de pointes, ventricular tachycardia, tubulointerstitial nephritis, and interstitial lung diseases, including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis, have been rarely reported during post-marketing surveillance.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Hypotension has been reported with higher than recommended doses. Postmarketing data has reported the occurrence of sinus tachycardia and vomiting following overdose. In general, it is anticipated that overdose effects are an extension of adverse effects observed with therapeutic doses.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever was reported with anagrelide therapy.
    0.2.20) REPRODUCTIVE
    A) Anagrelide is classified as FDA Pregnancy Category C. Although there are no well-controlled studies of anagrelide use in pregnant women, animal studies have reported skeletal ossification and developmental delays, including fetal weight reduction, when pregnant rats were administered oral doses of anagrelide during organogenesis.

Laboratory Monitoring

    A) Monitor vital signs following overdose.
    B) Obtain periodic complete blood counts, including platelet counts. Monitor for clinical evidence of bleeding. In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days).
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Obtain a chest x-ray in any patient with respiratory symptoms.
    F) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine, if unresponsive to fluids. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia and/or bleeding. Therapeutic doses of anagrelide may cause prolongation of the QT interval. Concomitant use of anagrelide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and the patient is able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and the airway can be maintained.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms or severe bleeding.
    E) ANTIDOTE
    1) None.
    F) TORSADES DE POINTES
    1) Therapeutic doses of anagrelide may cause prolongation of the QT interval. Concomitant use of anagrelide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, atrial overdrive pacing may be necessary. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 g IV (mixed in 50 to 100 mL D5W) infused over 5 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILD: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Rates of 100 to 120 beats/min may terminate torsades. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    G) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) When managing a suspected anagrelide overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    J) PHARMACOKINETICS
    1) Gastrointestinal absorption is at least 70% following oral administration, with peak plasma concentrations occurring within an hour after administration in fasting subjects. Primarily metabolized via cytochrome P450 1A2 enzymes to 3-hydroxy-anagrelide (the active metabolite). Less than 1% of a dose is recovered unchanged in the urine. Plasma elimination half-lives of anagrelide and 3-hydroxy-anagrelide are approximately 1.5 and 2.5 hours, respectively.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause orthostatic hypotension (eg, guanfacine, vasodilators) or thrombocytopenia.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established. Standing blood pressure fell an average of 22/15 mmHg in 9 subjects administered one dose of anagrelide 5 mg. Dizziness usually accompanied the blood pressure drop.
    B) THERAPEUTIC DOSE: ADULT: Starting dose is 0.5 mg orally 4 times daily or 1 mg orally twice daily ; may be adjusted after one week at 0.5 mg/day in weekly increments, not to exceed 10 mg/day or 2.5 mg in a single dose. PEDIATRIC: Starting dose is 0.5 mg orally daily; may be adjusted after one week at 0.5 mg/day in weekly increments, not to exceed 10 mg/day or 2.5 mg in a single dose.

Clinical Effects

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PALPITATIONS
    1) WITH THERAPEUTIC USE
    a) Palpitations were reported with anagrelide therapy in 26% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) Congestive heart failure, palpitations, and transient ischemic attack (TIA) occurred in a 48-year-old woman with polycythemia vera treated with anagrelide (2 milligrams three times daily). As anagrelide was gradually increased to control thrombocytosis, the patient reported increasing fatigue, dyspnea on exertion, and palpitations. She was hospitalized with headache and unilateral weakness in the left extremities which resolved following treatment with heparin and aspirin. She was found to have decreased left ventricular function and a pleural effusion requiring thoracentesis. Hydroxyurea replaced anagrelide therapy. Cardiomyopathy was successfully treated with furosemide, digoxin, enalapril, and carvedilol and resolved within 6 months. The patient was not rechallenged with anagrelide. The author advises adhering to the drug manufacturer's recommendation of baseline cardiac function testing and periodic monitoring (James, 2000).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported with anagrelide therapy in 8% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) Dose-related heart rate increases have been reported with anagrelide use. The maximum change in mean heart rate was +7.8 beats per minute (bpm) and +29.1 bpm after administration of anagrelide 0.5 mg and 2.5 mg, respectively, during a double-blind, randomized, placebo- and active-controlled, crossover study in healthy adult volunteers. These increases occurred 2 hours after administration (Prod Info AGRYLIN(R) oral capsules, 2014).
    2) WITH POISONING/EXPOSURE
    a) Sinus tachycardia has been reported following intentional overdose during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) VASODILATATION
    1) WITH THERAPEUTIC USE
    a) Vasodilatation was reported with anagrelide therapy in 1% to less than 5% of the patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    D) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) A slight tendency toward the development of orthostatic hypotension was observed during anagrelide administration in healthy volunteers (Andes et al, 1984).
    b) Postural hypotension was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    2) WITH POISONING/EXPOSURE
    a) Standing blood pressure fell an average of 22/15 mmHg in 9 subjects administered one dose of anagrelide 5 mg. Dizziness usually accompanied the blood pressure drop. Changes in blood pressure were minimal following a dose of anagrelide 2 mg (Prod Info AGRYLIN(R) oral capsules, 2010).
    E) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain was reported with anagrelide therapy in 8% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    F) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Heart failure was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) Congestive heart failure, palpitations, and transient ischemic attack (TIA) occurred in a 48-year-old woman with polycythemia vera treated with anagrelide (2 milligrams three times daily). As anagrelide was gradually increased to control thrombocytosis, the patient reported increasing fatigue, dyspnea on exertion, and palpitations. She was hospitalized with headache and unilateral weakness in the left extremities which resolved following treatment with heparin and aspirin. She was found to have decreased left ventricular function and a pleural effusion requiring thoracentesis. Hydroxyurea replaced anagrelide therapy. Cardiomyopathy was successfully treated with furosemide, digoxin, enalapril, and carvedilol and resolved within 6 months. The patient was not rechallenged with anagrelide. The author advises adhering to the drug manufacturer's recommendation of baseline cardiac function testing and periodic monitoring (James, 2000).
    G) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Ventricular tachycardia has been reported during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).
    H) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure, palpitations, and transient ischemic attack (TIA) occurred in a 48-year-old woman with polycythemia vera treated with anagrelide (2 milligrams three times daily). As anagrelide was gradually increased to control thrombocytosis, the patient reported increasing fatigue, dyspnea on exertion, and palpitations. She was hospitalized with headache and unilateral weakness in the left extremities which resolved following treatment with heparin and aspirin. She was found to have decreased left ventricular function and a pleural effusion requiring thoracentesis. Hydroxyurea replaced anagrelide therapy. Cardiomyopathy was successfully treated with furosemide, digoxin, enalapril, and carvedilol and resolved within 6 months. The patient was not rechallenged with anagrelide. The author advises adhering to the drug manufacturer's recommendation of baseline cardiac function testing and periodic monitoring (James, 2000).
    I) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) During a double-blind, randomized, placebo-controlled and active-controlled cross-over study, a dose-related increase in the mean QTc interval was observed with a QTc interval change from placebo of 7 ms and 13 ms following anagrelide doses of 0.5 mg and 2.5 mg, respectively (Prod Info AGRYLIN(R) oral capsules, 2014a).
    J) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Torsades de pointes has been reported during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).
    K) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema and peripheral edema were reported with anagrelide therapy in 21% and 9% of patients, respectively, with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea was reported with anagrelide therapy in 12% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough was reported with anagrelide therapy in 6% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) INTERSTITIAL LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Interstitial lung diseases, including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis, have been reported during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).
    1) Most cases manifested with signs and symptoms of progressive dyspnea with lung infiltrations, with a time of onset ranging from 1 week to several years after beginning anagrelide therapy (Prod Info AGRYLIN(R) oral capsules, 2014a).
    D) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Pneumonia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported with anagrelide therapy in 44% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) Migraine headaches were reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported with anagrelide therapy in 15% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion and nervousness were reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    D) TRANSIENT CEREBRAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure, palpitations, and transient ischemic attack (TIA) occurred in a 48-year-old woman with polycythemia vera treated with anagrelide (2 milligrams three times daily). As anagrelide was gradually increased to control thrombocytosis, the patient reported increasing fatigue, dyspnea on exertion, and palpitations. She was hospitalized with headache and unilateral weakness in the left extremities which resolved following treatment with heparin and aspirin. She was found to have decreased left ventricular function and a pleural effusion requiring thoracentesis. Hydroxyurea replaced anagrelide therapy. Cardiomyopathy was successfully treated with furosemide, digoxin, enalapril, and carvedilol and resolved within 6 months. The patient was not rechallenged with anagrelide. The author advises adhering to the drug manufacturer's recommendation of baseline cardiac function testing and periodic monitoring (James, 2000).
    E) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia was reported with anagrelide therapy in 23% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    F) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesias were reported with anagrelide therapy in 6% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    G) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    H) MALAISE
    1) WITH THERAPEUTIC USE
    a) Malaise was reported with anagrelide therapy in 6% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    I) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    J) AMNESIA
    1) WITH THERAPEUTIC USE
    a) Amnesia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting were reported with anagrelide therapy in 17% and 10% of patients, respectively, with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) A pediatric patient experienced mild gastrointestinal symptoms of nausea, diarrhea, and abdominal pain which resolved after 2 weeks of therapy (Lackner et al, 1998).
    2) WITH POISONING/EXPOSURE
    a) Vomiting has been reported following intentional overdose during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported with anagrelide therapy in 26% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) A pediatric patient experienced mild gastrointestinal symptoms of nausea, diarrhea, and abdominal pain which resolved after 2 weeks of therapy (Lackner et al, 1998).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain was reported with anagrelide therapy in 16% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) A pediatric patient experienced mild gastrointestinal symptoms of nausea, diarrhea, and abdominal pain which resolved after 2 weeks of therapy (Lackner et al, 1998).
    D) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia was reported with anagrelide therapy in 8% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2010).
    E) FLATULENCE/WIND
    1) WITH THERAPEUTIC USE
    a) Flatulence has been reported with anagrelide therapy in 10% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    G) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) Dyspepsia has been reported with anagrelide therapy in 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    H) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) Gastritis was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    I) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal hemorrhage was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes were reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Renal failure was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) NEPHRITIS
    1) WITH THERAPEUTIC USE
    a) Tubulointerstitial nephritis has been reported during postmarketing surveillance of anagrelide (Prod Info AGRYLIN(R) oral capsules, 2014a).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    b) Sudden drops in platelet count have been reported in patients receiving anagrelide therapy for thrombocytosis secondary to chronic myelogenous leukemia (Petitt, 1998; McCune & Lindley, 1998; McCune et al, 1997).
    c) Anagrelide has been associated with significant decreases in platelet counts in healthy volunteers (Fleming et al, 1976; Fleming et al, 1975; Andes et al, 1984), which appears to be related to a selective inhibition of platelet production by the drug.
    d) In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days). No prolongation of bleeding times or increased bruising was observed, suggesting nonsignificant platelet functional impairment. It is suggested that anagrelide may induce dysthrombopoiesis, with a fall in circulating platelets without an adequate response in platelet production, which is similar to erythroleukemia or megaloblastic states (Andes et al, 1984).
    C) ECCHYMOSIS
    1) WITH THERAPEUTIC USE
    a) Ecchymosis was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash and pruritus have been reported with anagrelide therapy in 8% and 6% of patients, respectively, with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain was reported with anagrelide therapy in 6% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Summary Of Exposure

    A) USES: Anagrelide is used to treat patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.
    B) PHARMACOLOGY: The exact mechanism is unknown. It's postulated that anagrelide reduces platelet production by decreasing megakaryocyte hypermaturation (size and ploidy and disrupting or preventing full megakaryocyte maturation). Anagrelide inhibits platelet aggregation by inhibition of cyclic adenosine monophosphate (cAMP) phosphodiesterase activity with subsequent increases in cAMP levels in the platelets.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse events following therapeutic administration, at an incidence of at least 5% during clinical trials, are headache, diarrhea, abdominal pain, nausea, vomiting, asthenia, edema, palpitations, dizziness, chest pain, dyspnea, cough, flatulence, fever, rash, anorexia, tachycardia, paresthesia, back pain, pruritus, and dyspepsia.
    2) INFREQUENT: Adverse effects that were reported less frequently include: congestive heart failure, cardiomyopathy, vasodilatation, postural hypotension, QT interval prolongation, constipation, gastrointestinal hemorrhage, gastritis, anemia, thrombocytopenia, ecchymosis, elevated liver enzymes, arthralgia, myalgia, confusion, somnolence, insomnia, epistaxis, pneumonia, alopecia, diplopia, tinnitus, hematuria, and renal failure.
    3) RARE: Torsades de pointes, ventricular tachycardia, tubulointerstitial nephritis, and interstitial lung diseases, including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis, have been rarely reported during post-marketing surveillance.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Hypotension has been reported with higher than recommended doses. Postmarketing data has reported the occurrence of sinus tachycardia and vomiting following overdose. In general, it is anticipated that overdose effects are an extension of adverse effects observed with therapeutic doses.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever was reported with anagrelide therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever was reported with anagrelide therapy in 9% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DIPLOPIA: Abnormal vision and diplopia were reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) Tinnitus was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Epistaxis was reported with anagrelide therapy in 1% to less than 5% of patients with myeloproliferative disease in clinical trials (n=942) (Prod Info AGRYLIN(R) oral capsules, 2014a).

Reproductive

    3.20.1) SUMMARY
    A) Anagrelide is classified as FDA Pregnancy Category C. Although there are no well-controlled studies of anagrelide use in pregnant women, animal studies have reported skeletal ossification and developmental delays, including fetal weight reduction, when pregnant rats were administered oral doses of anagrelide during organogenesis.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic. potential of anagrelide in humans (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) ANIMAL STUDIES
    1) RATS: Skeletal ossification resulted when pregnant rats were administered oral doses of anagrelide during organogenesis at 100 mg/kg/day (approximately 97 times the maximum clinical dose based on body surface area) or higher (Prod Info AGRYLIN(R) oral capsules, 2014a).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to anagrelide during pregnancy in humans (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) PREGNANCY CATEGORY
    1) U.S. Food and Drug Administration's Pregnancy Category C (Prod Info AGRYLIN(R) oral capsules, 2014a).
    C) ANIMAL STUDIES
    1) RATS: Developmental delays, including reductions in fetal weight, resulted when pregnant rats were administered oral doses of anagrelide at 300 and 900 mg/kg/day (Prod Info AGRYLIN(R) oral capsules, 2014a).
    2) RATS: A pre- and post-natal study on female rats administered oral doses of anagrelide at 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) experienced parturition blockage or delay, death of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born (Prod Info AGRYLIN(R) oral capsules, 2014a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to anagrelide during lactation in humans (Prod Info AGRYLIN(R) oral capsules, 2014a).
    B) ANIMAL STUDIES
    1) RATS: In animal studies, anagrelide radioactivity was detected in the maternal breast milk of rats (Prod Info AGRYLIN(R) oral capsules, 2014a).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs following overdose.
    B) Obtain periodic complete blood counts, including platelet counts. Monitor for clinical evidence of bleeding. In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days).
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Obtain a chest x-ray in any patient with respiratory symptoms.
    F) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) Obtain periodic complete blood counts, including platelet counts. Monitor for clinical evidence of bleeding. In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days) (Andes et al, 1984).
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG, and institute continuous cardiac monitoring.
    2) MONITORING
    a) Monitor vital signs following overdose.
    3) CHEST RADIOGRAPH
    a) Obtain a chest x-ray in any patient with respiratory symptoms.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor vital signs following overdose.
    B) Obtain periodic complete blood counts, including platelet counts. Monitor for clinical evidence of bleeding. In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days).
    C) Obtain an ECG, and institute continuous cardiac monitoring.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    E) Obtain a chest x-ray in any patient with respiratory symptoms.
    F) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine, if unresponsive to fluids. Monitor serial CBC with differential. Transfusions as needed for severe thrombocytopenia and/or bleeding. Therapeutic doses of anagrelide may cause prolongation of the QT interval. Concomitant use of anagrelide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    B) MONITORING OF PATIENT
    1) Monitor vital signs following overdose.
    2) Obtain periodic complete blood counts, including platelet counts. Monitor for clinical evidence of bleeding. In one study, the mean time to reach a nadir in platelet counts was approximately 18 days (range, 13 to 26 days) (Andes et al, 1984).
    3) Obtain an ECG, and institute continuous cardiac monitoring.
    4) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    5) Obtain a chest x-ray in any patient with respiratory symptoms.
    6) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) ACQUIRED THROMBOCYTOPENIA
    1) Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage.
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) TORSADES DE POINTES
    1) Therapeutic doses of anagrelide may cause prolongation of the QT interval. Concomitant use of anagrelide and other drugs that prolong the QT interval may increase the risk of torsade de pointes.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established. Standing blood pressure fell an average of 22/15 mmHg in 9 subjects administered one dose of anagrelide 5 mg. Dizziness usually accompanied the blood pressure drop.
    B) THERAPEUTIC DOSE: ADULT: Starting dose is 0.5 mg orally 4 times daily or 1 mg orally twice daily ; may be adjusted after one week at 0.5 mg/day in weekly increments, not to exceed 10 mg/day or 2.5 mg in a single dose. PEDIATRIC: Starting dose is 0.5 mg orally daily; may be adjusted after one week at 0.5 mg/day in weekly increments, not to exceed 10 mg/day or 2.5 mg in a single dose.

Therapeutic Dose

    7.2.1) ADULT
    A) THROMBOCYTHEMIA: Recommended initial oral dose is 0.5 mg orally 4 times daily or 1 mg orally twice daily; titrate to the lowest effective dose to maintain platelets below 600,000/mcL; do not exceed 0.5-mg/day dose increase in any 1 week; maximum dose 2.5 mg/dose and 10 mg/day (Prod Info AGRYLIN(R) oral capsules, 2014).
    B) The majority of patients respond with 4 mg/day or less (Anon, 1992).
    7.2.2) PEDIATRIC
    A) THROMBOCYTHEMIA, AGE 7 YEARS AND OLDER: Recommended initial oral dose is 0.5 mg orally once daily for at least 1 week; titrate to the lowest effective dose to maintain platelets below 600,000/mcL; do not exceed 0.5 mg/day dose increase in any 1 week; maximum dose 2.5 mg/dose and 10 mg/day (Prod Info AGRYLIN(R) oral capsules, 2010).
    B) Three pediatric patients (age range: 6 to 10 years) with symptomatic essential thrombocythemia were successfully treated with 1 to 2.5 mg/day orally of anagrelide. The initial dose was 0.5 mg twice daily (Lackner et al, 1998).

Maximum Tolerated Exposure

    A) Standing blood pressure fell an average of 22/15 mmHg in 9 subjects administered one dose of anagrelide 5 mg. Dizziness usually accompanied the blood pressure drop. Changes in blood pressure were minimal following a dose of anagrelide 2 mg (Prod Info AGRYLIN(R) oral capsules, 2010).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) PLATELET-REDUCING EFFECTS: The exact mechanism is unknown. It's postulated that anagrelide reduces platelet production by decreasing megakaryocyte hypermaturation (size and ploidy and disrupting or preventing full megakaryocyte maturation) (Prod Info Agrylin(R), 2002).
    B) PLATELET AGGREGATION INHIBITION: Inhibition of platelet aggregation occurs at doses which are higher than those required to reduce platelet count (Prod Info Agrylin(R), 2002). Anagrelide inhibits platelet aggregation by INHIBITION of CYCLIC ADENOSINE MONOPHOSPHATE (cAMP) PHOSPHODIESTERASE activity with subsequent increases in cAMP levels in the platelets (Spencer & Brogden, 1994; Vigdahl & Ferber, 1981; Tang & Frojmovic, 1980).

Physicochemical

Physical Characteristics

    A) Anagrelide hydrochloride is an off-white powder that is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and dimethylformamide (Prod Info AGRYLIN(R) oral capsules, 2010).

Molecular Weight

    A) ANAGRELIDE HYDROCHLORIDE: 310.55 (Prod Info AGRYLIN(R) oral capsules, 2010)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Andes WA, Noveck RJ, & Fleming JS: Inhibition of platelet production induced by an antiplatelet drug, anagrelide, in normal volunteers.. Thromb Haemost 1984; 52:325-328.
    4) Anon: Anagrelide, a therapy for thrombocythemic states: experience in 577 patients.. Am J Med 1992; 92:69-76.
    5) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    8) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    9) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    11) Fleming JS, Buchanan JO, & Buyniski JP: The effect of a potent inhibitor of platelet aggregation, BL 3459, on adrenaline-induced myocardial necrosis in beagle dogs.. Eur J Pharmacol 1976; 40:57-62.
    12) Fleming JS, Buyniski JP, Cavanagh RL, et al: Pharmacology of a potent, new antithrombotic agent, 6-methyl-1,2,3, 5-tetrahydroimidazo(2,1-b)quinazolin-2-one hydrochloride monohydrate (BL-3459).. J Pharmcol Exp Ther 1975; 194:435.
    13) Gaver RC, Deeb G, Pittman KA, et al: Disposition of anagrelide, an inhibitor of platelet aggregation.. Clin Pharmacol Ther 1981; 29:381-386.
    14) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    15) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    16) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    17) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    18) James CW: Anagrelide-induced cardiomyopathy.. Pharmacotherapy 2000; 20:1224-1227.
    19) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    20) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    21) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    22) Lackner H, Urban C, Beham-Schmid C, et al: Treatment of children with anagrelide for thrombocythemia.. J Pediatr Hematol Oncol 1998; 20(5):469-473.
    23) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    24) McCune JS & Lindley C: Precipitous fall in platelet count with anagrelide: case report and critique of dosing recommendations -- authors' reply.. Pharmacotherapy 1998; 18(3):660-661.
    25) McCune JS, Liles D, & Lindley C: Precipitous fall in platelet count with anagrelide: case report and critique of dosing recommendations.. Pharmacotherapy 1997; 17(4):822-826.
    26) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    27) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    28) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    29) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    30) Petitt RM: Precipitous fall in platelet count with anagrelide: case report and critique of dosing recommendations -- a comment.. Pharmacotherapy 1998; 18(3):659..
    31) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    32) Product Information: AGRYLIN(R) oral capsules, anagrelide HCl oral capsules. Shire US Inc. (per FDA), Wayne, PA, 2014.
    33) Product Information: AGRYLIN(R) oral capsules, anagrelide HCl oral capsules. Shire US Inc. (per FDA), Wayne, PA, 2014a.
    34) Product Information: AGRYLIN(R) oral capsules, anagrelide HCl oral capsules. Shire US Inc., Wayne, PA, 2010.
    35) Product Information: Agrylin(R), anagrelide. Shire US Inc, Florence, KY, 2002.
    36) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    37) Product Information: anagrelide HCl oral capsules, anagrelide HCl oral capsules. Teva Pharmaceuticals USA, Inc. (per DailyMed), North Wales, PA, 2014.
    38) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    39) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    40) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    41) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    42) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    43) Spencer CM & Brogden MM: Anagrelide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia.. Drugs 1994; 47:809-822..
    44) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    45) Tang SS & Frojmovic MM: Inhibition of platelet function by antithrombotic agents which selectively inhibit low-Km cyclic 3'-5'-adenosine monophosphate phosphodiesterase.. J Lab Clin Med 1980; 95:241-257..
    46) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    47) Vigdahl RL & Ferber RH: Comparison of sulfinpyrazone and BL-3459 with S-20344, a potent new antithrombotic agent.. Thromb Res 1981; 21:547-557..