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Anagrelide

Pronunciation

(an AG gre lide)

Index Terms

  • Anagrelide Hydrochloride
  • BL4162A

Dosage Forms

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

Capsule, Oral:

Agrylin: 0.5 mg

Generic: 0.5 mg, 1 mg

Brand Names: U.S.

  • Agrylin

Pharmacologic Category

  • Antiplatelet Agent
  • Phosphodiesterase-3 Enzyme Inhibitor

Pharmacology

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).

Metabolism

Hepatic, partially via CYP1A2; to two major metabolites, RL603 and 3-hydroxy anagrelide

Excretion

Urine (<1% as unchanged drug)

Onset of Action

Initial: Within 7 to 14 days; complete response (platelets ≤600,000/mm3): 4 to 12 weeks

Time to Peak

Serum: 1 hour, similar data reported in pediatric patients 7-14 years

Duration of Action

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

Half-Life Elimination

Anagrelide: 1.5 hours, similar data reported in pediatric patients 7-14 years; 3-hydroxy anagrelide: 2.5 hours

Special Populations: Hepatic Function Impairment

AUC increased 8-fold with moderate hepatic function impairment.

Special Populations: Elderly

AUC and Cmax of anagrelide were 36% and 61% higher, respectively, in fasting elderly patients with essential thrombocythemia compared to fasting adult patients, but the AUC and Cmax of the active metabolite, 3-hydroxy anagrelide, were 37% and 42% lower, respectively, in the elderly patient population.

Use: Labeled Indications

Thrombocythemia: Treatment of thrombocythemia associated with myeloproliferative disorders to reduce the risk of thrombosis and reduce associated symptoms (including thrombohemorrhagic events)

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Dosing: Adult

Thrombocythemia: Oral: Initial: 0.5 mg 4 times daily or 1 mg twice daily (most patients will experience adequate response at dose ranges of 1.5 to 3 mg per day)

Note: Maintain initial dose for ≥1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/mm3 ideally to the normal range; the dose must not be increased by >0.5 mg per day in any 1 week; maximum single dose: 2.5 mg; maximum daily dose: 10 mg

Thrombocythemia, essential (off-label dosing): Oral: 0.5 mg twice daily for 1 week, then adjust dose to maintain platelet counts at normal (≤450,000/mm3) or near normal (450,000/mm3 to 600,000/mm3) levels (Gisslinger, 2013).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Thrombocythemia: Oral: Initial: 0.5 mg once daily (range: 0.5 mg 1 to 4 times daily)

Note: Maintain initial dose for ≥1 week, then adjust to the lowest effective dose to reduce and maintain platelet count <600,000/mm3 ideally to the normal range; the dose must not be increased by >0.5 mg per day in any 1 week; maximum single dose: 2.5 mg; maximum daily dose: 10 mg

Dosing: Renal Impairment

No dosage adjustment necessary; monitor closely.

Dosing: Hepatic Impairment

Moderate impairment (Child-Pugh score 7 to 9): 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 per day in any 1 week.

Severe impairment (Child-Pugh score ≥10): Avoid use.

Administration

May be administered without regard to food.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy

Cilostazol: Anagrelide may enhance the adverse/toxic effect of Cilostazol. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

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

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Riociguat: Anagrelide may enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy

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

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin E (Oral): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Adverse Reactions

Frequency not always defined; reactions similar in adult and pediatric patients unless otherwise noted.

Cardiovascular: Palpitations (26%), edema (21%), peripheral edema (9%), chest pain (8%), tachycardia (8%), angina pectoris (1% to <5%), cardiac arrhythmia (1% to <5%), cardiac failure (1% to <5%), hypertension (1% to <5%), orthostatic hypotension (1% to <5%), syncope (1% to <5%), vasodilatation (1% to <5%), atrial fibrillation, cardiomegaly, cardiomyopathy, cerebrovascular accident, complete atrioventricular block, decreased diastolic pressure (pediatric patients), increased heart rate (pediatric patients), myocardial infarction, pericardial effusion, systolic hypotension (pediatric patients)

Central nervous system: Headache (44%), dizziness (15%), pain (15%), malaise (6%), paresthesia (6%), amnesia (1% to <5%), chills (1% to <5%), confusion (1% to <5%), depression (1% to <5%), drowsiness (1% to <5%), insomnia (1% to <5%), migraine (1% to <5%), nervousness (1% to <5%), fatigue (pediatric patients)

Dermatologic: Skin rash (8%), pruritus (6%), alopecia (1% to <5%)

Gastrointestinal: Diarrhea (26%), nausea (17%), abdominal pain (16%), flatulence (10%), vomiting (10%), anorexia (8%), dyspepsia (5%), constipation (1% to <5%), gastritis (1% to <5%), gastrointestinal hemorrhage (1% to <5%), pancreatitis

Hematologic & oncologic: Anemia (1% to <5%), bruise (1% to <5%), hemorrhage (1% to <5%), thrombocytopenia (1% to <5%)

Hepatic: Increased liver enzymes (1% to <5%)

Neuromuscular & skeletal: Weakness (23%), back pain (6%), arthralgia (1% to <5%), myalgia (1% to <5%), muscle cramps (pediatric patients)

Ophthalmic: Diplopia (1% to <5%), visual field defect (1% to <5%)

Otic: Tinnitus (1% to <5%)

Renal: Hematuria (1% to <5%), renal failure (1%)

Respiratory: Dyspnea (12%), cough (6%), epistaxis (1% to <5%), flu-like symptoms (1% to <5%), pneumonia (1% to <5%), pleural effusion, pulmonary hypertension, pulmonary fibrosis, pulmonary infiltrates

Miscellaneous: Fever (9%)

<1% (Limited to important or life-threatening): Eosinophilic pneumonitis, hepatotoxicity, hypersensitivity pneumonitis, interstitial nephritis, interstitial pneumonitis, leukocytosis, prolonged Q-T interval on ECG, skin photosensitivity (pediatric patients), torsades de pointes, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding risk: Major hemorrhagic events have occurred when used concomitantly with aspirin. Monitor closely for bleeding, particularly when used concurrently with other agents known to increase bleeding risk (eg, anticoagulants, NSAIDs, antiplatelet agents, other phosphodiesterase 3 (PDE) inhibitors, and selective serotonin reuptake inhibitors).

• Cardiovascular adverse events: Ventricular tachycardia and torsade de pointes have been reported. As with other PDE3 inhibitors, anagrelide may cause vasodilation, tachycardia, palpitations and heart failure. PDE3 inhibitors are associated with decreased survival (compared to placebo) in patients with class III or IV heart failure. Dose-related increases in heart rate and mean QTc interval have been observed in a clinical trial. The maximum change in mean heart rate was ~8 beats per minute (bpm) at a dose of 0.5 mg and ~29 bpm with a 2.5 mg dose. The maximum mean change in QTc I (individual subject correlation) from placebo was 7 ms and 13 ms with doses of 0.5 mg and 2.5 mg, respectively. Do not use in patients with hypokalemia, congenital long QT syndrome, a known history of acquired QTc prolongation, or when using concomitant therapy which may prolong the QTc interval. Hypotension accompanied by dizziness may occur, particularly with higher doses. Use with caution in patients with cardiovascular disease (eg, heart failure, bradyarrhythmias, electrolyte abnormalities); consider periodic ECGs; benefits should outweigh risks. Pretreatment cardiovascular evaluation (including ECG) and careful monitoring during treatment is recommended.

• 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 preexisting renal impairment, although dosage adjustment due to renal insufficiency was not required. Monitor closely in patients with renal insufficiency.

Disease-related concerns:

• 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 has not been studied in patients with severe impairment. Hepatic impairment increases anagrelide exposure and may increase the risk of QTc prolongation. Monitor liver function prior to and during treatment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

Platelet count (every 2 days during the first week of treatment and at least weekly until the maintenance dose is reached; continue to monitor after cessation of treatment); CBC with differential (monitor closely during first 2 weeks of treatment), liver function (ALT and AST; baseline and during treatment), BUN, and serum creatinine (monitor closely during first weeks of treatment); serum electrolytes; blood pressure; heart rate; cardiovascular exam, including ECG (pretreatment; monitor during therapy); signs/symptoms of interstitial lung disease; monitor for thrombosis or bleeding

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Data regarding use of anagrelide during pregnancy is limited. The manufacturer recommends effective contraception in women of childbearing potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, flatulence, diarrhea, or abdominal pain. Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds, coughing up blood, blood in the urine, black, red, or tarry stools, bleeding from the gums, abnormal vaginal bleeding, bruises without a reason or that get bigger, or any bleeding that is very bad or that will not stop), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, tachycardia, arrhythmia, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, severe headache, severe loss of strength and energy, vision changes, urinary retention, change in amount of urine passed, depression, confusion, memory impairment, seizures, or burning or numbness feeling (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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