Anagrelide

Anagrelide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]

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Overview

Anagrelide is a platelet reducing agent that is FDA approved for the treatment of thrombocythemia, secondary to myeloproliferative neoplasms. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events

Dosage

Starting Dose

• Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily.

• Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily.

Titration

• Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary.

Dose Modifications for Hepatic Impairment

• In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events. Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of AGRYLIN in patients with severe hepatic impairment.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Dosage

• The recommended starting dosage of AGRYLIN is 0.5 mg daily.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Anagrelide in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Anagrelide in pediatric patients.

Contraindications

• none

Warnings

Cardiovascular Toxicity

• Torsades de pointes and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular effects and evaluate as necessary.

• Anagrelide increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see CLINICAL PHARMACOLOGY (12.2)].

• Do not use AGRYLIN in patients with known risk factors for QT interval prolongation, such as congenital long QT syndrome, a known history of acquired QTc prolongation, medicinal products that can prolong QTc interval and hypokalemia [see DRUG INTERACTIONS (7.1)].

• Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Use of AGRYLIN in patients with severe hepatic impairment has not been studied.

• In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiogram.

• Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure.

• In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.

Bleeding Risk

• Use of concomitant anagrelide and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of anagrelide with aspirin, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

Pulmonary Toxicity

• Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of anagrelide in post-marketing reports. Most cases presented with progressive dyspnea with lung infiltrations. The time of onset ranged from 1 week to several years after initiating anagrelide. If suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation

Adverse Reactions

Clinical Trials Experience

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Studies in Adult Patients

In three single-arm clinical studies, 942 patients [see CLINICAL TRIALS (14)] diagnosed with myeloproliferative neoplasms of varying etiology (ET: 551; PV: 117; OMPN: 274) were exposed to anagrelide with a mean duration of approximately 65 weeks. Serious adverse reactions reported in these patients included the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericardial effusion [see WARNINGS AND PRECAUTIONS (5.1)], pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, and pancreatitis. Of the 942 patients treated with anagrelide, 161 (17%) were discontinued from the study because of adverse reactions or abnormal laboratory test results. The most common adverse reactions for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative neoplasms) in clinical trials were listed in Table 1.

Adverse Reactions (frequency 1% to < 5%) included:

General disorders and administration site conditions: Flu symptoms, chills.

Cardiac Disorders: Arrhythmia, angina pectoris, heart failure, syncope.

Vascular disorders: Hemorrhage, hypertension, postural hypotension, vasodilatation.

Gastrointestinal disorders: Constipation, gastrointestinal hemorrhage, gastritis.

Blood and lymphatic system disorders: Anemia, thrombocytopenia, ecchymosis.

Hepatobiliary disorders: Elevated liver enzymes.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Psychiatric disorders: Depression, confusion, nervousness.

Nervous system disorders: Somnolence, insomnia, amnesia, migraine headache.

Respiratory, thoracic and mediastinal disorders: Epistaxis, pneumonia.

Skin and subcutaneous tissue disorders: Alopecia.

Eye disorders: Abnormal vision, diplopia.

Ear and labyrinth disorders: Tinnitus

Renal and urinary disorders: Hematuria, renal failure.

Clinical Study in Pediatric Patients

The frequency of adverse events observed in pediatric patients was similar to adult patients. The most common adverse events observed in pediatric patients were fever, epistaxis, headache, and fatigue during the 3-month anagrelide treatment in the study. Episodes of increased pulse and decreased systolic or diastolic blood pressure beyond the normal ranges in the absence of clinical symptoms were observed. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.

Postmarketing Experience

• The following adverse reactions have been identified during post-marketing use of AGRYLIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of torsades de pointes, ventricular tachycardia, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) [see WARNINGS AND PRECAUTIONS (5)], tubulointerstitial nephritis and clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported.

Other adverse events in pediatric patients reported in spontaneous reports and literature reviews include anemia, cutaneous photosensitivity and elevated leukocyte count.

Drug Interactions

Drugs that prolong QT Do not use AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide and pimozide) [see WARNINGS AND PRECAUTIONS (5.1) and CLINICAL PHARMACOLOGY (12.2)].

7.2 PDE3 inhibitors Anagrelide is a phosphodiesterase 3 (PDE3) inhibitor. The effects of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) should be avoided [see WARNINGS AND PRECAUTIONS (5.1) and CLINICAL PHARMACOLOGY (12.2)].

7.3 Aspirin and Drugs that Increase Bleeding Risk Co-administration of single-dose or repeat-dose anagrelide and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone [see CLINICAL PHARMACOLOGY (12.3)]. Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with anagrelide is higher than in those subjects treated with another cytoreductive treatment. The majority of the major hemorrhagic events occurred in patients who were also receiving concomitant anti-aggregatory treatment (primarily, aspirin). Therefore, the potential risks of the concomitant use of anagrelide with aspirin should be assessed, particularly in patients with a high risk profile for hemorrhage, before treatment is initiated [see WARNINGS AND PRECAUTIONS (5.2)].

Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

7.4 CYP450 Interactions CYP1A2 inhibitors: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.

CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.

CYP1A2 substrates: Anagrelide demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g. theophylline, fluvoxamine, ondansetron).

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Anagrelide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Anagrelide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Anagrelide with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Anagrelide with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Anagrelide with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Anagrelide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Anagrelide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Anagrelide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Anagrelide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Anagrelide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Anagrelide in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

• AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes.

To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤ 600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.

IV Compatibility

There is limited information regarding IV Compatibility of Anagrelide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Anagrelide in the drug label.

Pharmacology

There is limited information regarding Anagrelide Pharmacology in the drug label.

Mechanism of Action

Structure

File:Anagrelide01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Anagrelide in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Anagrelide in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Anagrelide in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Anagrelide in the drug label.

How Supplied

Storage

There is limited information regarding Anagrelide Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Anagrelide in the drug label.

Precautions with Alcohol

• Alcohol-Anagrelide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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