HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AGRYLIN safely and effectively. See full prescribing information for AGRYLIN.
AGRYLIN ® (anagrelide hydrochloride) capsules, for oral use
Initial U.S. Approval: 1997
RECENT MAJOR CHANGES
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Dosage and Administration (2) |
10/2014 |
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Contraindications (4) |
10/2014 |
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Warnings and Precautions (5) |
10/2014 |
INDICATIONS AND USAGE
Anagrelide is a platelet reducing agent indicated for the treatment of 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. (1)
DOSAGE AND ADMINISTRATION
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The starting dose for adults is 0.5 mg four times a day or 1 mg twice a day (2.1)
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The starting dose for pediatric patients is 0.5 mg per day (2.1)
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Maintain the starting dose for at least one week and then titrate to maintain target platelet counts (2.2)
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Do not exceed a dose increment of 0.5 mg/day in any one week. Do not exceed 10 mg/day or 2.5 mg in a single dose. (2.2)
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Moderate hepatic impairment: Start with 0.5 mg per day (2.3)
DOSAGE FORMS AND STRENGTHS
Capsules: 0.5mg (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
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Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have been reported with anagrelide. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. Monitor patients for cardiovascular effects. (5.1)
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Bleeding Risk: Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (5.2)
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥ 5%) are headache, palpitations, diarrhea, asthenia, edema, nausea, abdominal pain, dizziness, pain, dyspnea, cough, flatulence, vomiting, fever, peripheral edema, rash, chest pain, anorexia, tachycardia, malaise, paresthesia, back pain, pruritus, dyspepsia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov./medwatch
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Other PDE 3 inhibitors: Exacerbation of inotropic effects (7.2)
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Aspirin and Drugs that Increase Bleeding Risk: Increased risk of bleeding with concomitant use (7.3)
USE IN SPECIFIC POPULATIONS
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Nursing Mothers: Discontinue nursing or discontinue the drug (8.3).
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 7/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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 [see Clinical Studies (14), Dosage and Administration (2)].
2 DOSAGE AND ADMINISTRATION
2.1 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.
2.2 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 [see Warnings and Precautions (5)]. 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.
2.3 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 [see Warnings and Precautions (5.1), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 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.
2.4 Clinical 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.
3 DOSAGE FORMS AND STRENGTHS
White, opaque capsule, containing 0.5 mg anagrelide (as anagrelide hydrochloride), imprinted with " 063" in black ink.
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 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 eva luate 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 [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)].
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms [see Clinical Pharmacology (12.2)].
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 [see Drug Interactions (7.2)].
In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
5.2 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) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
5.3 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 eva luate. Symptoms may improve after discontinuation [see Adverse Reactions (6)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
6.1 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.
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