essed before treatment is commenced. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for cardiovascular effects (see DOSAGE AND ADMINISTRATION for specific dosing recommendations).
Interstitial Lung Diseases
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. In most cases, the symptoms improved after discontinuation of anagrelide (See ADVERSE REACTIONS).
PRECAUTIONS Bleeding: 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, particularly in patients with a high risk profile for hemorrhage.
Laboratory Tests: Anagrelide therapy requires close clinical supervision of the patient. While the platelet count is being lowered (usually during the first two weeks of treatment), blood counts (hemoglobin, white blood cells), and renal function (serum creatinine, BUN) should be monitored. Cases of clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN) have been reported in post-marketing surveillance. Measure liver function tests (ALT, AST) before initiating anagrelide treatment and during therapy.
In 9 subjects receiving a single 5 mg dose of anagrelide, standing blood pressure fell an average of 22/15 mm Hg, usually accompanied by dizziness. Only minimal changes in blood pressure were observed following a dose of 2 mg.
Cessation of AGRYLIN ® Treatment: In general, interruption of anagrelide treatment is followed by an increase in platelet count. After sudden stoppage of anagrelide therapy, the increase in platelet count can be observed within four days.
Drug Interactions: Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
In two clinical interaction studies in healthy subjects, co-administration of single-dose anagrelide 1mg and aspirin 900mg or repeat-dose anagrelide 1mg once daily and aspirin 75mg once daily showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone. Co-administered anagrelide 1mg and aspirin 900mg single-doses had no effect on bleeding time, prothrombin time (PT) or activated partial thromboplastin time (aPTT).
Analyses of an ongoing observational study in patients with ET 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.
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