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Agrylin

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Agrylin

Agrylin

SIDE EFFECTS

Analysis of the adverse events in a population consisting of 942 patients in 3 clinical studies diagnosed with myeloproliferative diseases of varying etiology (ET: 551; PV: 117; OMPD: 274) has shown that all disease groups have the same adverse event profile. While most reported adverse events during anagrelide therapy have been mild in intensity and have decreased in frequency with continued therapy, serious adverse events were reported in these patients. These include the following: congestive heart failure, myocardial infarction, cardiomyopathy, cardiomegaly, complete heart block, atrial fibrillation, cerebrovascular accident, pericarditis, pericardial effusion, pleural effusion, pulmonary infiltrates, pulmonary fibrosis, pulmonary hypertension, pancreatitis, gastric/duodenal ulceration, and seizure.

Of the 942 patients treated with anagrelide for a mean duration of approximately 65 weeks, 161 (17%) were discontinued from the study because of adverse events or abnormal laboratory test results. The most common adverse events for treatment discontinuation were headache, diarrhea, edema, palpitations, and abdominal pain. Overall, the occurrence rate of all adverse events was 17.9 per 1,000 treatment days. The occurrence rate of adverse events increased at higher dosages of anagrelide.

The most frequently reported adverse reactions to anagrelide (in 5% or greater of 942 patients with myeloproliferative disease) in clinical trials were:

Headache ...............................43.5%
Palpitations.............................26.1%
Diarrhea..................................25.7%
Asthenia .................................23.1%
Edema, other ..........................20.6%
Nausea ...................................17.1%
Abdominal Pain .....................16.4%
Dizziness ................................15.4%
Pain, other ..............................15.0%
Dyspnea..................................11.9%
Flatulence ...............................10.2%
Vomiting ................................9.7%
Fever ......................................8.9%
Peripheral Edema ...................8.5%
Rash, including urticaria ........8.3%
Chest Pain ..............................7.8%
Anorexia.................................7.7%
Tachycardia ............................7.5%
Pharyngitis .............................6.8%
Malaise ...................................6.4%
Cough .....................................6.3%
Paresthesia..............................5.9%
Back Pain ...............................5.9%
Pruritus ...................................5.5%
Dyspepsia ...............................5.2%

Adverse events with an incidence of 1% to < 5% included:

Body as a Whole System: Flu symptoms, chills, photosensitivity.

Cardiovascular System: Arrhythmia, hemorrhage, hypertension, cardiovascular disease, angina pectoris, heart failure, postural hypotension, thrombosis, vasodilatation, migraine, syncope.

Digestive System: Constipation, GI distress, GI hemorrhage, gastritis, melena, aphthous stomatitis, eructation.

Hemic & Lymphatic System: Anemia, thrombocytopenia, ecchymosis, lymphadenopathy. Platelet counts below 100,000/μL occurred in 84 patients (ET: 35; PV: 9; OMPD: 40), reduction below 50,000/μL occurred in 44 patients (ET: 7; PV: 6; OMPD: 31) while on anagrelide therapy. Thrombocytopenia promptly recovered upon discontinuation of anagrelide.

Hepatic System: Elevated liver enzymes were observed in 3 patients (ET: 2; OMPD: 1) during anagrelide therapy. Musculoskeletal System: Arthralgia, myalgia, leg cramps.

Nervous System: Depression, somnolence, confusion, insomnia, nervousness, amnesia.

Nutritional Disorders: Dehydration.

Respiratory System: Rhinitis, epistaxis, respiratory disease, sinusitis, pneumonia, bronchitis, asthma.

Skin and Appendages System: Skin disease, alopecia.

Special Senses: Amblyopia, abnormal vision, tinnitus, visual field abnormality, diplopia.

Urogenital System: Dysuria, hematuria.

Renal abnormalities occurred in 15 patients (ET: 10; PV: 4; OMPD: 1). Six ET, 4 PV and 1 with OMPD experienced renal failure (approximately 1%) while on anagrelide treatment; in 4 cases, the renal failure was considered to be possibly related to anagrelide treatment. The remaining 11 were found to have pre-existing renal impairment. Doses ranged from 1.5-6.0 mg/day, with exposure periods of 2 to 12 months. No dose adjustment was required because of renal insufficiency.

The adverse event profile for patients in three clinical trials on anagrelide therapy (in 5% or greater of 942 patients with myeloproliferative diseases) is shown in the following bar graph:

All patients with Myeloproliferative Disease (N=942)

All patients with Myeloproliferative Disease - Illustration

Postmarketing Reports

Cases of torsades de pointes, ventricular tachycardia, interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis), tubulointerstitial nephritis and clinically significant hepatotoxicity have been reported (See WARNINGS, Cardiovascular, Interstitial Lung Diseases and PRECAUTIONS, Laboratory Tests).

Read the Agrylin (anagrelide) Side Effects Center for a complete guide to possible side effects

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. Coadministered 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.

Drug interaction studies have not been conducted with the other common medications used concomitantly with anagrelide in clinical trials which were acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol.

Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other co-administered medicinal products sharing that clearance mechanism e.g. theophylline.

Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.

There is a single case report which suggests that sucralfate may interfere with anagrelide absorption.

Food has no clinically significant effect on the bioavailability of anagrelide.

Read the Agrylin Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 2/20/2014
This monograph has been modified to include the generic and brand name in many instances.

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