Can Anagrelide cause fatigue?

ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Toxicity [see Warnings and Precautions (5.1)] Pulmonary Hypertension [see Warnings and Precautions (5.2)] Bleeding Risk [see Warnings and Precautions (5.3)] Pulmonary Toxicity [see Warnings and Precautions (5.4)] 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, and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 resulting in 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. Table 1 Adverse Reactions Reported in Clinical Studies of Anagrelide in at least 5% of Patients Adverse Reactions Anagrelide (N = 942) (%) Cardiac Disorders Palpitations 26% Tachycardia 8% Chest pain 8% General Disorders and Administration Site Conditions Asthenia 23% Edema 21% Pain 15% Fever 9% Peripheral edema 9% Malaise 6% Gastrointestinal Disorders Diarrhea 26% Nausea 17% Abdominal pain 16% Vomiting 10% Flatulence 10% Anorexia 8% Dyspepsia 5% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 12% Cough 6% Skin and Subcutaneous Tissue Disorders Rash 8% Pruritus 6% Musculoskeletal and Connective Tissue Disorders Back pain 6% Nervous System Disorders Headache 44% Dizziness 15% Paresthesia 6% 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. Other less frequent adverse reactions (< 1%) were: Cardiac Disorders: Ventricular tachycardia, supraventricular tachycardia. Nervous System Disorders: Hypoesthesia. Clinical Study in Pediatric Patients The frequency of adverse reactions observed in pediatric patients was similar to adult patients. The most common adverse reactions 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. Other adverse reactions reported in these pediatric patients receiving anagrelide treatment were palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-marketing use of anagrelide. 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. Cardiac Disorders: Prinzmetal angina, Torsades de pointes. Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia, and interstitial pneumonitis) [see Warnings and Precautions (5.4)] . Renal and Urinary Disorders: Tubulointerstitial nephritis. Hepatobiliary Disorders: Clinically significant hepatotoxicity (including symptomatic ALT and AST elevations and elevations greater than three times the ULN). Nervous System Disorders: Cerebral infarction Other adverse reactions in pediatric patients reported in spontaneous reports and literature reviews include: Blood and Lymphatic System Disorders: Anemia. Skin and Subcutaneous Tissue Disorders: Cutaneous photosensitivity. Investigations: Elevated leukocyte count.

WARNINGS AND PRECAUTIONS 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 ) Pulmonary Hypertension: Assess underlying cardiopulmonary disease prior to initiating therapy. ( 5.2 ) Bleeding Risk: Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding. ( 5.3 ) 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 anagrelide 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 anagrelide 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 anagrelide dose in patients with moderate hepatic impairment. Avoid use of anagrelide in patients with severe hepatic impairment. 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 anagrelide only when the benefits outweigh the risks. 5.2 Pulmonary Hypertension Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy [see Adverse Reactions ( 6.1 )] . 5.3 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) ]. 5.4 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 anagrelide and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions ( 6 )].