Anagrelideside effects

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Toxicity Pulmonary Hypertension Bleeding Risk Pulmonary Toxicity 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. 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 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, 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).

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.