Anagrelide Hydrochloride (Page 2 of 5)

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 anagrelide and evaluate. 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:

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Cardiovascular Toxicity [see Warnings and Precautions (5.1)]

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Bleeding Risk [see Warnings and Precautions (5.2)]

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Pulmonary Toxicity [see Warnings and Precautions (5.3)]

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.

Table 1: Adverse Reactions Reported in Clinical Studies 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 events observed in pediatric patients was similar to adult patients. The most common adverse events 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. Adverse events that had been reported in these pediatric patients prior to the study and were considered to be related to anagrelide treatment based on retrospective review were; palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.