anagrelide (Rx)

>10%

Headache (44%)

Palpitations (26%)

Diarrhea (26%)

Asthenia (23%)

Edema (21%)

Nausea (17%)

Abdominal pain (16%)

Dizziness (15%)

General pain (15%)

Dyspnea (12%)

1-10%

Flatulence (10%)

Vomiting (10%)

Fever (9%)

Edema (9%)

Rash (8%)

Chest pain (8%)

Anorexia (8%)

Tachycardia (8%)

Pharyngitis (7%)

Malaise (6%)

Cough (6%)

Paresthesia (6%)

Back pain (6%)

Pruritus (6%)

Confusion (1-5%)

Depression

Migraine

Myalgia

Nervousness

Photosensitivity

Arthralgia

Vision abnormalities

Angina

Arrhythmia

Cardiovascular disease

Heart failure

Hemorrhage

Hypertension

Postural hypotension

Syncope

Thrombosis

Vasodilation

Bronchitis

Rhinitis

Sinusitis

Constipation

Dyspepsia

Gastritis

Anemia

Elevated liver enzymes

Flu symptoms

Leg cramps

Dehydration

Postmarketing Reports

Interstitial lung diseases, including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis

Hepatotoxicity

Tubulointerstitial nephritis

Supraventricular tachycardia (SVT)

Hypoesthesia

Torsades de pointes

Cardiovascular toxicity

Pulmonary hypertension

Bleeding risk

Pulmonary toxicity

Contraindications

Severe hepatic impairment

Cautions

Caution in heart disease, renal impairment, mild-moderate hepatic impairment

Torsades de pointes and ventricular tachycardia reported; obtain pretreatment cardiovascular exam, including EKG, in all patients

Hepatic impairment increases anagrelide exposure and could increase risk of QTc prolongation; monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions

Increases QTc interval and heart rate in healthy volunteers; should not be used 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

In patients with cardiac disease, use only when benefits outweigh risks

In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic ECG monitoring

Orthostatic hypotension reported with higher doses; minimal BP changes observed following 2 mg/dose

Coadministration with aspirin increases risk for major hemorrhagic event

Cases of pulmonary hypertension reported; evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy

Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) reported to be associated with use of anagrelide in post-marketing reports; most cases presented with progressive dyspnea with lung infiltrations; time of onset ranged from 1 week to several years after initiating anagrelide; discontinue anagrelide if it occurs and evaluate; symptoms may improve after discontinuation

Monitor platelets, Hgb, WBC, LFTs, Cr, BUN for at least first 2 weeks

May induce highoutput heart failure by PDE4 inhibition (may be reversible upon discontinuation)

Pregnancy

Available data from case reports in pregnant women have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; in animal embryo-fetal studies, delayed fetal development (delayed skeletal ossification and reduced body weight) was observed in rats administered anagrelide hydrochloride during organogenesis at doses approximately 97 times the maximum clinical dose (10 mg/day) based on body surface area; there are adverse effects on maternal and fetal outcomes associated with thrombocythemia in pregnancy

Thrombotic events, such as stroke, deep vein thrombosis, or myocardial infarction, can be complications of thrombocythemia; thrombocythemia in pregnancy is associated with an increased risk for miscarriage, stillbirth, and other maternal outcomes, such as preeclampsia

Animal data

• In a pre- and post-natal study conducted in female rats, anagrelide hydrochloride administered at oral doses of 60 mg/kg/day (58 times the maximum clinical dose based on body surface area) or higher during organogenesis through lactation produced delay or blockage of parturition, deaths of non-delivering pregnant dams and their fully developed fetuses, and increased mortality in the pups born

Infertility

• Based on findings from animal studies, therapy may impair female fertility

Lactation

There is no information regarding presence of drug in human milk, effect on breastfed child, or on milk production; the drug or its metabolites have been detected in milk of lactating rats; because of potential for serious adverse reactions, including thrombocytopenia, in a breastfed child, advise patients that breastfeeding is not recommended during treatment, and for one week following last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Phosphodiesterase 3 (PDE3) inhibitor; inhibits nucleotide PDE and the release of arachidonic acid from phospholipase A2; reduces also platelet production by disrupting the maturation phase of megakaryocytes

Pharmacokinetics

Onset of action: Within 7-14 days (initial); 4-12 weeks (complete)

Peak plasma time: 1 hr

Duration: 6-24 hr

Metabolism: Extensive; partially through CYP1A2

Half-life: 1.3 hr

Excretion: Urine (<1%)