Anagrelide

Other PDE3 inhibitors: Exacerbation of inotropic effects. ( 7.2 ) Aspirin and Drugs that Increase Bleeding Risk : Increased risk of bleeding with concomitant use. ( 7.3 )

7.1 Drugs that Prolong QT Avoid use of AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide, and pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .

7.2 PDE3 Inhibitors AGRYLIN is a phosphodiesterase 3 (PDE3) inhibitor. Avoid use of drug products with similar properties such as inotropes and other PDE3 inhibitors (e.g., cilostazol, milrinone) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .

7.3 Aspirin and Drugs that Increase Bleeding Risk Co-administration of single-dose or repeat-dose AGRYLIN and aspirin showed greater ex vivo anti-platelet aggregation effects than administration of aspirin alone [see Clinical Pharmacology (12.3) ] . Results from an observational study in patients with essential thrombocythemia suggest the rate of major hemorrhagic events (MHEs) in patients treated with AGRYLIN 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 AGRYLIN with aspirin should be assessed, particularly in patients with a high-risk profile for hemorrhage, before treatment is initiated [see Warnings and Precautions (5.3) ] . Monitor patients for bleeding, particularly those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors).

7.4 CYP450 Interactions CYP1A2 inhibitors: AGRYLIN and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of AGRYLIN. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered. CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of AGRYLIN. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in AGRYLIN exposure.

CYP1A2 substrates: AGRYLIN demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g., theophylline, fluvoxamine, ondansetron).

8.1 Pregnancy Risk Summary Available data from case reports with AGRYLIN use in pregnant women have not identified a 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 (see Data ) . There are adverse effects on maternal and fetal outcomes associated with thrombocythemia in pregnancy (see Clinical Considerations ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk 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. Data Animal Data Anagrelide hydrochloride was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 900 mg/kg/day in rats and up to 20 mg/kg/day in rabbits (875 and 39 times, respectively, the maximum clinical dose of 10 mg/day based on body surface area). In rats, developmental delays were observed including reductions in fetal weight at 300 and 900 mg/kg/day and delays in skeletal ossification at doses of 100 mg/kg/day and higher.

The dose of 100 mg/kg/day (600 mg/m 2 /day) in rats is approximately 97 times the maximum clinical dose based on body surface area. No adverse embryo-fetal effects were detected in rabbits at the highest dose of 20 mg/kg/day (39 times the maximal clinical dose based on body surface area). 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.

In a placental transfer study, a single oral dose of…