Anagrelide (Page 2 of 4)

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).

Other adverse reactions in pediatric patients reported in spontaneous reports an literature reviews include:

Blood and lymphatic system disorders: Anemia.
Skin and subcutaneous tissue disorders: Cutaneous photosensitivity.
Investigations: Elevated leukocyte count.

7 DRUG INTERACTIONS

7.1 Drug that Prolong QT

Avoid use anagrelide 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

Anagrelide 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 anagrelide 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 anagrelide 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 anagrelide 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: Anagrelide and its active metabolite are primarily metabolized by CYP1A2. Drugs that inhibit CYP1A2 (e.g., fluvoxamine, ciprofloxacin) could increase the exposure of anagrelide. Monitor patients for cardiovascular events and titrate doses accordingly when CYP1A2 inhibitors are co-administered.

CYP1A2 inducers: CYP1A2 inducers could decrease the exposure of anagrelide. Patients taking concomitant CYP1A2 inducers (e.g., omeprazole) may need to have their dose titrated to compensate for the decrease in anagrelide exposure.

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from case reports with anagrelide 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/m2/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 [14 C]-anagrelide hydrochloride (3 mg/kg) was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.

8.2 Lactation

Risk Summary

There is no information regarding the presence of anagrelide in human milk, the effect on the breastfed child, or the effects on milk production. Anagrelide or its metabolites have been detected in the milk of lactating rats (see Data). Because of the potential for serious adverse reactions, including thrombocytopenia, in breastfed child, advise patients that breastfeeding is not recommended during treatment with anagrelide, and for one week following the last dose.

Data

In a rat milk secretion study, a single oral dose of [14 C]-anagrelide hydrochloride (3 mg/kg) was administered to lactating female rats on postnatal Day 10. Drug-related radioactivity was detected in the maternal milk and blood.

8.3 Females and Males of Reproductive Potential

Infertility

Females

Based on findings from animal studies, anagrelide may impair female fertility [see Nonclinical Toxicology (13.1) ].

8.4 Pediatric Use

Of the 942 subjects in clinical studies of anagrelide, 42.1% were 65 years and over, while 14.9% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.5 Geriatric Use

Hepatic metabolism is the major route of anagrelide clearance. Exposure to anagrelide is increased 8- fold in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)] and dose reduction is required [see Dosage and Administration (2.3)]. Use of anagrelide in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during anagrelide treatment [see Warnings and Precautions (5.1)].

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