Source: FDA, National Drug Code (US) Revision Year: 2020
None.
Torsades de pointes and ventricular tachycardia have been reported with AGRYLIN. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. During treatment with AGRYLIN monitor patients for cardiovascular effects and evaluate as necessary.
AGRYLIN increases the QTc interval of the electrocardiogram and increases the heart rate in healthy volunteers [see Clinical Pharmacology (12.2)].
Do not use AGRYLIN 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 [see Drug Interactions (7.1)].
Hepatic impairment increases anagrelide exposure and could increase the risk of QTc prolongation. Monitor patients with hepatic impairment for QTc prolongation and other cardiovascular adverse reactions. The potential risks and benefits of AGRYLIN therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Reduce AGRYLIN dose in patients with moderate hepatic impairment. Avoid use of AGRYLIN in patients with severe hepatic impairment.
In patients with heart failure, bradyarrhythmias, or electrolyte abnormalities, consider periodic monitoring with electrocardiograms [see Clinical Pharmacology (12.2)].
AGRYLIN is a phosphodiesterase 3 (PDE3) inhibitor and may cause vasodilation, tachycardia, palpitations, and congestive heart failure. Other drugs that inhibit PDE3 have caused decreased survival when compared with placebo in patients with Class III-IV congestive heart failure [see Drug Interactions (7.2)].
In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks.
Cases of pulmonary hypertension have been reported in patients treated with AGRYLIN. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during AGRYLIN therapy [see Adverse Reactions (6.1)].
Use of concomitant AGRYLIN and aspirin increased major hemorrhagic events in a postmarketing study. Assess the potential risks and benefits for concomitant use of AGRYLIN with aspirin, since bleeding risks may be increased. Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding (e.g., anticoagulants, PDE3 inhibitors, NSAIDs, antiplatelet agents, selective serotonin reuptake inhibitors) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
Interstitial lung diseases (including allergic alveolitis, eosinophilic pneumonia and interstitial pneumonitis) have been reported to be associated with the use of AGRYLIN 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 AGRYLIN. If suspected, discontinue AGRYLIN and evaluate. Symptoms may improve after discontinuation [see Adverse Reactions (6)].
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:
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.
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 AGRYLIN 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 AGRYLIN, 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 AGRYLIN (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 AGRYLIN in at least 5% of Patients:
| Adverse Reactions | AGRYLIN (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.
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 AGRYLIN 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 AGRYLIN treatment were palpitations, headache, nausea, vomiting, abdominal pain, back pain, anorexia, fatigue, and muscle cramps.
The following adverse reactions have been identified during post-marketing use of AGRYLIN. 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 and literature reviews include:
Blood and lymphatic system disorders: Anemia.
Skin and subcutaneous tissue disorders: Cutaneous photosensitivity.
Investigations: Elevated leukocyte count.
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)].
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)].
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).
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 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.
AGRYLIN demonstrates limited inhibitory activity towards CYP1A2 in vitro and may alter the exposure of concomitant CYP1A2 substrates (e.g., theophylline, fluvoxamine, ondansetron).
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.
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.
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 [14C]-anagrelide hydrochloride (3 mg/kg) was administered to pregnant rats on gestation Day 17. Drug-related radioactivity was detected in maternal and fetal tissue.
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 a breastfed child, advise patients that breastfeeding is not recommended during treatment with AGRYLIN, and for one week following the last dose.
In a rat milk secretion study, a single oral dose of [14C]-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.
Based on findings from animal studies, AGRYLIN may impair female fertility [see Nonclinical Toxicology (13.1)].
The safety and effectiveness of AGRYLIN have been established in pediatric patients 7 years of age and older. There are no data for pediatric patients less than 7 years of age. Use of AGRYLIN in these pediatric patients is supported by evidence from adequate and well controlled studies of AGRYLIN in adults with additional pharmacokinetic, pharmacodynamic, and safety data in 18 pediatric patients aged 7 through 16 years with thrombocythemia secondary to ET [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
There were no apparent trends or differences in the types of adverse events observed between the pediatric patients compared with those of the adult patients [see Adverse Reactions (6.1)].
Of the 942 subjects in clinical studies of AGRYLIN, 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.
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 AGRYLIN in patients with severe hepatic impairment has not been studied. Avoid use of AGRYLIN in patients with severe hepatic impairment. The potential risks and benefits of AGRYLIN therapy in a patient with mild and moderate hepatic impairment should be assessed before treatment is commenced. Assess hepatic function before and during AGRYLIN treatment [see Warnings and Precautions (5.1)].
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