AGRYLIN (anagrelide hydrochloride) is a platelet-reducing agent. Its chemical name is 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2(3H)-one monohydrochloride monohydrate. The molecular formula is C 10 H 7 Cl 2 N 3 O∙HCl∙H 2 O which corresponds to a molecular weight of 310.55. The structural formula is: Anagrelide hydrochloride is an off-white powder. It is very slightly soluble in water and sparingly soluble in dimethyl sulfoxide and dimethylformamide. AGRYLIN is supplied as capsules for oral administration, containing 0.5 mg of anagrelide (equivalent to 0.61 mg of anagrelide hydrochloride USP). The capsules also contain anhydrous lactose NF, crospovidone NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, and povidone NF as inactive ingredients. The capsule shell contains gelatin, titanium dioxide, and black iron oxide. chemical structure

AGRYLIN is indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events. AGRYLIN is a platelet reducing agent indicated for the treatment of thrombocythemia, secondary to myeloproliferative neoplasms, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.

Capsules: White, opaque capsule, imprinted with " 063" in black ink. Each capsule contains 0.5 mg anagrelide equivalent to 0.61 mg anagrelide hydrochloride USP. Capsules: 0.5 mg. Imprint

The starting dose for adults is 0.5 mg four times a day or 1 mg twice a day. The starting dose for pediatric patients is 0.5 mg per day. Maintain the starting dose for at least one week and then titrate to maintain target platelet counts. Do not exceed a dose increment of 0.5 mg/day in any one week. Do not exceed 10 mg/day or 2.5 mg in a single dose. Moderate hepatic impairment: Start with 0.5 mg per day

Recommended Starting Dosage Adults: The recommended starting dosage of AGRYLIN is 0.5 mg four times daily or 1 mg twice daily. Pediatric Patients: The recommended starting dosage of AGRYLIN is 0.5 mg daily

Dose Titration Based Upon Platelet Response Continue the starting dose for at least one week and then titrate to reduce and maintain the platelet count below 600,000/µL, and ideally between 150,000/µL and 400,000/µL. The dose increment should not exceed 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose. Most patients will experience an adequate response at a dose of 1.5 to 3.0 mg/day. Monitor platelet counts weekly during titration then monthly or as necessary

Dose Modifications for Hepatic Impairment In patients with moderate hepatic impairment (Child Pugh score 7-9) start AGRYLIN therapy at a dose of 0.5 mg/day and monitor frequently for cardiovascular events . Patients with moderate hepatic impairment who have tolerated AGRYLIN therapy for one week may have their dose increased. The dose increase increment should not exceed 0.5 mg/day in any one week. Avoid use of AGRYLIN in patients with severe hepatic impairment

Clinical Monitoring AGRYLIN therapy requires clinical monitoring, including complete blood counts, assessment of hepatic and renal function, and electrolytes. To prevent the occurrence of thrombocytopenia, monitor platelet counts every two days during the first week of treatment and at least weekly thereafter until the maintenance dosage is reached. Typically, platelet counts begin to respond within 7 to 14 days at the proper dosage. In the clinical trials, the time to complete response, defined as platelet count ≤600,000/µL, ranged from 4 to 12 weeks. In the event of dosage interruption or treatment withdrawal, the rebound in platelet count is variable, but platelet counts typically will start to rise within 4 days and return to baseline levels in one to two weeks, possibly rebounding above baseline values. Monitor platelet counts frequently.

Cardiovascular Toxicity: QT prolongation and ventricular tachycardia have been reported with AGRYLIN. Obtain a pre-treatment cardiovascular examination including an ECG in all patients. Monitor patients for cardiovascular effects. Pulmonary Hypertension: Assess underlying cardiopulmonary disease prior to initiating therapy. Bleeding Risk: Monitor patients for bleeding, including those receiving concomitant therapy with other drugs known to cause bleeding. 5.1 Cardiovascular Toxicity 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 ] . 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 . 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 . 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 . In patients with cardiac disease, use AGRYLIN only when the benefits outweigh the risks

Pulmonary Hypertension 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

Bleeding Risk 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)

Pulmonary Toxicity 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 .

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

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)

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)

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 . 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 . 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)

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).