Argatroban

Heparin-Induced Thrombocytopenia, Percutaneous Coronary Intervention

Intravenous Heparin-Induced Thrombocytopenia Indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia Initial: 2 mcg/kg/min IV continuous infusion over 1-3 hours until steady-state aPTT is 1.5-3 times the initial baseline value Not to exceed infusion rate of 10 mcg/kg/min Check aPTT and adjust the dose until target aPTT is achieved Percutaneous Coronary Intervention Indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI) Initial: 25 mcg/kg/min IV infusion, AND A bolus of 350 mcg/kg IV over 3-5 minutes via a large-bore IV line Check activated clotting time (ACT) 5-10 minutes after the bolus dose is completed; the procedure may proceed if ACT is >300 seconds If ACT is <300 seconds, administer an additional IV bolus dose of 150 mcg/kg, increase the infusion dose to 30 mcg/kg/min, and check ACT 5-10 minutes later If ACT >450 seconds, decrease infusion rate to 15 mcg/kg/min, and check ACT 5-10 minutes later After therapeutic ACT (300-450 sec) is achieved, continue this infusion dose for the duration of the procedure

In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients had increased underlying conditions, which may predispose them to adverse reactions. The studies were not sized appropriately to detect differences in safety between age groups.

Hepatic impairment Approximately a 4-fold decrease in clearance relative to those with normal hepatic function, so dosing modification is warranted; monitor aPTT and adjust dosage as clinically indicated Thrombocytopenia: Decrease initial dose to 0.5 mcg/kg/min IV PCI: For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved; use of the drug in PCI patients with clinically significant hepatic disease or AST/ALT levels >3 times the upper limit of normal should be avoided

IV Preparation 100 mg/mL injectable, dilute to final concentration of 1 mg/mL in NS, D5W, or LR Ready-to-use preparations (1 mg/mL) require no further dilution; vial may be inverted for use with an infusion set IV Administration See adult dosing for infusion rate

History of hypersensitivity to this product, Active major bleeding. Severe hepatic impairment.

Disease states and other circumstances in which there is an increased risk of hemorrhage (e.g. severe HTN, major surgery). Critically ill patients. Moderate hepatic impairment. Children. Pregnancy and lactation. Use caution in hepatic impairment; achievement of steady-state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function; avoid use of high doses in patients undergoing percutaneous coronary intervention (PCI) who have clinically significant hepatic disease. Risk of hemorrhage Hemorrhage can occur at any site in the body Intracranial and retroperitoneal hemorrhage reported Unexplained fall in hematocrit or blood pressure after lumbar puncture, spinal anesthesia, major surgery (especially involving the brain, spinal cord, or eye) associated with hemorrhage; Hematologic conditions may increase risk of hemorrhage, such as congenital or acquired bleeding disorders, and gastrointestinal lesions such as ulcerations Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase risk of bleeding Monitoring Parameters Monitor Hb, hematocrit, signs/symptoms of bleeding; aPTT, ACT. Determine activated partial thromboplastin time 2 hours after the start of treatment, then 2 or 4 hours after infusion rate altered, and at least once daily thereafter.

Not Classi Pregnancy Limited data from published literature and postmarketing reports do not suggest an association between argatroban and adverse fetal developmental outcomes; there are risks to the mother associated with untreated thrombosis in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions; published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy Use of anticoagulants, including argatroban, may increase the risk of bleeding in the fetus and neonate; monitor neonates for bleeding Pregnant women should be carefully monitored for evidence of excessive bleeding or unexpected changes in coagulation parameters during labor or delivery Animal data In animal reproduction studies, there was no evidence of adverse developmental outcomes with intravenous administration of argatroban during organogenesis in rats and rabbits at doses up to 0.3- and 0.2-times, respectively, the maximum recommended human dose (MHRD) Lactation There are no data on the presence in human milk or its effects on milk production; it is present in rat milk; developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from therapy or from the underlying maternal condition

Heparin: Allow sufficient time for heparin’s effect on activated partial thromboplastin time (aPTT) to decrease before initiating Argatroban Injection therapy. Warfarin: Concomitant use results in increased prolongation of PT and INR. Thrombolytic agents or glycoprotein IIb/IIIa antagonists: The safety and effectiveness of concomitant use with argatroban have not been established. Contraindicated (3) defibrotide mifepristone prothrombin complex concentrate, human

>10% GI bleeding (14%) Hematuria (12%) 1-10% Chest pain (1-15%) Hemoglobin and hematocrit decrease (10%) Hypotension (7-10%) Dyspnea (8%) Fever (7%) Sepsis (6%) Cardiac arrest (6%) Diarrhea (6%) Nausea (5%) Groin hemorrhage (5%) Pain (5%) Urinary tract infection (5%) Ventricular tachycardia (5%) Bradyarrhythmia (4.5%) Infection (4%) Vomiting (2.6-4%) Intracranial hemorrhage (1-4%) Myocardial infarction (3.5%) Hemoptysis (3%) Nephrotoxicity (3%) Cough (3%) Atrial fibrillation (3%) Brachial hemorrhage (2%) Major GI hemorrhage (1-2%) Angina (1.8%) Coronary arterial hemorrhage (1.8%) Coronary artery thrombosis (1.8%)

Argatroban is a synthetic direct thrombin inhibitor which reversibly binds to the active thrombin site of free and clot-associated thrombin. It exerts its anticoagulant effects by inhibiting thrombin-catalysed or -induced reactions, e.g. fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.