WARNINGS AND PRECAUTIONS
Risk of Hemorrhage
Hemorrhage can occur at any site in the body in patients receiving argatroban. Unexplained fall in hematocrit or blood pressure may indicate hemorrhage. Intracranial and retroprtiotoneal hemorrahage [see Adverse Reactions (6.2 and 6.3)] have been reported. The risk of hemorrahage with argatroban may be increased in severe hypertension; immediately following lumbar puncture, spinal anesthesia, major surgery (especially involving the brain, spinal cord, or eye), hematologic conditions associated with increased bleeding tendencies 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 the risk of bleeding.
Use in Hepatic Impairment
When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved. 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 [see Use in Specific Populations
]. Also, upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban [see Dosage and Administration and Clinical Pharmacology
]. Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.
Anticoagulation effects associated with Argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT). Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by Argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy. In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring argatroban anticoagulant activity during the procedure. The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone [see Dosage and Administration and Clinical Pharmacology
USE IN SPECIFIC POPULATIONS
Pregnancy Category B
There are no adequate and well-controlled studies of argatroban use in pregnant women. Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
It is not known whether argatroban is excreted in human milk. Argatroban is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were <6 months, n = 8; six months to <8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received argatroban solely as a continuous infusion (no bolus dose). Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min. Dosing was titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during argatroban administration to two patients and following argatroban discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of argatroban therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of argatroban treatment in the study, but experienced an intracranial hemorrhage while receiving argatroban following completion of the study treatment period.
When argatroban is used among seriously ill pediatric patients with HIT/HITTS who require an alternative to heparin and who have normal hepatic function, initiate a continuous infusion of argatroban at a dose of 0.75 mcg/kg/min. Initiate the infusion at a dose of 0.2 mcg/kg/min among seriously ill pediatric patients with impaired hepatic function [see Clinical Pharmacology
]. Check the aPTT two hours after the initiation of the argatroban infusion and adjust the dose to achieve the target aPTT. Increments of 0.1 to 0.25 mcg/kg/min for pediatric patients with normal hepatic function and increments of 0.05 mcg/kg/min or lower for pediatric patients with impaired hepatic function may be considered but dose selection must take into account multiple factors including the current Argatroban dose, the current aPTT, target aPTT, and the clinical status of the patient. These dose recommendations are based upon a goal of aPTT prolongation of 1.5 to 3 times the baseline value and avoidance of an aPTT >100 seconds.
Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over. 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 events. The studies were not sized appropriately to detect differences in safety between age groups.
Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population [see Dosage and Administration, Warning and Precautions, Clinical Pharmacology].