Usual Adult Dose for Thrombotic/Thromboembolic Disorder

Heparin-induced thrombocytopenic (HIT) thrombosis treatment or prophylaxis:
Initial: 2 mcg/kg/min administered as a constant infusion. Begin infusion only after obtaining a baseline activated partial thromboplastin time (aPTT).
Maintenance: The infusion rate may be adjusted as needed (not to exceed 10 mcg/kg/min) until the steady state aPTT value is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Dosage adjustments should be based on aPTT results from blood samples obtained at least 2 hours after the most recent infusion rate change.

Percutaneous Coronary Interventions (PCI) in HIT/HITTS patients:
Initial: 25 mcg/kg/min infusion and a bolus of 350 mcg/kg administered via a large bore intravenous line over 3 to 5 minutes. Activated clotting time (ACT) should be checked 5 to 10 minutes after the bolus dose is completed. The procedure may proceed if the ACT is greater than 300 seconds.
If the ACT is less than 300 seconds, an additional IV bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later. If the ACT is greater than 450 seconds, the infusion rate should be decreased to 15 mcg/kg/min, and the ACT checked 5 to 10 minutes later. Once a therapeutic ACT (between 300 and 450 seconds) has been achieved, this infusion dose should be continued for the duration of the procedure.

Usual Pediatric Dose for Thrombotic/Thromboembolic Disorder

Infants and Children 16 years or younger: The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients.

Note: Limited data available; dosing regimens not established. Titration of maintenance dose must consider multiple factors including current argatroban dose, current aPTT, target aPTT, and clinical status of the patient. For specific uses, required maintenance dose is highly variable between patients. Additionally, during the course of treatment, patient's dosing requirements may change as clinical status changes (e.g., sicker patients require lower dose); frequent dosage adjustments may be required to maintain desired anticoagulant activity. If argatroban therapy is used concurrently with or following FFP or a thrombolytic, some centers decrease dose by half.

Heparin-induced thrombocytopenia:
Initial dose: 0.75 mcg/kg/minute by continuous IV infusion
Maintenance dose: Measure aPTT after 2 hours; adjust dose until the steady-state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; adjust in increments of 0.1 to 0.25 mcg/kg/minute for normal hepatic function; reduce dose in hepatic impairment (see liver dose adjustment).
Note: A lower initial infusion rate may be needed in other pediatric patients with reduced clearance of argatroban (e.g., patients with heart failure, multiple organ system failure, severe anasarca, or postcardiac surgery). This precaution is based on adult studies of patients with these disease states who had reduced argatroban clearance.

Renal Dose Adjustments

No adjustment recommended

Liver Dose Adjustments

Moderately impaired hepatic function:
Initial: 0.5 mcg/kg/min administered as a constant infusion.

Maintenance: The infusion rate may be adjusted as needed (not to exceed 10 mcg/kg/min) until the steady state aPTT value is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Dosage adjustments should be based on aPTT results from blood samples obtained at least 2 hours after the most recent infusion rate change.

Infants and children 16 years or younger:
Note: Limited data available; dosing regimens not established.
Initial dose: 0.2 mcg/kg/minute
Maintenance dose: Measure aPTT after 2 hours; adjust dose until the steady-state aPTT is 1.5 to 3 times the initial baseline value, not exceeding 100 seconds; adjust in increments of not greater than 0.05 mcg/kg/minute.

Dose Adjustments

When initiating the conversion from argatroban to oral warfarin therapy, the effect of argatroban on the International Normalized Ratio (INR) must be acknowledged to accurately determine the appropriate warfarin dose. Since argatroban influences the INR, no loading dose of warfarin should be administered. Warfarin therapy should be initiated at the expected daily dose and should begin before the argatroban infusion has been discontinued. In general, with doses of argatroban up to 2 mcg/kg/min, argatroban may be discontinued once the INR is greater than 4 while the patient is receiving combination therapy. After argatroban is discontinued, a repeat INR should be obtained 4 to 6 hours after stopping the infusion. If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

For doses greater than 2 mcg/kg/min, the relationship of INR on warfarin alone to the INR on warfarin plus argatroban is less predictable. In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of argatroban to a dose of 2 mcg/kg/min. Repeat the INR on argatroban and warfarin 4 to 6 hours after reduction of the argatroban dose and follow the process outlined above for administering argatroban at doses up to 2 mcg/kg/min.

A smaller initial dose (0.2 mcg/kg/min), to achieve a target aPTT of 1.5 to 2 times the baseline value, than recommended by the manufacturer has been suggested for critically ill patients with multiple organ dysfunction at risk for heparin-induced thrombocytopenia. The authors of this study state that the lower initial dose provides sufficient anticoagulation without bleeding complications (i.e., excessive anticoagulation, overt bleeding) in this patient population.

According to pharmacokinetic studies, no dosage adjustment is necessary based on age, gender, or race.

The results of a retrospective analysis indicate that actual body weight-adjusted argatroban dosing is safe and effective in obese patients and that adjustment of the initial dose is unnecessary in obesity.

Precautions

Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.

In patients with moderate hepatic dysfunction (Child-Pugh score greater than 6), hepatic dysfunction was associated with about a 4-fold decrease in systemic clearance and a 3-fold increase in elimination half-life of argatroban.

Dialysis

When argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to and during a 4-hour hemodialysis session, approximately 20% was cleared through dialysis.

A retrospective analysis and case reports indicate that patients with HIT and renal failure requiring renal replacement therapy and undergo hemodialysis or continuous venovenous hemofiltration, no dosing adjustment is necessary. However, careful monitoring of aPTT is suggested.

Other Comments

Activated partial thromboplastin time (aPTT) should be obtained 2 hours after the start of treatment and after each dosage adjustment. Dosing is usually titrated to maintain an aPTT of 1.5 to 3 times baseline, but not exceeding 100 seconds.

Following cessation of argatroban therapy in patients with normal renal and hepatic function, full reversal of anticoagulation occurs within 2 to 4 hours; however, in patients with hepatic dysfunction, full reversal of anticoagulation may require at least 6 hours to achieve.

In a case series, argatroban was successfully used to treat patients with HIT and an elevated aPTT due to antiphospholipid antibody syndrome. Since aPTT monitoring is of uncertain reliability in this patient population, an alternative means of monitoring argatroban, such as ecarin clotting time and thrombin inhibitor management testing, has been suggested.