Argatroban is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia.

Argatroban is indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI).

Each 2.5-mL vial contains 250 mg of Argatroban; and, as supplied, is a concentrated drug (100 mg/mL), which must be diluted 100-fold prior to infusion. Argatroban should not be mixed with other drugs prior to dilution in a suitable intravenous fluid.

Preparation for Intravenous Administration: Argatroban should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent. The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5.

Heparin-Induced Thrombocytopenia (HIT/HITTS): Initial Dosage: Before administering Argatroban, discontinue heparin therapy and obtain a baseline aPTT. The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 8).

Table 8. Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban for Patients With HIT/HITTS (Without Hepatic Impairment) (1 mg/mL Final Concentration)

Monitoring Therapy: In general, therapy with Argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of Argatroban. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment: After the initial dose of Argatroban, the dose can be adjusted as clinically indicated (not to exceed 10 mcg/kg/min), until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed 100 seconds) (see Clinical Studies for mean values of aPTT obtained after initial doses of Argatroban).

Percutaneous Coronary Interventions (PCI) in HIT/HITTS Patients: Initial Dosage: An infusion of Argatroban should be started at 25 mcg/kg/min and a bolus of 350 mcg/kg administered via a large bore intravenous (IV) line over 3 to 5 minutes (see Table 9). 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.

Dosage Adjustment: 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 (see Table 9). 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 (see Table 9). Once a therapeutic ACT (between 300 and 450 seconds) has been achieved, this infusion dose should be continued for the duration of the procedure.

Table 9. Recommended Doses and Infusion Rates of Argatroban for Patients Undergoing PCI (Without Hepatic Impairment) (1 mg/mL Final Concentration)

In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min. The ACT should be checked after each additional bolus or change in the rate of infusion.

Monitoring therapy: Therapy with Argatroban is monitored using ACT. ACTs should be obtained before dosing, 5 to 10 minutes after bolus dosing and after change in the infusion rate, and at the end of the PCI procedure. Additional ACTs should be drawn about every 20 to 30 minutes during a prolonged procedure.

Continued Anticoagulation after PCI: If a patient requires anticoagulation after the procedure, Argatroban may be continued, but at a lower infusion dose [see DOSAGE AND ADMINISTRATION, Heparin-Induced Thrombocytopenia (HIT/HITTS)].

Dosing in Special Populations: Hepatic Impairment: For adult patients with heparin-induced thrombocytopenia with hepatic impairment, the initial dose of Argatroban should be reduced. For adult patients with moderate hepatic impairment, an initial dose of 0.5 mcg/kg/min is recommended, based on the approximate 4-fold decrease in Argatroban clearance relative to those with normal hepatic function. The aPTT should be monitored closely, and the dosage should be adjusted as clinically indicated (see PRECAUTIONS).

Hepatic Impairment in HIT/HITTS Patients Undergoing PCI: Carefully titrate Argatroban until the desired level of anticoagulation is achieved (see PRECAUTIONS, Hepatic Impairment).

Renal Impairment: No dosage adjustment is necessary in patients with renal impairment (see SPECIAL POPULATIONS, Renal Impairment).

Pediatric HIT/HITTS Patients: Initial Argatroban infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function (see PRECAUTIONS, Pediatric Use).

Monitoring Therapy: In general, therapy with Argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of Argatroban in patients without hepatic impairment (see PRECAUTIONS, Hepatic Impairment). Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

Dosage Adjustment: See PRECAUTIONS, Pediatric Use.

Conversion To Oral Anticoagulant Therapy

Initiating Oral Anticoagulant Therapy: Once the decision is made to initiate oral anticoagulant therapy, recognize the potential for combined effects on INR with co-administration of Argatroban and warfarin. A loading dose of warfarin should not be used. Initiate therapy using the expected daily dose of warfarin. To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that Argatroban and warfarin therapy be overlapped. There are insufficient data available to recommend the duration of the overlap.

Co-Administration of Warfarin and Argatroban at Doses Up to 2 mcg/kg/min: Use of Argatroban with warfarin results in prolongation of INR beyond that produced by warfarin alone. To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that warfarin be co-administered before discontinuing Argatroban. There are insufficient data available to recommend the duration of the co-administration. The previously established relationship between INR and bleeding risk is altered. The combination of Argatroban and warfarin does not cause further reduction in the vitamin K–dependent factor Xa activity than that which is seen with warfarin alone. The relationship between INR obtained on combined therapy and INR obtained on warfarin alone is dependent on both the dose of Argatroban and the thromboplastin reagent used. The INR value on warfarin alone (INRW) can be calculated from the INR value on combination Argatroban and warfarin therapy (see CLINICAL PHARMACOLOGY, Figure 2 explanation and PRECAUTIONS: DRUG INTERACTIONS).

INR should be measured daily while Argatroban and warfarin are co-administered. In general, with doses of Argatroban up to 2 mcg/kg/min, Argatroban can be discontinued when the INR is > 4 on combined therapy. After Argatroban is discontinued, repeat the INR measurement in 4 to 6 hours. 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.

Co-Administration of Warfarin and Argatroban at Doses Greater than 2 mcg/kg/min: For doses greater than 2 mcg/kg/min, the relationship of INR between 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.

Stability/Compatibility

Argatroban is a clear, colorless to pale yellow, slightly viscous solution. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.

Solutions prepared as recommended are stable at 25°C (77°F), with excursions permitted to 15° to 30°C (59° to 86°F) in ambient indoor light for 24 hours; therefore, light-resistant measures such as foil protection for intravenous lines are unnecessary. Solutions are physically and chemically stable for up to 96 hours when protected from light and stored at controlled room temperature, 20° to 25°C (68° to 77°F) (see USP), or at refrigerated conditions, 5° ± 3°C (41°± 5°F). Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

Argatroban Injection is supplied in 2.5-mL solution in single-use vials at the concentration of 100 mg/mL. Each vial contains 250 mg of Argatroban.

NDC 0007-4407-01 (Package of 1)

Storage: Store the vials in original cartons at room temperature [25°C (77°F), with excursions permitted to 15° to 30°C (59° to 86°F)]. Do not freeze. Retain in the original carton to protect from light.

Manufactured by: GlaxoSmithKline, Research Triangle Park, NC 27709 for Encysive Pharmaceuticals Inc., Houston, TX 77081. FDA revision date: 5/5/2008

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