Argatroban

Name: Argatroban

Uses of Argatroban

Argatroban is a prescription medication used to treat or prevent a blood clot in patients with a specific condition called heparin-induced thrombocytopenia (HIT). HIT is a complication of treatment with a blood thinner called heparin that puts patients at a high risk for a blood clot.

Argatroban is also used to prevent blood clots in adult patients with or at risk for HIT who are undergoing a percutaneous coronary intervention (PCI), which is a procedure to open up narrowed or blocked blood vessels that supply blood to the heart.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Argatroban Brand Names

Argatroban may be found in some form under the following brand names:

  • Acova

Argatroban Drug Class

Argatroban is part of the drug class:

  • Direct thrombin inhibitors

What is the most important information I should know about argatroban?

You should not use this medicine if you have any major bleeding from a surgery, injury, or other medical trauma.

Tell your doctor if you are using or receiving blood thinners or any other medications used to treat or prevent blood clots.

Argatroban can make it easier for you to bleed, even from a minor injury.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while receiving argatroban?

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Avoid drinking alcohol. It may increase your risk of bleeding in your stomach or intestines.

Argatroban dosing information

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.

Argatroban Dosage and Administration

General

Laboratory Monitoring

  • Discontinue all parenteral anticoagulants and obtain a baseline aPTT before initiation of therapy.1 9

  • Determine aPTT 2 hours after initiation of infusion and/or dosage adjustment to confirm achievement of a target aPTT of 1.5–3 times the initial baseline aPTT (not to exceed 100 seconds).1 6

  • Monitor therapy prior to and during PCI using the activated clotting time (ACT).1 Determine ACT 5–10 minutes after infusion of the loading dose.1 Initiate the PCI procedure once an ACT of >300 seconds (target range ACT 300–450 seconds) has been achieved, and continue the infusion for the duration of the procedure.1 Determine additional ACT values every 20–30 minutes during a prolonged procedure.1 Determine the ACT values 5–10 minutes after each additional direct injection or change in the infusion rate, and at the completion of the procedure.1

Converting to Oral Anticoagulant Therapy

  • Initiate warfarin therapy only after a substantial recovery from acute HIT has occurred (i.e., as indicated by platelet counts that have increased to ≥150,000/mm3 and are stable) with argatroban therapy.1 16 1006

  • Initiate oral anticoagulation therapy using modest dosages of warfarin (2.5–5 mg, maximum of 5 mg); a loading dose should not be used.1 9 16

  • Monitor aPTT/INR during concomitant argatroban and warfarin therapy.1 6

  • Overlap argatroban and warfarin therapy to avoid prothrombotic effects and ensure continuous anticoagulation.1

  • Generally, discontinue argatroban infusion (2 mcg/kg per minute) when the INR on combined warfarin-argatroban therapy (INRWA) is >4.1 Determine INR 4–6 hours after discontinuance of the argatroban infusion; if it is not within the desired therapeutic range for warfarin, resume argatroban infusion.1 16 If infusion rate is >2 mcg/kg per minute, temporarily reduce rate to 2 mcg/kg per minute and calculate INRWA 4–6 hours later.1

  • Consult manufacturer’s labeling for detailed information regarding calculation of INR on warfarin alone and conversion from warfarin–argatroban to warfarin alone.1

Administration

IV Administration

Administer by continuous IV infusion.1

For solution and drug compatibility information, see Compatibility under Stability.

Dilution

Must be diluted prior to administration in 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to a final concentration of 1 mg/mL.1 Mix by repeated inversion of the IV container for 1 minute.1 Solution may be slightly hazy just after preparation because of the formation of microprecipitates that rapidly dissolve upon further mixing.1

Dosage

Pediatric Patients

HIT IV

Initially, 0.75 mcg/kg per minute by continuous infusion.1 9 Adjust infusion rate as clinically indicated to achieve desired aPTT.1 9 Adjust subsequent dosage in increments of 0.1–0.25 mcg/kg per minute.1 9

Adults

HIT IV

Initially, 2 mcg/kg per minute by continuous infusion.1 3 6 9 Adjust infusion rate as clinically indicated to achieve desired aPTT.1 9

HIT in Patients Undergoing PCI IV

Initially, administer loading dose of 350 mcg/kg by slow IV injection (over 3–5 minutes) followed by continuous IV infusion at 25 mcg/kg per minute.1 10 If an ACT value is <300 seconds, give IV loading dose of 150 mcg/kg and increase infusion rate to 30 mcg/kg per minute.1

If an ACT value is >450 seconds, decrease infusion rate to 15 mcg/kg per minute.1

If dissection, impending abrupt closure, or thrombus of the coronary artery occurs during the procedure, or if an ACT >300 seconds cannot be maintained, give 150 mcg/kg by direct IV injection and increase infusion rate to 40 mcg/kg per minute.1

If a patient requires anticoagulation after the procedure, decrease the infusion rate to that used in nonsurgical patients (2 mcg/kg per minute).1

Prescribing Limits

Adults

HIT IV

Maximum 10 mcg/kg per minute.1 9

HIT in Patients Undergoing PCI IV

Maximum 40 mcg/kg per minute.1

Special Populations

Hepatic Impairment

Decreased clearance; use with caution, reduce initial dosage, and titrate carefully.1

Patients with hepatic impairment may require a longer time and more dosage adjustments to achieve steady-state aPTT concentrations.1

In pediatric patients with HIT and hepatic impairment, administer 0.2 mcg/kg per minute by continuous infusion initially.1 9 Adjust infusion rate as clinically indicated to achieve desired aPTT.1 9 Adjust subsequent dosage in increments of ≤0.05 mcg/kg per minute.1 9

In adults with HIT and moderate hepatic impairment, administer 0.5 mcg/kg per minute initially.1 3 Carefully monitor aPTT and adjust dosage as clinically indicated.1

Avoid high dosages in patients undergoing PCI who have clinically important hepatic disease or serum AST/ALT concentrations ≥3 times the ULN; such patients not studied in clinical trials.1

Renal Impairment

No dosage adjustment required.1 3 9

Geriatric Patients

No dosage adjustment required.1 3 9

Interactions for Argatroban

Metabolized by CYP isoenzymes 3A4/5 in vitro; CYP3A4/5-mediated metabolism not an important elimination pathway in vivo.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Interaction unlikely1

Anticoagulants, other

Increased risk of bleeding1

Aspirin

Increased risk of bleeding1

No observed pharmacokinetic or pharmacodynamic interaction with low-dose aspirin prior to argatroban infusion1

Digoxin

Interaction unlikely1

Erythromycin

Pharmacokinetic interactions unlikely1

Glycoprotein IIb/IIIa receptor inhibitors

Increased risk of bleeding1

Safety and efficacy of concomitant therapy not established1

Heparin

Increased risk of bleeding1

Contraindicated in patients with HIT; unlikely to be used concomitantly1

Delay initiation of argatroban to allow sufficient time for anticoagulant effects of heparin to dissipate (check aPTT)1

Thrombolytic agents

Increased risk of bleeding, including intracranial hemorrhage1

Warfarin

Prolongation of PT/INR; skin and limb necrosis or gangrene observed1 16

Pharmacokinetic interaction unlikely1

Overlap warfarin and argatroban therapy and closely monitor INR during transition to warfarin monotherapy1 16 (See Converting to Oral Anticoagulant Therapy under Dosage and Administration)

Actions

  • Selective, reversible, small-molecule direct thrombin inhibitor that binds to circulating and clot-bound thrombin.1 2 3 5 6 Inhibition of thrombin prevents various steps in the coagulation process (e.g., activation of factors V, VIII, and XIII and of protein C; conversion of fibrinogen to fibrin; platelet activation and aggregation).1 2

  • Prolongs ACT, aPTT, thrombin time (TT), and PT.1

    Does not appear to induce antibody formation or interact with heparin-induced antibodies.1 3 5 9

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with Argatroban have not been performed.

Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte, and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.

Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

Onset of Action

Immediate

Time to Peak

Steady-state: 1 to 3 hours

Half-Life Elimination

39 to 51 minutes; Hepatic impairment: 181 minutes

Protein Binding

Albumin: 20%; alpha1-acid glycoprotein: 34%

Contraindications

Hypersensitivity to argatroban or any component of the formulation; major bleeding

Storage

Vials, 2.5 mL (100 mg/mL) concentrate: Prior to use, store vial in original carton at 20°C to 25°C (68°F to 77°F); excursions permitted to 15ºC to 30ºC (59ºF to 86°F). Do not freeze. Protect from light. The prepared solution, diluted in D5W, LR, or NS, is stable for 24 hours at 20°C to 25°C (68°F to 77°F) in ambient indoor light. Do not expose prepared solutions to direct sunlight. Prepared solutions that are protected from light and kept at 20°C to 25°C (68°F to 77°F) or under refrigeration at 2°C to 8°C (36°F to 46°F) are stable for up to 96 hours.

Premixed vials (50 mL or 125 mL) and single-use bags for infusion (1 mg/mL): Store at 20°C to 25°C (68°F to 77°F). Do not refrigerate or freeze. Protect from light.

Test Interactions

Argatroban may elevate PT/INR levels in the absence of warfarin. If warfarin is started, initial PT/INR goals while on argatroban may require modification. The American College of Chest Physicians suggests monitoring chromogenic factor X assay when transitioning from argatroban to warfarin (Garcia, 2012) or overlapping administration of warfarin for a minimum of 5 days until INR is within target range; recheck INR after anticoagulant effect of argatroban has dissipated (Guyatt, 2012). Factor Xa levels <45% have been associated with INR values >2 after the effects of argatroban have been eliminated (Arpino, 2005).

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