Drug class: Direct Thrombin Inhibitors

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Anticoagulant; synthetic piperidinecarboxylic acid derivative of l-arginine that acts as a direct thrombin inhibitor.

Uses for Argatroban

Heparin-induced Thrombocytopenia (HIT)

Prevention and treatment of thrombosis in patients with HIT.

In patients with acute HIT or HIT and thrombosis syndrome (HITTS), all forms of heparin (e.g., unfractionated heparin, low molecular weight heparin [LMWH]) should be discontinued and a nonheparin anticoagulant initiated.

The American College of Chest Physicians (ACCP) and American Society of Hematology (ASH) suggest argatroban as one of several nonheparin anticoagulants that can be used in these patients.

Drug- and patient-related factors (e.g., availability, cost, ability to monitor anticoagulant effect, route of administration, kidney function, liver function, bleeding risk) should be considered when selecting an appropriate agent.

Not FDA-labeled for use in pediatric patients^{† [off-label]}; however the drug has been used in a limited number of seriously ill pediatric patients with HIT/HITTS.

HIT in Patients Undergoing Percutaneous Coronary Intervention (PCI)

Used as an anticoagulant in patients with or at risk of HIT undergoing PCI.

Experts generally suggest the use of bivalirudin or argatroban in patients with HIT undergoing PCI; factors such as availability, cost, experience, and ease of monitoring may influence choice of drug.

Argatroban Dosage and Administration

General

Laboratory Monitoring

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

• 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).

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

Converting to Warfarin Therapy

• Initiate warfarin therapy only after substantial recovery from acute HIT has occurred (i.e., platelet counts ≥150,000/mm³ and are stable) with argatroban therapy.

• Initiate oral anticoagulation therapy using the expected daily dosage of warfarin; a loading dose should not be used.

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

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

• Generally, discontinue argatroban infusion (2 mcg/kg per minute) when the INR on combined warfarin-argatroban therapy (INR_WA) is >4. 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. If infusion rate is >2 mcg/kg per minute, temporarily reduce rate to 2 mcg/kg per minute and calculate INR_WA 4–6 hours later.

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

Converting to Direct Oral Anticoagulant Therapy

• Dabigatran: start dabigatran at the time of discontinuance of the parenteral anticoagulant.

• Apixaban: start apixaban at the time of next dose of parenteral anticoagulant; no specific recommendation given for parenteral anticoagulants administered by continuous IV infusion.

• Rivaroxaban: no specific recommendation for argatroban. Recommendations given for other continuous infusion anticoagulants (e.g., unfractionated heparin) are to discontinue the infusion and start rivaroxaban at the same time.

• Edoxaban: no specific recommendation for argatroban. Recommendations given for other continuous infusion anticoagulants (e.g., unfractionated heparin) are to discontinue the infusion and start edoxaban 4 hours later.

Administration

IV Administration

Administer by continuous IV infusion.

Commercially available as a 100-mg/mL injection concentrate that must be diluted prior to use; also available as 1-mg/mL ready-to-use preparations.

Dilution

The commercially available 100-mg/mL injection concentration must be diluted 100-fold 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. Mix by repeated inversion of the IV container for 1 minute. Solution may be slightly hazy just after preparation because of the formation of microprecipitates that rapidly dissolve upon further mixing.

The commercially available 1-mg/mL ready-to-use preparations do not require dilution; the vials may be inverted for use with a medical infusion set.

Standardize 4 Safety

Standardized concentrations for argatroban have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. Because recommendations from the S4S panels may differ from the manufacturer’s prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. For additional information, see [Web].

Dosing units differ from concentration units

Dosage

Pediatric Patients

HIT/HITTS

IV

Not FDA-labeled for use in pediatric patients^{† [off-label]}; however, limited data are used to inform the following dosage recommendations.

Pediatric patients without hepatic impairment: 0.75 mcg/kg per minute by continuous infusion. Adjust infusion rate as clinically indicated to achieve desired aPTT. Adjust subsequent dosage in increments of 0.1–0.25 mcg/kg per minute.

Pediatric patients with hepatic impairment: 0.2 mcg/kg per minute by continuous infusion. Adjust infusion rate as clinically indicated to achieve desired aPTT. Adjust subsequent dosage in increments of ≤0.05 mcg/kg per minute.

Adults

HIT/HITTS

IV

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

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. Some experts recommend lower initial dosages (200 mcg/kg by slow IV injection followed by continuous IV infusion at 15 mcg/kg per minute) in patients who have received prior anticoagulant therapy.

If ACT <300 seconds, give IV loading dose of 150 mcg/kg and increase infusion rate to 30 mcg/kg per minute.

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

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

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

Prescribing Limits

Adults

HIT/HITTS

IV

Manufacturer states not to exceed 10 mcg/kg per minute.

Special Populations

Hepatic Impairment

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

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

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

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.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No dosage adjustment required.

Critically Ill Patients

For the treatment of HIT/HITTS, ACCP suggests reduced initial IV infusion rate of 0.5–1.2 mcg/kg per minute in patients with heart failure, multiple organ system failure, or severe anasarca, and for patients following cardiac surgery due to increased risk of bleeding.

Obese Patients

Manufacturer makes no recommendations. Limited data suggest using actual body weight.

Cautions for Argatroban

Contraindications

• Major bleeding.

• Known hypersensitivity to argatroban or any ingredient in the formulation.

Warnings/Precautions

Warnings

Bleeding

Use with extreme caution in disease states or circumstances associated with increased risk of hemorrhage (e.g., severe hypertension; post-lumbar puncture; spinal anesthesia; major surgery, particularly of the brain, spinal cord, or eye; GI ulceration; congenital or acquired bleeding disorders).

Discontinue all parenteral anticoagulants and obtain a baseline aPTT before initiation of argatroban in patients with HIT/HITTS.

Unexplained decreases in hematocrit, hemoglobin, or BP may indicate hemorrhage.

In the event of overdose or excessive anticoagulation, discontinue or reduce dose of argatroban and monitor aPTT and other coagulation tests (PT, INR). Reversal of anticoagulation may be prolonged in patients with hepatic impairment. No specific antidote is currently available.

Laboratory Monitoring

Anticoagulant effects of argatroban correlate with increases in aPTT; while the drug can also prolong PT, INR, and thrombin time (TT), therapeutic ranges for these tests have not been identified.

Specific Populations

Pregnancy

Available data do not support association between argatroban and adverse fetal outcomes.

Lactation

Distributed into milk in rats. Unknown whether distributed into human milk.

Pediatric Use

Safety and efficacy not established in pediatric patients.

The drug has been evaluated in a limited number of seriously ill pediatric patients <16 years of age with HIT or HITTS. Decreased clearance observed.

Geriatric Use

No substantial differences in efficacy relative to younger adults.

Hepatic Impairment

Decreased clearance; use with caution. Dosage reduction and careful monitoring of the aPTT required.

Common Adverse Effects

Dyspnea, hypotension, fever, diarrhea, sepsis, cardiac arrest, chest pain, back pain, nausea, vomiting, headache.

Drug Interactions

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

Specific Drugs

Argatroban Pharmacokinetics

Absorption

Onset

Immediate anticoagulant effect. Steady-state anticoagulant effect achieved 1–3 hours after start of infusion.

Duration

The aPTT generally returns to normal within 2–4 hours following discontinuance of infusion.

Special Populations

In patients with hepatic impairment, reversal of anticoagulant effect may take >4 hours.

Distribution

Extent

Mainly in extracellular fluid as evidenced by apparent steady-state volume of distribution of 174 mL/kg. Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

54% (20% to albumin and 34% to α₁-acid glycoprotein).

Elimination

Metabolism

Mainly hepatic hydroxylation and aromatization. CYP isoenzymes 3A4/5 catalyze the formation of metabolites in vitro; CYP3A4/5-mediated metabolism not an important elimination pathway in vivo.

Elimination Route

Excreted primarily in feces (65%), presumably through biliary secretion. Also eliminated in urine (22%). Partially (20%) removed by hemodialysis.

Half-life

Terminal half-life 39–51 minutes.

Special Populations

Hepatic impairment associated with decreased clearance and increased elimination half-life (to 1.9 mL/kg per minute and 181 minutes, respectively, in patients with Child-Pugh score >6). Clearance is decreased fourfold in patients with HIT and moderate hepatic impairment.

No appreciable effects of gender on the pharmacokinetics or pharmacodynamics of argatroban.

In seriously ill pediatric patients, clearance was reduced by 50%. Clearance was reduced approximately 80% in pediatric patients with elevated bilirubin concentrations compared with pediatric patients with normal concentrations.

Stability

Storage

Parenteral

Injection Concentrate

Commercially available concentrated 100-mg/mL injection in vial: 20–25°C in original carton to protect from light. Do not freeze. Discard unused vial if solution is cloudy or if an insoluble precipitate is formed.

After dilution to 1-mg/mL final concentration for administration: 20–25°C in ambient indoor light for 24 hours. When protected from light, diluted solutions are stable for 96 hours at 20–25°C or under refrigeration (2–8°C). Do not expose diluted solutions to direct sunlight.

Diluted solutions may be slightly but transiently hazy just after preparation because of the formation of microprecipitates that rapidly dissolve upon further mixing.

Ready-to-use Injection

Commercially available ready-to-use 1-mg/mL injection in vial: 20–25°C in original carton to protect from light. Do not freeze. Discard unused vial if solution is cloudy or if an insoluble precipitate is formed.

Actions

• Synthetic piperidinecarboxylic acid derivative of l-arginine.

• Selective, reversible, small-molecule direct thrombin inhibitor that binds to circulating and clot-bound thrombin. 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).

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

• Does not appear to induce antibody formation or interact with heparin-induced antibodies.

Advice to Patients

• Importance of reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinician immediately.

• Importance of patients informing clinician of history of bleeding disorders.

• Importance of reporting signs of allergic reactions (e.g., airway reactions, skin reactions, vasodilation reactions).

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants) and OTC drugs.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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