Argatroban

Pronunciation

Class: Direct Thrombin Inhibitors
VA Class: BL110
Chemical Name: 1 - [5 - [(aminoiminomethyl)amino] - 1 - oxo - 2 - [[(1,2,3,4 - tetrahydro - 3 - methyl - 8 - quinolinyl)sulfonyl]amino]pentyl] - 4 - methyl - 2 - piperidinecarboxylic acid monohydrate
CAS Number: 141396-28-3

Introduction

Anticoagulant; synthetic piperidinecarboxylic acid derivative of l-arginine.1 2 3 6

Uses for Argatroban

Thrombosis Associated with Heparin-induced Thrombocytopenia (HIT)

Prevention and treatment of thrombosis in patients with HIT.1 2 3 4 5 6 7 8 9 1006

The American College of Chest Physicians (ACCP) recommends use of a nonheparin anticoagulant (e.g., lepirudin, argatroban) as an alternative to further use of heparin (referring throughout this monograph to unfractionated heparin)or a low molecular weight heparin (LMWH) or the initiation/continuation of warfarin for initial management of patients with HIT with or without thrombosis.1006

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HIT in Patients Undergoing PCI

Used in patients undergoing PCI, including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, and atherectomy, who have or are at risk for HIT.1 2 3 4 5 10 11 20 994 1006

All patients in clinical trials received oral aspirin (325 mg) prior to PCI.1

Experts recommend use of bivalirudin or argatroban as a substitute for heparin or an LMWH in patients with HIT undergoing PCI.994 1006

Acute Coronary Syndromes (ACS)

Although argatroban has been used concomitantly with aspirin as an adjunct to thrombolysis in patients with ACS,2 3 4 5 9 the American College of Cardiology Foundation and AHA state that monovalent direct thrombin inhibitors such as argatroban are ineffective antithrombotic agents compared with heparin in patients with ACS, and therefore do not recommend their use.991

Manufacturer states that safety and efficacy of argatroban for cardiac indications other than PCI in patients with HIT not established.1 9

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

Cautions for Argatroban

Contraindications

  • Active major bleeding.1

  • Known hypersensitivity to argatroban or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hematologic Effects

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).1

Discontinue all parenteral anticoagulants and obtain a baseline aPTT before initiation of argatroban.1

Unexplained decreases in hematocrit, hemoglobin, or BP may indicate hemorrhage.1

Sensitivity Reactions

Documented or suspected sensitivity reactions (e.g., coughing, dyspnea, rash, bullous eruption, vasodilation) reported in up to 15% of patients receiving argatroban for indications other than HIT or heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) who usually were receiving concomitant thrombolytic agents or radiographic contrast media.1 2 3

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not fully established in pediatric patients.1

The drug has been evaluated in a limited number of seriously ill pediatric patients <16 years of age with HIT or HITTS.1 9 Decreased clearance; reduced dosages recommended in such patients.1 9 (See Dosage under Dosage and Administration.)

Geriatric Use

No substantial differences in efficacy relative to younger adults.1

Hepatic Impairment

Decreased clearance; use with caution.1 Dosage reduction and careful monitoring of the aPTT required.1 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Hemorrhagic events (e.g., minor GI or GU bleeding, hematuria, decreased hemoglobin/hematocrit, bleeding at femoral catheter insertion site [groin]), dyspnea, hypotension, fever, diarrhea, sepsis, cardiac arrest, nausea, ventricular tachycardia, pain, urinary tract infection, vomiting.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)

Argatroban Pharmacokinetics

Absorption

Onset

Immediate anticoagulant effect.1 Steady-state anticoagulant effect achieved 1–3 hours after start of infusion.1 3 6 9

Duration

The aPTT generally returns to normal within 2–4 hours following discontinuance of infusion.1 3

Special Populations

In patients with hepatic impairment, reversal of anticoagulant effect may take >4 hours.1

Distribution

Extent

Mainly in extracellular fluid as evidenced by apparent steady-state volume of distribution of 174 mL/kg.1 21 Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

54% (20% to albumin and 34% to α1-acid glycoprotein).1

Elimination

Metabolism

Mainly hepatic hydroxylation and aromatization.1 CYP isoenzymes 3A4/5 catalyze the formation of metabolites in vitro; CYP3A4/5-mediated metabolism not an important elimination pathway in vivo.1

Elimination Route

Excreted primarily in feces (65%), presumably through biliary secretion.1 Also eliminated in urine (22%).1 Partially removed by hemodialysis.1

Half-life

Terminal half-life 39–51 minutes.1 2

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).1 21 Clearance is decreased fourfold in patients with HIT and moderate hepatic impairment.1 3 (See Hepatic Impairment under Cautions.)

No appreciable effects of gender on the pharmacokinetics or pharmacodynamics of argatroban.1

In seriously ill pediatric patients, clearance was reduced by 50%.1 9 Clearance was reduced approximately 80% in pediatric patients with elevated bilirubin concentrations.1 9

Stability

Storage

Parenteral

Injection Concentrate

Diluted solutions: 25°C (may be exposed to 15–30°C) in ambient indoor light for 24 hours.1 When protected from light, diluted solutions are stable for 96 hours at 20–25°C or under refrigeration (5°C).1 Do not expose diluted solutions to direct sunlight.1

Solution may be slightly but transiently hazy just after preparation because of the formation of microprecipitates that rapidly dissolve upon further mixing.1

Discard unused vial if solution is cloudy or if an insoluble precipitate is formed.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Atropine sulfate

Diltiazem HCl

Diphenhydramine HCl

Dobutamine HCl

Dopamine HCl

Fenoldopam mesylate

Fentanyl citrate

Furosemide

Hydrocortisone sodium succinate

Lidocaine HCI

Metoprolol tartrate

Midazolam HCl

Milrinone lactate

Morphine sulfate

Nesiritide

Nitroglycerin

Norepinephrine bitartrate

Phenylephrine HCl

Sodium nitroprusside

Vasopressin

Verapamil HCl

Incompatible

Amiodarone HCI

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

Advice to Patients

  • Importance of reporting any signs of bleeding (e.g., bruising, petechiae, hematuria) to clinician immediately.9

  • Importance of patients informing clinician of history of bleeding disorders.1

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants) and OTC drugs.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

Argatroban

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion only

100 mg/mL (250 mg)

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

1. GlaxoSmithKline. Argatroban injection prescribing information. RTP, NC; 2008 May

2. Hursting MJ, Alford KL, Becker JP et al. Novastan(Brand of Argatroban): A small-molecule, direct thrombin inhibitor. Semin Thromb Hemost. 1997; 23:503-16. [PubMed 9469622]

3. Anon. Argatroban for treatment of heparin-induced thrombocytopenia. Med Lett Drugs Ther. 2001; 43:11-2. [PubMed 11177224]

4. Jang IK, Brown DFM, Guigliano RP et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: Myocardial Infarction with Novastan and TPA (MINT) Study. J Am Coll Cardiol. 1999; 33:1879-85. [IDIS 429498] [PubMed 10362188]

5. Fareed J, Lewis BE, Callas DD et al. Antithrombin agents: the new class of anticoagulant and antithrombotic drugs. Clin Appl Thromb Hemost. 1999; 5(Suppl 1):S45-55. [PubMed 10726036]

6. Januzzi JL. Heparin induced thrombocytopenia: diagnosis and contemporary antithrombin management. J Thromb Thrombolysis. 1999; 7:259-64. [PubMed 10375387]

7. Lewis BE, Walenga JM. Anticoagulation with Novastan(Argatroban) in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. Semin Thromb Hemost. 1997; 23:197-202. [PubMed 9200347]

8. Lewis BE, Wallis DE, Berkowitz SD et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001; 103:1838-43. [IDIS 464711] [PubMed 11294800]

9. GlaxoSmithKline, Philadelphia, PA: Personal communication.

10. Matthai WH. Use of argatroban during percutaneous coronary interventions in patients with heparin-induced thrombocytopenia. Semin Thromb Hemost. 1999; 25(Suppl 1):57-60. [PubMed 10357153]

11. Lewis BE, Matthai W, Grassman ED et al et al. Results of phase 2/3 trial of argatroban anticoagulation during PTCA of patients with heparin-induced thrombocytopenia (HIT). Circulation. 1997; 96:I-217.

16. Messmore HL, Jeske WP, Wehmacher WH et al. Benefit-rsk assessment of treatments for heparin-induced thrombocytopenia. Drug Safety. 2003; 26:625-41. [PubMed 12814331]

20. Lansky AJ, Hochman JS, Ward PA et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: a statement for healthcare professional from the American Heart Association. Circulation. 2005; 111:940-3. [PubMed 15687113]

21. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy. 2000; 20:318-29. [PubMed 10730687]

991. Wright RS, Anderson JL, Adams CD et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011; 57:e215-367.

994. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011; 58:e44-122. [PubMed 22070834]

1006. Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e495S-530S.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:169-70.

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