Argatroban

ED / ICU / Transport

• HIT with thrombosis (treatment): treatment of thrombosis in adults with heparin-induced thrombocytopenia, after heparin is stopped
• HIT (prophylaxis): prevention of thrombosis in adults with HIT (label: prophylaxis or treatment)
• PCI in patients with or at risk for HIT: anticoagulant during percutaneous coronary intervention when heparin cannot be used

Other Uses

• ECMO circuit anticoagulation in HIT (off-label): Most published data are retrospective case series. See ECMO

Doses vary by protocol; follow local protocols and medical direction.

Available Forms

• Concentrate: 250 mg/2.5 mL (100 mg/mL) single-dose vial; must be diluted 100-fold to 1 mg/mL before use
• Ready to infuse: 50 mg/50 mL (1 mg/mL) single-dose vial; do not dilute

Adult Dosing

Pediatric Dosing

Continuous Infusion

Preparation & Administration

• Dilution: Concentrate: 250 mg (2.5 mL) per 250 mL of 0.9% sodium chloride, 5% dextrose or lactated Ringer's (1 mg/mL); mix by repeated inversion for 1 minute. Ready-to-infuse vial: no dilution.
• Before starting: discontinue heparin and draw a baseline aPTT (label). Allow heparin's aPTT effect to fall before the first dose.
• Push rate (PCI bolus): over 3–5 minutes via a large-bore IV line.
• Stability: diluted solution stays stable for 24 hours at room temperature in ambient light. Protected from light, it stays stable up to 96 hours at room temperature or refrigerated. It must be clear before use.
• Line: IV only. No IO or intranasal use appears in the labelling reviewed. Do not mix it with other drugs before dilution.

Contraindications

• Major bleeding (labelled contraindication)
• Hypersensitivity to argatroban: airway, skin and generalized reactions have been reported

Precautions

• Bleeding risk: severe hypertension; recent lumbar puncture or spinal anesthesia; major surgery of the brain, spinal cord or eye; bleeding disorders; GI ulcers
• Other antithrombotics: antiplatelets, thrombolytics and other anticoagulants stack bleeding risk on top of argatroban. Safety of thrombolytics and GP IIb/IIIa antagonists with argatroban is not established.
• Hepatic impairment: Start lower and titrate more slowly. Reversal can take longer than 4 hours after stopping.

Hold / Reassess If

• Unexplained fall in hematocrit or blood pressure: stop, notify, and evaluate for hemorrhage
• aPTT above 100 s or above 3 times baseline: reduce the rate per protocol and recheck aPTT 2 hours after the change
• PCI with AST or ALT at least 3 times ULN, or clinically significant liver disease: avoid (label)
• PCI ACT below 300 s: extra 150 mcg/kg bolus, infusion to 30 mcg/kg/min, recheck ACT in 5–10 min. PCI ACT above 450 s: reduce to 15 mcg/kg/min, no bolus

Common

• In HIT patients: dyspnea (8.1%), hypotension (7.2%), fever (6.9%), diarrhea (6.2%). Many of these overlap with critical illness. Attribution is uncertain (label).
• In PCI patients (over 5%): chest pain, hypotension, back pain, nausea, vomiting, headache (label).
• PCI access-site bleeding: groin bleeding or hematoma in 3.6% of procedures (label).

Serious / Life-Threatening

Overdose & Toxicity Management

• Signs: excessive aPTT, with or without bleeding
• Immediate: Stop or reduce the infusion. Measure aPTT and other coagulation tests. In trials, the parameters were back to baseline in 2 to 4 hours. Hepatic impairment makes that longer.
• Antidote: none specific (label). Protamine is not a labelled reversal for argatroban. Read the protamine page.
• Dialysis: About 20% comes out in a 4-hour hemodialysis session (label).
• Poison help: 1-800-222-1222 or a medical toxicologist (label).

Clinically Significant Interactions

IV Compatibility

• Diluents: 0.9% sodium chloride, 5% dextrose or lactated Ringer's (label).
• Do not mix with other drugs before dilution (label).
• Final solution must be clear; discard if cloudy or precipitated.
• Verify with an institutional compatibility resource.

• Pediatrics: Safety and effectiveness are not established. See Pediatric Dosing. Clearance in seriously ill children runs about 50% lower than in adults (label).
• Neonates: There is no labelled neonatal dosing. Infants under 6 months were among the 18 children studied (label).
• Pregnancy: Published and postmarketing data are limited, and they do not suggest an association with adverse fetal developmental outcomes. Animal studies showed no fetal harm at up to 0.3 times the maximum human dose. Untreated thrombosis is a risk to the mother. Anticoagulants carry a risk of hemorrhage in both mother and fetus. Weigh the need against that risk (label sec 8.1).
• Lactation: No human milk data exist. The drug is present in rat milk. The label advises weighing the mother's need against infant risk (discontinue nursing or drug as indicated).
• Older Adults: 35% of the 1,340 trial patients were 65 or older. Age did not change the effect. Comorbidity does raise adverse reaction risk (label).
• Renal Impairment: Renal dysfunction does not call for an adjustment up to 5 mcg/kg/min (label). Hemodialysis clears about 20% in a 4-hour session.
• Hepatic Impairment: Moderate or severe (Child-Pugh): start at 0.5 mcg/kg/min. In Child-Pugh above 6, the half-life reached 181 minutes at 2.5 mcg/kg/min. In PCI with AST or ALT at least 3 times ULN, avoid high doses.
• Obesity / Dosing Weight: Label dosing uses kg body weight. The label gives no obesity-specific adjustment. Use the protocol's weight type.
• Critically Ill Adults: There is no labelled dose for critical illness. Protocols often start lower (protocol-dependent). Use the protocol's starting dose and check aPTT 2 hours after each change. Expect a lower requirement when clearance is reduced (see Dosing & Administration).

• Scope: Mainly ICU and critical-care transport. It varies by state and agency protocol.
• Storage & Stability: Store at 20–25 °C (68–77 °F). Do not freeze it. Keep vials in the carton to protect them from light. A diluted bag stays stable 24 hours in ambient light, or up to 96 hours protected from light.
• Carried Concentration: The 100 mg/mL concentrate and the 1 mg/mL ready-to-infuse vial are not interchangeable. Keep them visibly apart. Never dilute the 1 mg/mL vial.
• Infusions in Transport: The pump controls the rate. Check mcg/kg/min and mL/hr at every handoff and bag change. Use diluted bags inside the stability window.
• Altitude / Environment: The labelling reviewed gives no specific guidance.
• Handoff Essentials: time started, dose in mcg/kg/min and mL/hr, weight used, last aPTT with time, last change, bleeding status, time heparin was stopped.

Mechanism of Action

• Target: Argatroban binds the thrombin active site reversibly. Antithrombin is not required (label).
• Effect: It stops fibrin formation. It also blocks activation of factors V, VIII and XIII, protein C activation and platelet aggregation (label).
• Consequence: It inhibits free and clot-bound thrombin. That prolongs aPTT, ACT, PT, INR and thrombin time (label).

Pharmacokinetics

• Half-life: 39–51 minutes; 181 minutes with Child-Pugh above 6 at 2.5 mcg/kg/min.
• Metabolism: Hepatic hydroxylation. CYP3A4/5 forms metabolites in vitro. In vivo it is not an important elimination pathway (label).
• Active metabolites: M1 has 3- to 5-fold weaker anticoagulant effect; plasma levels 0–20% of parent.
• Elimination: mostly fecal (biliary); total clearance about 0.31 L/kg/hr.
• Protein binding / Vd: about 54% protein bound; volume of distribution 174 mL/kg.

Generic Name

Argatroban (labelled as argatroban, monohydrate)

Brand Names

None listed on the labels reviewed; US products are marketed under the generic name

Pharmacologic Class

Direct thrombin inhibitor (synthetic)

Therapeutic Class

Anticoagulant (HIT and PCI)

Controlled Substance

Not controlled

ISMP High-Alert

Yes: ISMP high-alert medication (direct thrombin inhibitors, 2018 list)

Look-Alike / Sound-Alike

None listed on the labels reviewed