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Argatroban


Pronunciation

 (ar GA troh ban)


Generic Available

 No


Use

 Prophylaxis or treatment of thrombosis in adults with heparin-induced thrombocytopenia; adjunct to percutaneous coronary intervention (PCI) in patients who have or are at risk of thrombosis associated with heparin-induced thrombocytopenia


Pregnancy Risk Factor

 B


Pregnancy Implications

 No adequate and well-controlled studies have been done in pregnant women. Argatroban should be used in pregnant women only if clearly needed.


Lactation

 Excretion in breast milk unknown/not recommended


Contraindications

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


Warnings/Precautions

 Hemorrhage can occur at any site in the body. Extreme caution should be used when there is an increased danger of hemorrhage, such as severe hypertension, immediately following lumbar puncture, spinal anesthesia, major surgery (including brain, spinal cord, or eye surgery), congenital or acquired bleeding disorders, and gastrointestinal ulcers. Use caution in critically-ill patients; reduced clearance may require dosage reduction. Use caution with hepatic dysfunction. Concomitant use with warfarin will cause increased prolongation of the PT and INR greater than that of warfarin alone; alternative guidelines for monitoring therapy should be followed. Safety and efficacy for use with other thrombolytic agents has not been established. Discontinue all parenteral anticoagulants prior to starting therapy. Allow reversal of heparin's effects before initiation. Patients with hepatic dysfunction may require >4 hours to achieve full reversal of argatroban's anticoagulant effect following treatment. Avoid use during PCI in patients with elevations of ALT/AST (>3 times ULN); the use of argatroban in these patients has not been evaluated. Safety and efficacy in children <18 years of age have not been established.


Adverse Reactions

 As with all anticoagulants, bleeding is the major adverse effect of argatroban. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

>10%:

Gastrointestinal: Gastrointestinal bleed (minor, 14%; <1% in PCI)

Genitourinary: Genitourinary bleed and hematuria (minor, 12%)

1% to 10%:

Cardiovascular: Hypotension (7%), cardiac arrest (6%), ventricular tachycardia (5%), atrial fibrillation (3%), cerebrovascular disorder (2%)

Central nervous system: Fever (7%), pain (5%), intracranial bleeding (1%, only observed in patients also receiving streptokinase or tissue plasminogen activator)

Gastrointestinal: Diarrhea (6%), nausea (5%), vomiting (4%), abdominal pain (3%), bleeding (major, 2%)

Genitourinary: Urinary tract infection (5%)

Hematologic: Decreased hemoglobin <2 g/dL and hematocrit (minor, 10%)

Local: Bleeding at the injection site (minor, 2% to 5%)

Renal: Abnormal renal function (3%)

Respiratory: Dyspnea (8% to 10%), cough (3% to 10%), hemoptysis (minor, 3%), pneumonia (3%)

Miscellaneous: Sepsis (6%), infection (4%)

<1% (Limited to important or life-threatening): Allergic reactions including cough, dyspnea, rash, bullous eruption, and vasodilation (increased to 14% in patients also receiving thrombolytic therapy and/or contrast media); genitourinary bleeding and hematuria (major, 0.9%); hemoglobin and hematocrit decreased (major, 0.7%); limb and below-the-knee stump bleed; multisystem hemorrhage and DIC; retroperitoneal bleeding


Overdosage/Toxicology

 No specific antidote is available. Treatment should be symptomatic and supportive. Discontinue or decrease infusion to control excessive anticoagulation with or without bleeding. Reversal of anticoagulant effects may be longer than 4 hours in patients with hepatic impairment.


Drug Interactions

 Substrate of CYP3A4 (minor)

Drugs which affect platelet function (eg, aspirin, NSAIDs, dipyridamole, ticlopidine, clopidogrel): May potentiate the risk of hemorrhage.

Erythromycin: Concurrent therapy failed to demonstrate a significant effect on argatroban pharmacokinetics, indicating CYP3A4/5 is not a major route of argatroban metabolism.

Glycoprotein IIb/IIIa antagonists: Concurrent therapy has not been evaluated. An increased risk of bleeding would be expected.

Heparin: Sufficient time must pass after heparin therapy is discontinued; allow heparin's effect on the aPTT to decrease

Thrombolytics: Safety and efficacy for concomitant use have not been established. May increase risk of bleeding. Intracranial bleeding has been reported.

Warfarin: Concomitant use with argatroban increases PT and INR greater than that of warfarin alone. Argatroban is commonly continued during the initiation of warfarin therapy to assure anticoagulation and to protect against possible transient hypercoagulability.


Stability

 Store at 25°C (77°F). Protect from light. May be mixed with 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection. Do not mix with other medications. To prepare solution for I.V. administration, dilute each 250 mg vial with 250 mL of diluent. Mix by repeated inversion for one minute. Once mixed, final concentration should be 1 mg/mL. A slight but brief haziness may occur prior to mixing. The prepared solution is stable for 24 hours at 25°C (77°F) in ambient indoor light. Do not expose to direct sunlight. Prepared solutions are stable for 48 hours at 2°C to 8°C when stored in the dark.


Mechanism of Action

 A direct, highly selective thrombin inhibitor. Reversibly binds to the active thrombin site of free and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V, VIII, and XIII; protein C; and platelet aggregation.


Pharmacodynamics/Kinetics

Onset of action: Immediate

Distribution: 174 mL/kg

Protein binding: Albumin: 20%; 1-acid glycoprotein: 35%

Metabolism: Hepatic via hydroxylation and aromatization. Metabolism via CYP3A4/5 to four known metabolites plays a minor role. Unchanged argatroban is the major plasma component. Plasma concentration of metabolite M1 is 0% to 20% of the parent drug and is three- to fivefold weaker.

Half-life elimination: 39-51 minutes; Hepatic impairment: 181 minutes

Time to peak: Steady-state: 1-3 hours

Excretion: Feces (65%); urine (22%); low quantities of metabolites M2-4 in urine


Dosage

 I.V.: Adults:

Heparin-induced thrombocytopenia:

Initial dose: 2 mcg/kg/minute

Maintenance dose: Measure aPTT after 2 hours, adjust dose until the steady-state aPTT is 1.5-3.0 times the initial baseline value, not exceeding 100 seconds; dosage should not exceed 10 mcg/kg/minute

Conversion to oral anticoagulant: Because there may be a combined effect on the INR when argatroban is combined with warfarin, loading doses of warfarin should not be used. Warfarin therapy should be started at the expected daily dose.

Patients receiving 2 mcg/kg/minute of argatroban: Argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4; repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Patients receiving >2 mcg/kg/minute of argatroban: Reduce dose of argatroban to 2 mcg/kg/minute; measure INR for argatroban and warfarin 4-6 hours after dose reduction; argatroban therapy can be stopped when the combined INR on warfarin and argatroban is >4. Repeat INR measurement in 4-6 hours; if INR is below therapeutic level, argatroban therapy may be restarted. Repeat procedure daily until desired INR on warfarin alone is obtained.

Note: Critically-ill patients with normal hepatic function became excessively anticoagulated with FDA-approved or lower starting doses of argatroban (Reichert MG, 2003). Doses between 0.15-1.3 mcg/kg/minute were required to maintain aPTTs in the target range. Another report of a cardiac patient with anasarca secondary to acute renal failure had a reduction in argatroban clearance similar to patient with hepatic dysfunction (de Denus S, 2003). Reduced clearance may have been attributed to reduced perfusion to the liver. Consider reducing starting dose to 0.5-1 mcg/kg/minute in critically-ill patients who may have impaired hepatic perfusion (eg, patients requiring vasopressors, having decreased cardiac output, having fluid overload).

Percutaneous coronary intervention (PCI):

Initial: Begin infusion of 25 mcg/kg/minute and administer bolus dose of 350 mcg/kg (over 3-5 minutes). ACT should be checked 5-10 minutes after bolus infusion; proceed with procedure if ACT >300 seconds. Following initial bolus:

ACT <300 seconds: Give an additional 150 mcg/kg bolus, and increase infusion rate to 30 mcg/kg/minute (recheck ACT in 5-10 minutes)

ACT >450 seconds: Decrease infusion rate to 15 mcg/kg/minute (recheck ACT in 5-10 minutes)

Once a therapeutic ACT (300-450 seconds) is achieved, infusion should be continued at this dose for the duration of the procedure.

Impending abrupt closure, thrombus formation during PCI, or inability to achieve ACT >300 sec: An additional bolus of 150 mcg/kg, followed by an increase in infusion rate to 40 mcg/kg/minute may be administered.

Dosage adjustment in renal impairment: No adjustment is necessary

Dosage adjustment in hepatic impairment: Decreased clearance and increased elimination half-life are seen with hepatic impairment; dose should be reduced. Initial dose for moderate hepatic impairment is 0.5 mcg/kg/minute. Note: During PCI, avoid use in patients with elevations of ALT/AST (>3 times ULN); the use of argatroban in these patients has not been evaluated.

Elderly: No adjustment is necessary for patients with normal liver function


Administration

 Solution must be diluted to 1 mg/mL prior to administration.


Monitoring Parameters

 Obtain baseline aPTT prior to start of therapy. Check aPTT 2 hours after start of therapy to adjust dose, keeping the steady-state aPTT 1.5-3 times the initial baseline value (not exceeding 100 seconds). Monitor hemoglobin, hematocrit, signs and symptoms of bleeding.


Test Interactions

 Argatroban produces dose-dependent effects on PT, INR, ACT, and TT, however, therapeutic ranges are not established.


Patient Education

 This medication can only be administered by intravenous infusion and you will be monitored with blood tests during therapy. You may have a tendency to bleed easily; use electric razor, brush teeth with soft brush, floss with waxed floss, avoid all scissors or sharp instruments (knives, needles, etc), and avoid injury or bruising. Report stomach cramping or pain; dark or bloody stools; blood in urine; acute headache or confusion; respiratory difficulty; nosebleed; or bleeding from gums. Breast-feeding precaution: Breast-feeding is not recommended.


Additional Information

 Platelet counts recovered by day 3 in 53% of patients with heparin-induced thrombocytopenia and in 58% of patients with heparin-induced thrombocytopenia with thrombosis syndrome.


Anesthesia and Critical Care Concerns/Other Considerations

 Argatroban achieves steady state rapidly (4-5 hours after initiating therapy) when administered I.V., with a predictable dose-response effect. PTTs generally remain stable at a given dose. It does not induce formation of antibodies that can alter its clearance, as is seen with lepirudin. Reduce dose in critically-ill patients, particularly those who may have impaired hepatic perfusion.


Cardiovascular Considerations

 Argatroban achieves steady state rapidly (4-5 hours after initiating therapy) when administered I.V., with a predictable dose-response effect. PTTs generally remain stable at a given dose. It does not induce formation of antibodies that can alter its clearance, as is seen with lepirudin. Patients with a reduced cardiac output and/or fluid overload may require a reduced dose. Reduced clearance may be attributed to hepatic congestion.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: As with all anticoagulants, bleeding is a potential adverse effect of argatroban during dental surgery; risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. Medical consult is suggested. It is unlikely that ambulatory patients presenting for dental treatment will be taking intravenous anticoagulant therapy.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 None reported


Mental Health: Effects on Psychiatric Treatment

 None reported


Dosage Forms

 Injection, solution: 100 mg/mL (2.5 mL) [contains dehydrated alcohol 1000 mg/mL]


References

Dager WE and White RH, "Pharmacotherapy of Heparin-Induced Thrombocytopenia," Expert Opin Pharmacother , 2003, 4(6):919-40.

de Denus S and Spinler SA, "Decreased Argatroban Clearance Unaffected by Hemodialysis in Anasarca," Ann Pharmacother , 2003, 37(9):1237-40.

Lewis BE, Matthai WH, Cohen M, et al, "Argatroban Anticoagulation During Percutaneous Coronary Intervention in Patients With Heparin-Induced Thrombocytopenia," Cathet Cardiovasc Intervent , 2002, 57(2):177-84.

Lewis BE, Wallis DE, Berkowitz SD, et al, "Argatroban Anticoagulant Therapy in Patients With Heparin-Induced Thrombocytopenia," Circulation , 2001, 103(14):1838-43.

Reichert MG, MacGregor DA, Kincaid EH, et al, " Excessive Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia," Ann Pharmacother , 2003, 37(5):652-4.


International Brand Names

 Novastan® (CN, JP)


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