| Mechanism of Action
Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.
Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 µM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).
Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
Argatroban does not interact with heparin-induced antibodies. Evaluation of sera in 12 healthy subjects and 8 patients who received multiple doses of Argatroban did not reveal antibody formation to Argatroban
INDICATIONS AND USAGE
Argatroban is indicated as an anticoagulant in patients with or at risk for heparin-induced thrombocytopenia undergoing percutaneous coronary intervention (PCI).
DOSAGE AND ADMINISTRATION
Preparation for Intravenous Administration
Dosage - I.V.: Adults:
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).
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.
Percutaneous coronary intervention (PCI):
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 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
Angiomax directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. Thrombin is a serine proteinase that plays a central role in the thrombotic process, acting to cleave fibrinogen into fibrin monomers and to activate Factor XIII to Factor XIIIa, allowing fibrin to develop a covalently cross-linked framework which stabilizes the thrombus; thrombin also activates Factors V and VIII, promoting further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of Angiomax to thrombin is reversible as thrombin slowly cleaves the Angiomax-Arg3-Pro4 bond, resulting in recovery of thrombin active site functions.
In in vitro studies, Angiomax inhibited both soluble (free) and clot-bound thrombin, was not neutralized by products of the platelet release reaction, and prolonged the activated partial thromboplastin time (aPTT), thrombin time (TT), and prothrombin time (PT) of normal human plasma in a concentration-dependent manner. The clinical relevance of these findings is unknown
INDICATIONS AND USAGE
Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the CLINICAL TRIALS REPLACE-2 section (see package insert) is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).
Angiomax is indicated for patients with, or at risk of, HIT/HITTS undergoing PCI.
Angiomax is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin.
The safety and effectiveness of Angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
active major bleeding;
hypersensitivity to Angiomax or its components.
An increased risk of thrombus formation has been associated with the use of Angiomax in gamma brachytherapy, including fatal outcomes.
There is no known antidote to Angiomax. Angiomax is hemodialyzable
| INDICATIONS AND USAGE
PRADAXA is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation
DOSAGE AND ADMINISTRATION
In patients with moderate renal impairment (CrCl 30-50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment. Consider reducing the dose of PRADAXA to 75 mg twice daily.
Renal function should be assessed by calculating the CrCl prior to initiation of treatment with PRADAXA. While on treatment, renal function should be assessed in clinical situations which may be associated with a decline in renal function. In patients with CrCl <50 mL/min or >75 years of age, renal function should be assessed at least once a year.
Instruct patients to swallow the capsules whole. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure.
If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
Converting from or to Warfarin
When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
Converting from or to Parenteral Anticoagulants
For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.
Surgery and Interventions
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Bleeding risk can be assessed by the ecarin clotting time (ECT). This test is a better marker of the anticoagulant activity of dabigatran than activated partial thromboplastin time (aPTT) or thrombin time (TT). If ECT is not available, the aPTT test provides an approximation of PRADAXA’s anticoagulant activity. INR tests are unreliable in patients on PRADAXA.
| INDICATIONS AND USAGE
Refludan is indicated for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) and associated thromboembolic disease in order to prevent further thromboembolic complications.
Dosing: Initially give bolus: 0.4 mg/kg (use maximum weight of 110kg) over 15-20 seconds followed by maintenance dose of 0.15 mg/kg/hr (use maximum weight of 110kg) x 2-10 days as needed.
Maximum dose: Do not exceed 0.21 mg/kg/hour unless an evaluation of coagulation abnormalities limiting response has been completed. Dosing is weight-based, however, patients weighing >110 kg should not receive doses greater than the recommended dose for a patient weighing 110 kg (44 mg bolus and initial maximal infusion rate of 16.5 mg/hour).
Heparin-induced thrombocytopenia: Bolus dose: 0.4 mg/kg IVP (over 15-20 seconds), followed by continuous infusion at 0.15 mg/kg/hour; bolus and infusion must be reduced in renal insufficiency.
Dosing adjustments during infusions: Monitor first aPTT 4 hours after the start of the infusion. Subsequent determinations of aPTT should be obtained at least once daily during treatment. More frequent monitoring is recommended in renally impaired patients. Any aPTT ratio measurement out of range (1.5-2.5) should be confirmed prior to adjusting dose, unless a clinical need for immediate reaction exists. If the aPTT is below target range, increase infusion by 20%. If the aPTT is in excess of the target range, decrease infusion rate by 50%. A repeat aPTT should be obtained 4 hours after any dosing change.
Use in patients scheduled for switch to oral anticoagulants: Reduce lepirudin dose gradually to reach aPTT ratio just above 1.5 before starting warfarin therapy; as soon as INR reaches 2.0, lepirudin therapy should be discontinued.
Supplied: 50 mg (powder for reconstitution).
| Drug UPDATES: PRAXBIND ®- idarucizumab injection
[Drug information / PDF] Click link for the latest monograph
Dosing: Click (+) next to Dosage and Administration section (drug info link)
Initial U.S. Approval: 2015
Mechanism of Action: Idarucizumab is a specific reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acylglucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect.
INDICATIONS AND USAGE:
This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.
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