• the use of idarucizumab as an antidote (to reverse the anticoagulant effects of dabigatran) was approved by the FDA in October 2015   [Cassels, 2015]
  • it has a 300 times greater affinity for thrombin than dabigatran
  • indicated in adult patients treated with dabigatran (PRADAXA) in situations where the anticoagulant effects need to be rapidly reversed:
    • urgent surgery/urgent procedures (including intravenous thrombolysis)
    • life-threatening/uncontrolled bleeding (including ICH)
  • virtually no contraindications (except allergy) or relevant drug interactions, no serious AEs

Mechanism of action

  • idarucizumab is a fragment of a humanized monoclonal antibody that acts as a specific reversal agent for dabigatran
  • it binds tightly to dabigatran and its acyl glucuronide metabolites and forms a complex with it, thereby immediately halting the anticoagulant effect of dabigatran
    • dabigatran has a 300-fold higher affinity for idarucizumab than for thrombin
  • no interference with other anticoagulants and no secondary hypercoagulable state
  • administered as an IV bolus with rapid onset of action
  • allows rapid resumption of anticoagulant therapy (24h after administration)
  • several pathways contribute to antibody metabolism – all  involve the biodegradation of antibodies into smaller molecules, which are then reabsorbed and incorporated into the general protein synthesis
Idarucizumab (PRAXBIND) - mechanism of action

Clinial trials

  • RE-VERSE AD trial with idarucizumab at a dose of 5g IV
    • effective within minutes
    • analysis of 90 patients showed a reliable reduction of anticoagulant activity (normal coagulation in 90% of patients at 4 and 12 hours)  → see here
  • there is growing clinical experience with PRAXBIND administration prior to thrombolysis and in the acute treatment of ICH see here
Results of REVERESE-AD trial
REVERSE-AD trial results

Contraindications and precautions

  • allergy to idarucizumab or ingredients
  • patients with hereditary fructose intolerance may be at risk of adverse reactions (such as low blood sugar, low phosphate, metabolic acidosis, increase in uric acid, and acute liver failure)
  • no adequate and well-controlled studies on pregnant women
  • it is not known whether idarucizumab can cause fetal harm when administered to a pregnant woman ⇒ should be given to a pregnant woman only if absolutely necessary
  • no data for use during labor and delivery
  • it is not known whether idarucizumab passes into human milk
  • no data on the effects of idarucizumab on nursing infants or on milk production
  • the benefits of breastfeeding should be weighed against the mother’s clinical need for the drug (the benefits must outweigh the risks)

Idarucizumab administration

  • aseptic handling is required during the preparation
  • visually inspect for particulates and discoloration before infusion
  • once the solution is removed from the vial, the administration should begin immediately; vials may be stored at room temperature (25°C /77°F) but must be used within 6h
  • do not mix with other medication
  • PRAXBIND 2 x 2.5g/50 ml
    • administer 5g dose IV as two consecutive 2.5 g infusions or bolus injections
    • an existing intravenous line may be used; flush with sterile 0.9% NS solution prior to infusion
    • no other infusion should be administered simultaneously via the same IV access
    • renal impairment does not affect the reversal effect of idarucizumab ⇒ no dose adjustment is required
  • resuming antithrombotic therapy
    • patients treated with dabigatran have underlying conditions predisposing them to thromboembolic events
    • resumption of anticoagulant therapy should be considered ASAP to reduce this risk
    • idarucizumab does not interfere with other anticoagulant or antithrombotic therapies
    • dabigatran treatment can be started 24h after idarucizumab administration
Idarucizumab (PRAXBIND) administration

Praxbind and intravenous thrombolysis

  • intravenous thrombolysis (IVT)  in patients with acute ischemic stroke is possible with dabigatran therapy if aPTT + TT, ECT, or HEMOCLOT values do not exceed the upper limits of normal  (AHA/ASA 2013 III/C)
    • normal aPTT alone is not sufficient; it does not completely rule out an elevated TT  [Kermer, 2017] [Hankey, 2014]
    • IVT may be considered in patients with normal TT or TT <60 s and normal APTT   (ESO guidelines 2021)

      • expert opinion, insufficient evidence to make an evidence-based recommendation
    • Hemoclot – a dabigatran level < 50 ng/ml > 6h after the last dose of the drug indicates the absence of anticoagulant activity
  • administration of thrombolysis after prior neutralization of the effect of dabigatran with the antidote PRAXBIND is possible (IVT is an emergency procedure)
    • according to expert consensus, the combination of idarucizumab and IVT is suggested for patients with acute ischemic stroke of <4.5 h duration   (ESO guidelines 2021)   [Diener, 2017]
    • according to registry data, administration of the antidote PRAXBIND in patients with acute stroke followed by thrombolysis is effective, safe, and easy to perform [Kermer, 2017]

Adverse events

  • common side effects
    • hypokalemia (7%)
    • delirium (7%)
    • constipation (7%)
    • fever (6%)
    • pneumonia (6%)
    • headache (5%)
  • serious side effects:
    • blood clots – patients are exposed to increased thrombotic risk of the underlying condition for which dabigatran is being given
    • recurrent bleeding (some patients may require an additional dose of idarucizumab)
    • hypersensitivity reactions (severe allergic reaction – fever, difficulty breathing due to airway spasms, hyperventilation, rash, and itching)
  • patients with hereditary fructose intolerance may be at risk for adverse effects such as low blood glucose, low phosphate, metabolic acidosis, increased uric acid, and acute liver failure
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Idarucizumab (PRAXBIND)
link: https://www.stroke-manual.com/praxbind-idarucizumab/