Idarucizumab (PRAXBIND)

• the use of idarucizumab as an antidote was approved by the FDA in October 2015   [Cassels, 2015]
• it has a 300 times higher affinity for thrombin than dabigatran
• indicated in adult patients treated with dabigatran (PRADAXA) in situations where its anticoagulant effects need to be reversed rapidly:
  • 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 stopping the anticoagulant effect of dabigatran
  • dabigatran has a 300 times higher affinity for idarucizumab than for thrombin
• does not interfere with the effects of other anticoagulants
• does not lead to a hypercoagulable state
• allows a bolus IV administration with rapid onset of action
• allows fast restart 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

Clinial trials

• RE-VERSE AD trial with the i.v. idarucizumab at a dose of 5 g i.v.
  • 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

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)

Idarucizumab administration

• aseptic handling during preparation is required
  
• inspect visually 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

• restarting 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

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 for
  • 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 sugar, low phosphate, metabolic acidosis, increased uric acid, and acute liver failure