ADD-ONS / ANTICOAGULANT THERAPY
Idarucizumab (PRAXBIND)
Created 10/11/2021, last revision 19/01/2023
- 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)
- no adequate and well-controlled studies with pregnant women are available
- 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 unquestionably needed
- it has not been studied 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
- consider the benefits of breastfeeding along with the mother’s clinical need for the drug (the benefits must outweigh the risk)
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
- administer 5g dose IV as two consecutive 2.5 g infusions or bolus injections
- 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
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 the reference values (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 (indications for Praxbind include emergency procedures that may involve thrombolysis)
- 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 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