ADD-ONS / ANTICOAGULANT THERAPY

Praxbind (idarucizumab)

Created 10/11/2021, last revision 11/09/2022

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
it is indicated in adult patients treated with dabigatran (PRADAXA) in situations where its anticoagulant effects need to be promptly reversed:
- urgent surgery/urgent procedures (urgent procedures include intravenous thrombolysis)
- life-threatening/uncontrolled bleeding (including ICH)
it has virtually no contraindications (except allergy) or relevant drug interactions, no serious AEs

Mechanism of action

idarucizumab is a fragment of a humanized monoclonal antibody acting like 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 the metabolism of antibodies – all involve biodegradation of the antibody to smaller molecules, which are then reabsorbed and incorporated in the general protein synthesis

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 after 4 and 12 h) → see here
there is an increasing clinical experience with PRAXBIND administration before thrombolysis and in acute ICH treatment → see here

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 crosses into human milk
no data on the effects of idarucizumab on the breastfed child or milk production
consider benefits of breastfeeding along with the mother’s clinical need for the drug (benefits must outweigh the risk)

aseptic handling during preparation is required
inspect visually for particulates and discoloration before infusion
once the solution has been removed from the vial, the administration should begin promptly; solution in vials may be stored at room temperature (25°C [77°F]) but must be used within 6 h
do not mix with other drugs

PRAXBIND 2 x 2.5g/50 ml
- infuse 5 g dose IV as two consecutive 2.5 g infusions or administer as bolus injections by injecting both 2.5 g vials consecutively one after another via syringe
- a preexisting intravenous line can be used
- flush with sterile 0.9% NS solution before infusion
- no other infusion should be administered simultaneously via the same IV access
- renal impairment does not impact the reversal effect of idarucizumab ⇒ no dosage adjustment is required

restarting antithrombotic therapy
- patients treated with dabigatran have underlying diseases predisposing them to thromboembolic events
- resumption of anticoagulant therapy should be considered as soon as possible to reduce the risk of thromboembolism
- idarucizumab has no impact on the effect of other anticoagulant or antithrombotic therapies
- dabigatran treatment can be initiated 24h after administration of idarucizumab

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 entirely rule out elevated TT [Kermer, 2017] [Hankey, 2014]
- IVT can be considered in patients with normal TT or TT <60 s and normal APTT (ESO guidelines 2021)
  - expert opinion, no sufficient 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, which may include 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]

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 disease that dabigatran is being given for
- recurrence of bleeding (some patients may require an additional dose of idarucizumab)
- hypersensitivity reactions (serious allergic reaction – fever, difficulty breathing due to airways spasms, hyperventilation, rash, and itching)
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