FDA approves new Pradaxa reversal agent

January 10, 2016

Patients taking Pradaxa had no option for anticoagulation reversal; it was this unmet medical need that caused FDA to grant idarucizumab accelerated approval.

On October 16, FDA approved idarucizumab (Praxbind; Boehringer Ingelheim) to reverse the anticoagulant effects of dabigatran in patients who take dabigatran rand require emergent surgery or urgent procedures, or who experience situations of life-threatening or uncontrolled bleeding.

Kathryn WheelerIdarucizumab is a humanized monoclonal antibody fragment, which binds dabigatran and its acyl glucuronide metabolites in vivo, rendering the anticoagulant effect neutralized. Patients taking dabigatran (Pradaxa; Boehringer Ingelheim) had no option for anticoagulation reversal; it was this unmet medical need that caused FDA to grant idarucizumab accelerated approval. It is a reversal agent specific to dabigatran. It is not for use as a reversal agent of other anticoagulants.

Efficacy

The approval of idarucizumab was based on the findings of pharmacokinetic and pharmacodynamic studies in 283 healthy volunteers, as well as on an ongoing single cohort case series trial of patients taking idarucizumab who experience life-threatening or uncontrolled bleeding or require emergency surgery or an urgent procedure.

See also: FDA approves Patiromer

In the 224 healthy volunteers who received idarucizumab, plasma concentrations of free dabigatran were immediately reduced below quantifiable levels after the administration of five grams of idarucizumab. Plasma concentrations of free dabigatran remained unquantifiable for the duration of a 24-hour observation period. These findings were consistent in participants 65 to 80 years of age and in those with mild and moderate renal impairment. The effects of dabigatran were unchanged when reinitiated at 24 hours post-administration of idarucizumab.

Of the 123 patients taking dabigatran who are represented in the case series of patients requiring emergent or urgent anticoagulation reversal, 89% experienced a full reversal of dabigatran within four hours of receiving idarucizumab. Full reversal of dabigatran activity was defined in the study by laboratory levels of dilute thrombin time (dTT) or ecarin clotting time (ECT). These tests measure the activity of dabigatran in a blood sample.

Safety

In trials of healthy volunteers, the most common adverse effect reported among recipients of idarucizumab was headache (5%). Among patients taking dabigatran who received idarucizumab because they required urgent or emergent reversal, adverse events reported to occur in at least 5% of all recipients included hypokalemia, delirium, constipation, pyrexia, and pneumonia.

Of the 123 patients in this cohort case series, 26 patients died. Each death in the study could be related to complications of the index event requiring anticoagulation reversal or to other comorbidities. Manufacturer warnings remind providers that use of idarucizumab places patients at an increased risk of thrombosis due to the underlying clinical reason for dabigatran administration. Anticoagulant administration should resume as soon as is medically appropriate for the patient.

A second 5-gram dose of idarucizumab may be considered in patients with elevated coagulation results and recurrent bleeding or need for additional urgent procedures or emergent surgery. Patients with hereditary fructose intolerance may be at risk of serious adverse event with this drug due to the sorbitol excipient in the product.

Dosage

Praxbind is available for intravenous use only. The recommended dose is five grams as a single dose, provided by the manufacturer in two vials, each containing 2.5 g/50mL of idarucizumab. Administration of the 5 g dose may be accomplished by hanging the vials as two consecutive infusions or by consecutively injecting the contents of two vials via syringe. No dosage adjustment is required for patients with renal impairment. Do not shake or freeze vials.

Idarucizumab should be stored in the refrigerator. An unopened vial may be stored at room temperature up to 48 hours if protected from light before use or up to six hours if the product has been exposed to light.

References

Praxbind [package insert] Ridgefield, Conn.: Boehringer Ingelheim Pharmaceuticals, Inc.; October 2015.

Pollack CV, Reilly PA, Eikelboom MB, et al. Idarucizumab for dabigatran reversal. NEJM. 2015;373:511–520.

Kathryn Wheeleris associate clinical professor of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.