4.1. Therapeutic indications

Praxbind is a specific reversal agent for dabigatran and is indicated in adult patients treated with dabigatran etexilate when rapid reversal of its anticoagulant effects is required:

• For emergency surgery/urgent procedures;

• In life-threatening or uncontrolled bleeding.

4.2. Posology and method of administration

Restricted to hospital use only.

Posology

The recommended dose is 5 g idarucizumab (2 vials of 2.5 g/50 mL).

In a subset of patients, recurrence of plasma concentrations of unbound dabigatran and concomitant prolongation of clotting tests have occurred up to 24 hours after administration of idarucizumab (see section 5.1).

Administration of a second 5 g dose of idarucizumab may be considered in the following situations:

• recurrence of clinically relevant bleeding together with prolonged clotting times, or

• if potential re-bleeding would be life-threatening and prolonged clotting times are observed, or

• patients require a second emergency surgery/urgent procedure and have prolonged clotting times.

Relevant coagulation parameters are activated partial thromboplastin time (aPTT), diluted thrombin time (dTT) or ecarin clotting time (ECT) (see section 5.1).

A maximum daily dose has not been investigated.

Restarting antithrombotic therapy

Dabigatran etexilate treatment can be re-initiated 24 hours after administration of idarucizumab, if the patient is clinically stable and adequate haemostasis has been achieved.

After administration of idarucizumab, other antithrombotic therapy (e.g. low-molecular weight heparin) can be started at any time, if the patient is clinically stable and adequate haemostasis has been achieved.

Absence of antithrombotic therapy exposes patients to the thrombotic risk of their underlying disease or condition.

Special populations

Elderly

No dose adjustment is required in elderly patients aged 65 years and above (see section 5.2).

Patients with renal impairment

No dose adjustment is required in renally impaired patients. Renal impairment did not impact the reversal effect of idarucizumab (see section 5.2).

Patients with hepatic impairment

No dose adjustment is required in patients with hepatic injury (see section 5.2).

Paediatric population

The safety and efficacy of Praxbind in children below the age of 18 years have not been established. Currently available data are described in section 5.1.

Method of administration

Intravenous use.

Praxbind (2 vials of 2.5 g/50 mL) is administered intravenously as two consecutive infusions over 5 to 10 minutes each or as a bolus injection.

For additional instructions for use and handling see section 6.6.

4.3. Contraindications

None.

4.4. Special warnings and precautions for use

Idarucizumab binds specifically to dabigatran and reverses its anticoagulant effect. It will not reverse the effects of other anticoagulants (see section 5.1).

Praxbind treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity

The risk of using Praxbind in patients with known hypersensitivity (e.g. anaphylactoid reaction) to idarucizumab or to any of the excipients needs to be weighed cautiously against the potential benefit of such an emergency treatment. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Praxbind should be discontinued immediately and appropriate therapy initiated.

Hereditary fructose intolerance

The recommended dose of Praxbind contains 4 g sorbitol as an excipient. In patients with hereditary fructose intolerance, parenteral administration of sorbitol has been associated with reports of hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of excretory and synthetic function, and death. Therefore, in patients with hereditary fructose intolerance the risk of treatment with Praxbind must be weighed against the potential benefit of such an emergency treatment. If Praxbind is administered in these patients, intensified medical care during Praxbind exposure and within 24 hours of exposure is required.

Thromboembolic events

Patients being treated with dabigatran have underlying disease states that predispose them to thromboembolic events. Reversing dabigatran therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate (see section 4.2).

Urinary protein testing

Praxbind causes transient proteinuria as a physiologic reaction to renal protein overflow after bolus/short term application of 5 g idarucizumab intravenously (see section 5.2). The transient proteinuria is not indicative of renal damage, which should be taken into account for urine testing.

Sodium content

This medicinal product contains 50 mg sodium per dose, equivalent to 2.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5. Interaction with other medicinal products and other forms of interaction

No formal interaction studies with Praxbind and other medicinal products have been performed. Based on the pharmacokinetic properties and the high specificity in binding to dabigatran, clinically relevant interactions with other medicinal products are considered unlikely.

Preclinical investigations with idarucizumab have shown no interactions with

• volume expanders.

• coagulation factor concentrates, such as prothrombin complex concentrates (PCCs, e.g. 3 factor and 4 factor), activated PCCs (aPCCs) and recombinant factor VIIa.

• other anticoagulants (e.g. thrombin inhibitors other than dabigatran, factor Xa inhibitors including low-molecular weight heparin, vitamin K-antagonists, heparin). Thus idarucizumab will not reverse the effects of other anticoagulants.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data for the use of idarucizumab in pregnant women. Reproductive and developmental toxicity studies have not been performed, given the nature and the intended clinical use of the medicinal product. Praxbind may be used during pregnancy, if the expected clinical benefit outweighs the potential risks.

Breast-feeding

It is unknown whether idarucizumab/metabolites are excreted in human milk.

Fertility

There are no data on the effect of idarucizumab on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

In a phase III study the safety of Praxbind has been evaluated in 503 patients, who had uncontrolled bleeding or required emergency surgery or procedures and were under treatment with Pradaxa (dabigatran etexilate), as well as in 224 volunteers in phase I studies. Furthermore, 359 patients were enrolled in a global idarucizumab administration surveillance program to collect data on usage patterns in a real-world-setting. One paediatric patient was treated in the context of a paediatric safety trial.

No adverse reactions have been identified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no clinical experience with overdoses of idarucizumab.

The highest single dose of idarucizumab studied in healthy subjects was 8 g. No safety signals have been identified in this group.