Data from FDA - Curated by Marshall Pearce - Last updated 11 January 2018

Indication(s)

1 INDICATIONS AND USAGE PRAXBIND is indicated in patients treated with Pradaxa when reversal of the anticoagulant effects of dabigatran is needed: For emergency surgery/urgent procedures In life-threatening or uncontrolled bleeding This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers [see Clinical Studies (14)].

Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.

PRAXBIND is a humanized monoclonal antibody fragment (Fab) indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed: For emergency surgery/urgent procedures In life-threatening or uncontrolled bleeding (1) This indication is approved under accelerated approval based on a reduction in unbound dabigatran and normalization of coagulation parameters in healthy volunteers.

Continued approval for this indication may be contingent upon the results of an ongoing cohort case series study.

(1)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions

6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail elsewhere in the labeling: Thromboembolic Risk [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions (5.3)] Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient [see Warnings and Precautions (5.4)] In healthy volunteers, the most frequently reported adverse reactions in greater than or equal to 5 % of subjects treated with idarucizumab was headache.

(6.1) In patients, the most frequently reported adverse reactions in greater than or equal to 5 % of patients treated with idarucizumab were hypokalemia, delirium, constipation, pyrexia, and pneumonia.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Three clinical trials in healthy volunteers have been completed, in which 224 subjects were treated with idarucizumab.

In these trials during the treatment period the overall frequency of adverse events was similar between idarucizumab-treated subjects (55/224, 25 %) and placebo-treated subjects (26/105, 25 %).

Among those subjects treated with idarucizumab, adverse reactions reported in greater than or equal to 5 % of subjects was headache (12/224, 5 %).

In the interim analysis of the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 123 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding [see Clinical Studies (14)].

Adverse reactions reported in greater than or equal to 5 % of patients were: hypokalemia (9/123, 7 %), delirium (9/123, 7 %), constipation (8/123, 7 %), pyrexia (7/123, 6 %), pneumonia (7/123, 6 %).

Of the total, 26 patients died, 11 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.

Thromboembolic Events In the interim analysis of the RE-VERSE AD trial, 5 of 123 patients reported thrombotic events, 1 patient 2 days after treatment with idarucizumab and 4 patients 7 days or more after treatment with idarucizumab.

None of these patients were on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient [see Warnings and Precautions (5.1)].

Hypersensitivity Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab [see Warnings and Precautions (5.3)].

6.2 Immunogenicity As with all proteins there is a potential for immunogenicity with idarucizumab.

Using an electro-chemiluminescence (ECL) based assay, plasma samples from 283 subjects (224 treated with idarucizumab) were tested for antibodies cross-reacting with idarucizumab.

Pre-existing antibodies with cross-reactivity to idarucizumab were detected in approximately 13 % (36/283) of the subjects.

The majority of pre-existing antibodies were shown to have low titers.

No impact on the pharmacokinetics or the reversal effect of idarucizumab or hypersensitivity reactions were observed in these subjects.

Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4 % (9/224) of the subjects treated with idarucizumab.

The epitope specificity of antibodies to idarucizumab was characterized using probe molecules.

For pre-existing antibodies, 97 % (35/36) had specificity for the C-terminus, a region of idarucizumab to which dabigatran does not bind.

For treatment emergent possibly persisting antibodies, 56 % (5/9) had specificity for the C-terminus, 22 % (2/9) had specificity for the variable region, 11 % (1/9) had mixed specificity and 11 % (1/9) was indeterminate.

Detection of antibody formation is dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody positivity may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease.

For these reasons, comparison of the incidence of antibodies to idarucizumab with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION For intravenous use only.

For intravenous use only.

The recommended dose of PRAXBIND is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab.

(2.1) There is limited data to support administration of an additional 5 g of PRAXBIND. (2.1) 2.1 Recommended Dose The recommended dose of PRAXBIND is 5 g, provided as two separate vials each containing 2.5 g/50 mL idarucizumab (see Figure 1).

There is limited data to support administration of an additional 5 g of PRAXBIND [see Warnings and Precautions (5.2)].

2.2 Preparation Ensure aseptic handling when preparing the infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Once solution has been removed from the vial, administration should begin promptly or within 1 hour.

2.3 Administration Do not mix with other medicinal products.

Use aseptic technique when administering PRAXBIND.

Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g) as Two consecutive infusions (see Figure 2) or Bolus injection by injecting both vials consecutively one after another via syringe (see Figure 3).

A pre-existing intravenous line may be used for administration of PRAXBIND.

The line must be flushed with sterile 0.9 % Sodium Chloride Injection, USP solution prior to infusion.

No other infusion should be administered in parallel via the same intravenous access.

PRAXBIND treatment can be used in conjunction with standard supportive measures, which should be considered as medically appropriate [see Clinical Pharmacology (12.2)].

figure-1 figure-2 figure-3 2.4 Restarting Antithrombotic Therapy Patients being treated with dabigatran therapy 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.

Idarucizumab is a specific reversal agent for dabigatran, with no impact on the effect of other anticoagulant or antithrombotic therapies.

Pradaxa treatment can be initiated 24 hours after administration of PRAXBIND [see Clinical Pharmacology (12.2)].

Use in special populations

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of PRAXBIND in pregnant women to inform on associated risks.

Animal reproductive and development studies have not been conducted with idarucizumab.

It is also not known whether PRAXBIND can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

PRAXBIND should be given to a pregnant woman only if clearly needed.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively.

Clinical Considerations Labor or Delivery PRAXBIND has not been studied for use during labor and delivery.

Safety and effectiveness of PRAXBIND during labor and delivery have not been studied in clinical trials.

8.2 Lactation Risk Summary There are no data on the effects of PRAXBIND on the breastfed child or on milk production.

It is not known whether idarucizumab is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when PRAXBIND is administered to a nursing woman.

The developmental and health benefits of breastfeeding should be considered along with the mother 's clinical need for PRAXBIND and any potential adverse effects on the breastfed child from PRAXBIND or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use A total of 111 (90 %) patients treated with idarucizumab in the case series trial were 65 years of age and older, and 74 (60 %) were 75 years of age and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not be ruled out.

8.6 Renal Impairment Renal impairment did not impact the reversal effect of idarucizumab [see Clinical Pharmacology (12.3)].

No dose adjustment is required in renally impaired patients.

8.7 Hepatic Impairment No formal studies of PRAXBIND in patients with hepatic impairment have been conducted.

More information

Category Value
Authorisation number BLA761025
Agency product number 97RWB5S1U6
Orphan designation No
Product NDC 0597-0197
Date Last Revised 28-10-2015
Type HUMAN PRESCRIPTION DRUG
RXCUI 1716200
Marketing authorisation holder Boehringer Ingelheim Pharmaceuticals, Inc.