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IDARUCIZUMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Idarucizumab is a humanized monoclonal antibody fragment (Fab) used to reverse the anticoagulant effects of dabigatran for life-threatening or uncontrolled bleeding or when an emergency procedure or surgery is required.

Specific Substances

    1) CAS 1362509-93-0

Available Forms Sources

    A) FORMS
    1) Idarucizumab is available as 2.5 g/50 mL solution in a single-use vial (Prod Info PRAXBIND(R) intravenous injection, 2015).
    B) USES
    1) Idarucizumab is a humanized monoclonal antibody fragment (Fab) indicated in adults for reversal of the anticoagulant effects of dabigatran for life-threatening or uncontrolled bleeding or when an emergency procedure or surgery is required. Praxbind(R) received accelerated approval for this indication based on results from healthy volunteer studies. Continued approval may be based on results from an ongoing cohort case series study. Idarucizumab will not reverse the effects of other anticoagulant or antithrombotic therapies (Prod Info PRAXBIND(R) intravenous injection, 2015).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Idarucizumab is indicated for reversal of the anticoagulant effects of dabigatran for life-threatening or uncontrolled bleeding or when an emergency procedure or surgery is required.
    B) PHARMACOLOGY: Idarucizumab, a humanized monoclonal antibody fragment, neutralizes the anticoagulant effect of dabigatran by binding to dabigatran and its acylglucuronide metabolites. The binding affinity for idarucizumab is higher than that of dabigatran to thrombin.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (5% OR GREATER): Headache, hypokalemia, delirium, constipation, pyrexia, and pneumonia have been reported. OTHERS: Hypersensitivity reactions, elevated coagulation parameters, as well as thrombotic events have also been reported. Idarucizumab IV product contains sorbitol which may cause serious adverse reactions, including fatalities, with parenteral administration.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an exaggeration of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) There are no adequate or well controlled studies of idarucizumab use during human pregnancy and animal studies have not yet been conducted. Use during pregnancy only if clearly needed. It is unknown whether idarucizumab is excreted into human breast milk. Exercise caution when administering to a lactating woman.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, human carcinogenicity studies with idarucizumab have not been conducted.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and CBC with differential and platelet count in symptomatic patients.
    C) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    D) Monitor patients carefully for clinical evidence of thromboembolic events.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) DECONTAMINATION
    1) Decontamination is not indicated; idarucizumab is only available parenterally.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reaction.
    D) ANTIDOTE
    1) None.
    E) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) When managing a suspected overdose, the possibility of multi-drug involvement should be considered.
    H) PHARMACOKINETICS
    1) Vd: 8.9 L. Renal excretion: 32.1%. Total body clearance: Idarucizumab is eliminated rapidly at a total body clearance rate of 47 mL/min. Elimination half-life: Idarucizumab is eliminated rapidly with an initial half-life of 47 minutes and a terminal half life of 10.3 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents (eg,. oral contraceptives) that may cause thromboembolic events or disorders such as a history of deep vein thrombosis, superficial thrombophlebitis, trauma, soft tissue injury, immobility, or cellulitis.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established for idarucizumab.
    B) THERAPEUTIC DOSE: ADULT: 5 g (2 vials) IV; limited data support the use of an additional 5 g if coagulation parameters re-elevate in the presence of clinically relevant bleeding, or if another emergency procedure is needed. Dabigatran can be reinitiated 24 hours after administration. PEDIATRIC: Safety and efficacy not established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Idarucizumab is indicated for reversal of the anticoagulant effects of dabigatran for life-threatening or uncontrolled bleeding or when an emergency procedure or surgery is required.
    B) PHARMACOLOGY: Idarucizumab, a humanized monoclonal antibody fragment, neutralizes the anticoagulant effect of dabigatran by binding to dabigatran and its acylglucuronide metabolites. The binding affinity for idarucizumab is higher than that of dabigatran to thrombin.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (5% OR GREATER): Headache, hypokalemia, delirium, constipation, pyrexia, and pneumonia have been reported. OTHERS: Hypersensitivity reactions, elevated coagulation parameters, as well as thrombotic events have also been reported. Idarucizumab IV product contains sorbitol which may cause serious adverse reactions, including fatalities, with parenteral administration.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an exaggeration of adverse effects following therapeutic doses.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In the interim analysis of a clinical trial (RE-VERSal Effects of idarucizumab on Active Dabigatran), pyrexia developed in 7 (6%) of 123 dabigatran-treated patients who were administered idarucizumab for either an emergency surgery or urgent procedure, or for a life-threatening or uncontrolled bleeding (Prod Info PRAXBIND(R) intravenous injection, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) In the interim analysis of a clinical trial (RE-VERSal Effects of idarucizumab on Active Dabigatran), pneumonia developed in 7 (6%) of 123 dabigatran-treated patients who were administered idarucizumab for either an emergency surgery or urgent procedure, or for a life-threatening or uncontrolled bleeding (Prod Info PRAXBIND(R) intravenous injection, 2015).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In 3 clinical trials, headache developed in 12 (5%) of 224 healthy volunteers who were treated with idarucizumab (Prod Info PRAXBIND(R) intravenous injection, 2015).
    B) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) In the interim analysis of a clinical trial (RE-VERSal Effects of idarucizumab on Active Dabigatran), delirium developed in 9 (7%) of 123 dabigatran-treated patients who were administered idarucizumab for either an emergency surgery or urgent procedure, or for a life-threatening or uncontrolled bleeding (Prod Info PRAXBIND(R) intravenous injection, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In the interim analysis of a clinical trial (RE-VERSal Effects of idarucizumab on Active Dabigatran), constipation developed in 8 (7%) of 123 dabigatran-treated patients who were administered idarucizumab for either an emergency surgery or urgent procedure, or for a life-threatening or uncontrolled bleeding (Prod Info PRAXBIND(R) intravenous injection, 2015).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) COAG./BLEEDING TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated coagulation parameters (eg, aPTT, ecarin clotting time) have been reported in a limited number of patients between 12 and 24 hours after idarucizumab administration (Prod Info PRAXBIND(R) intravenous injection, 2015).
    B) THROMBOEMBOLIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In the interim analysis of a clinical trial (RE-VERSal Effects of idarucizumab on Active Dabigatran), thrombotic events developed in 5 (4%) of 123 dabigatran-treated patients who were administered idarucizumab for either an emergency surgery or urgent procedure, or for a life-threatening or uncontrolled bleeding. Thrombotic events developed in one patient 2 days after treatment and in 4 patients 7 days or more after treatment with idarucizumab. These thrombotic events were attributed to underlying conditions of the patient; none of the patients who had an event were on antithrombotic therapy at the time (Prod Info PRAXBIND(R) intravenous injection, 2015).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions, including pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported with idarucizumab therapy (Prod Info PRAXBIND(R) intravenous injection, 2015).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate or well controlled studies of idarucizumab use during human pregnancy and animal studies have not yet been conducted. Use during pregnancy only if clearly needed. It is unknown whether idarucizumab is excreted into human breast milk. Exercise caution when administering to a lactating woman.
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate or well controlled studies of idarucizumab use during human pregnancy and animal studies have not yet been conducted. Use during pregnancy only if clearly needed (Prod Info PRAXBIND(R) intravenous injection, 2015).
    B) LABOR AND DELIVERY
    1) It is unknown whether idarucizumab is safe to use during labor and delivery. No studies have been conducted with idarucizumab (Prod Info PRAXBIND(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether idarucizumab is excreted into human breast milk. Exercise caution when administering to a lactating woman (Prod Info PRAXBIND(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) No fertility studies have been conducted with idarucizumab (Prod Info PRAXBIND(R) intravenous injection, 2015).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, human carcinogenicity studies with idarucizumab have not been conducted.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, human carcinogenicity studies with idarucizumab have not been conducted (Prod Info PRAXBIND(R) intravenous injection, 2015).

Genotoxicity

    A) At the time of this review, genotoxicity studies with idarucizumab have not been conducted (Prod Info PRAXBIND(R) intravenous injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and CBC with differential and platelet count in symptomatic patients.
    C) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    D) Monitor patients carefully for clinical evidence of thromboembolic events.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and CBC with differential and platelet count in symptomatic patients.
    C) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    D) Monitor patients carefully for clinical evidence of thromboembolic events.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated; idarucizumab is only available parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established for idarucizumab.
    B) THERAPEUTIC DOSE: ADULT: 5 g (2 vials) IV; limited data support the use of an additional 5 g if coagulation parameters re-elevate in the presence of clinically relevant bleeding, or if another emergency procedure is needed. Dabigatran can be reinitiated 24 hours after administration. PEDIATRIC: Safety and efficacy not established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) 5 g (2 vials) IV; limited data support the use of an additional 5 g if coagulation parameters re-elevate in the presence of clinically relevant bleeding, or if another emergency procedure is needed. Dabigatran can be reinitiated 24 hours after administration (Prod Info PRAXBIND(R) intravenous injection, 2015).
    7.2.2) PEDIATRIC
    A) Safety and efficacy not established in pediatric patients (Prod Info PRAXBIND(R) intravenous injection, 2015).

Maximum Tolerated Exposure

    A) A specific minimum toxic dose has not been established for idarucizumab.

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Idarucizumab, a humanized monoclonal antibody fragment, neutralizes the anticoagulant effect of dabigatran by binding to dabigatran and its acylglucuronide metabolites. The binding affinity for idarucizumab is higher than that of dabigatran to thrombin (Prod Info PRAXBIND(R) intravenous injection, 2015).

Physicochemical

Physical Characteristics

    A) A sterile, preservative-free, colorless to slightly yellow, clear to slightly opalescent solution for IV administration (Prod Info PRAXBIND(R) intravenous injection, 2015).

Molecular Weight

    A) Approximately 47,766 Daltons (Prod Info PRAXBIND(R) intravenous injection, 2015).

References

General Bibliography

    1) Product Information: PRAXBIND(R) intravenous injection, idarucizumab intravenous injection. Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015.