Idarucizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Praxbind: 2.5 g/50 mL (50 mL)

Pharmacology

Mechanism of Action

Idarucizumab, a specific reversal agent for dabigatran, is a humanized monoclonal antibody fragment (Fab) that binds specifically to dabigatran and its acylglucuronide metabolites with an affinity for dabigatran that is ~350 times greater than that of thrombin, and neutralizes the anticoagulant effect within minutes (Das 2015; Schiele 2013).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 8.9 L

Metabolism

Biodegradation of small peptides and amino acids

Excretion

Urine (~32% within the first 6 hours and <1% in the following 18 hours)

Onset of Action

Uncontrolled bleeding: Effects observed within minutes and hemostasis is restored at a median of 11.4 hours (Pollack 2015)

Duration of Action

Usually at least 24 hours

Half-Life Elimination

47 minutes (initial); 10.3 hours (terminal)

Use in Specific Populations

Special Populations: Renal Function Impairment

Total clearance was reduced and mean exposure (AUC) was increased in varying degrees of renal impairment. However, renal impairment did not impact the reversal effect of idarucizumab.

Use: Labeled Indications

Reversal of dabigatran: Reversal of the anticoagulant effects of dabigatran for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to idarucizumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Reversal of dabigatran: IV: 5 g (administered as 2 separate 2.5 g doses no more than 15 minutes apart) (Pollack 2017). If coagulation parameters (eg, aPTT) re-elevate and clinically relevant bleeding occurs or if a second emergency surgery/urgent procedure is required and patient has elevated coagulation parameters, consider administration of an additional 5 g (limited data to support); in patients with dabigatran-associated intracranial hemorrhage, if refractory bleeding occurs after initial idarucizumab dose, consider re-dosing and/or hemodialysis (NCS/SCCM [Frontera 2016]).

Dosing: Geriatric

Refer to adult dosing.

Administration

IV: For IV use only. Do not shake. Prior to administration, flush preexisting IV line with sodium chloride 0.9%. Administer dose undiluted as an IV bolus either via syringe or as an infusion by hanging the vials. Do not mix with other drugs or administer any other infusion in the same IV line. Administer promptly once solution has been removed from vial. Infusion of each vial should take no longer than 5 to 10 minutes with the second vial of 2.5 g administered no later than 15 minutes after the end of the first 2.5 g vial (Pollack 2015 [protocol]).

Storage

Store intact vials at 2ºC to 8ºC (36ºF to 46ºF) in original packaging (to protect from light). Do not freeze. May store intact vials in the original packaging (to protect from light) at room temperature, 25°C (77°F), for up to 48 hours or up to 6 hours if exposed to light.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

1% to 10%:

Central nervous system: Headache (5%)

Gastrointestinal: Constipation (7%), nausea (5%)

Frequency not defined:

Hypersensitivity: Hypersensitivity reaction (including bronchospasm, fever, hyperventilation, pruritus, skin rash)

<1%, postmarketing, and/or case reports (Pollack 2015): Acute ischemic stroke, circulatory shock, deep vein thrombosis, intracardiac thrombus (left atrium), multiorgan failure, myocardial infarction (NSTEMI), pulmonary edema, pulmonary embolism, right heart failure, thromboembolic complications (Pollack 2017)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity reactions: Although there is insufficient clinical experience with idarucizumab to fully evaluate the risk of hypersensitivity reactions, some reported adverse events possibly indicative of hypersensitivity reactions could not exclude a potential relationship. The risk of using idarucizumab in patients with known hypersensitivity (eg, anaphylactoid reaction) to idarucizumab or any of the components of the formulation should be evaluated cautiously against the potential benefit of emergency dabigatran reversal. Discontinue use if serious allergic reaction occurs (eg, anaphylaxis) and institute appropriate management.
• Thromboembolic risk: Since patients being treated with dabigatran, have underlying disease states predisposing them to thromboembolic events and reversing the effects of dabigatran will expose the patient to an elevated thrombotic risk; resume anticoagulant therapy as soon as it is appropriate. Dabigatran can be re-initiated 24 hours after idarucizumab administration if appropriate. In the phase 3 clinical trial, not all thromboembolic events that occurred reflected the underlying disease state being treated with dabigatran; adverse thromboembolic events included DVT, PE, atrial thrombus, NSTEMI, and ischemic stroke (Giannandrea 2018; Pollack 2015).

Disease-related concerns:

• Hereditary fructose intolerance: Formulation contains 4 grams of sorbitol as an excipient. Since IV administration of sorbitol in patients with hereditary fructose intolerance has been reported to result in serious reactions (eg, acute hepatic failure, hypoglycemia, hypophosphatemia, metabolic acidosis, uric acid elevations) including fatalities, consider the combined daily metabolic load of sorbitol/fructose from all sources including idarucizumab and other drugs containing sorbitol; minimum amount of sorbitol known to cause serious adverse reactions is unknown.

Other warnings/precautions:

• Coagulation parameter re-elevation: Although the duration of effect typically lasts at least 24 hours, in the phase 3 clinical trial, coagulation parameters (eg, aPTT, TT, ecarin clotting time [not routinely available]) re-elevated in a limited number of patients between 12 and 24 hours after administration; some patients experienced re-elevation as early as 1 to 4 hours after administration which may have been due to high initial baseline dabigatran concentrations. If clinically relevant bleeding in conjunction with elevated coagulation parameters reoccurs following an idarucizumab 5 g dose, administration of a second dose should be considered (Pollack 2015; Pollack 2017).
• Incomplete reversal: Potential for incomplete reversal of dabigatran exists with idarucizumab. Case reports have described patients with very high initial serum dabigatran concentrations who experienced unsuccessful reversal of the anticoagulant effects of dabigatran after idarucizumab and required repeat doses; early detection of excessive dabigatran concentrations measured using the chromogenic ecarin clotting time assay or reflected as elevated coagulation parameters (ie, INR or thrombin time) is essential (Steele 2017).

Monitoring Parameters

Monitor for re-elevation of coagulation parameters (eg, aPTT); signs/symptoms of clinically relevant bleeding and thromboembolic events.

In patients overdosed with dabigatran, consider the following monitoring schedule (Alikhan 2014): Baseline aPTT (at presentation), repeat at 2 hours postexposure (if exposure time is known) or post-presentation (if exposure time is unknown) and every 12 hours thereafter until aPTT returns to normal.

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted.

Patient Education

What is this drug used for?

• It is used to undo the effects of a certain blood thinner.

Frequently reported side effects of this drug

• Headache
• Nausea
• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.
• Bleeding
• Shortness of breath
• Fast breathing
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

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