Idarucizumab (Monograph)

Brand name: Praxbind
Drug class: Antihemorrhagic Agents, Miscellaneous
Chemical name: Anti-(dabigatran) (human-Mus musculus κ-chain), anti-(dabigatran) (human-Mus musculus γ1-chain) (225→219′)-disulfide with immunoglobulin G1, 1-225-immunoglobulin G1
Molecular formula: C₂₁₃₁H₃₂₉₉N₅₅₅O₆₇₁S₁₁
CAS number: 1362509-93-0

Medically reviewed by Drugs.com on Dec 4, 2023. Written by ASHP.

Introduction

Specific reversal agent for anticoagulant effects of dabigatran; recombinant humanized monoclonal antibody fragment capable of binding dabigatran.

Uses for Idarucizumab

Reversal of Dabigatran Anticoagulation

Used for urgent reversal of dabigatran anticoagulation in patients with life-threatening or uncontrolled bleeding or need for emergency surgery/urgent procedures; designated an orphan drug by FDA for this use.

Specifically reverses dabigatran-induced anticoagulation; no impact on the effect of other anticoagulant or antithrombotic therapies.

Management of bleeding complications in patients receiving direct oral anticoagulants (DOACs) should be individualized according to severity and location of hemorrhage.

Reversal agents should generally be reserved for patients with severe and life-threatening bleeding. Experts state that reversal agents should only be administered when clinically relevant DOAC concentrations are documented or expected. If a reversal agent is warranted in a patient with dabigatran-associated bleeding, idarucizumab may be used if available.

Experts state that reversal agents should only be considered in patients undergoing invasive procedures or surgery if the procedure cannot be safely performed while the patient is anticoagulated and cannot be delayed; in addition, clinically relevant plasma concentrations of the DOAC should be demonstrated or expected. If a reversal agent for dabigatran is warranted in a patient requiring urgent surgery, idarucizumab may be used if available.

Use in conjunction with supportive measures (e.g., maintenance of adequate diuresis, mechanical compression, surgical hemostasis, volume replacement, blood products) as appropriate.

Idarucizumab Dosage and Administration

Administration

IV Administration

Administer as 2 consecutive IV infusions directly from 50-mL vials of idarucizumab or as 2 consecutive rapid IV (“bolus”) injections via syringe; administer undiluted.

Once the solution is withdrawn from vial, begin administration promptly.

Do not mix or administer with any other drug.

May be administered through existing IV line; flush line with 0.9% sodium chloride injection prior to and at the end of idarucizumab infusion.

Rate of Administration

IV infusion and rapid IV injection: Administer as rapidly as clinically feasible. Some clinicians state that infusion of each vial via syringe, infusion pump, or other appropriate equipment should take no longer than 5–10 minutes.

Dosage

Adults

Urgent Reversal of Dabigatran Anticoagulation

IV

5 g administered in 2 divided (2.5 g each) consecutive doses via IV infusion or rapid IV injection.

If reappearance of clinically relevant bleeding and elevated coagulation parameters occur or patient requires second emergency surgery/urgent procedure and has elevated coagulation parameters, may administer additional 5-g dose. Safety and efficacy of repeat treatment with idarucizumab not well established. (See Re-elevation of Coagulation Parameters under Cautions.)

Dabigatran therapy can be reinitiated 24 hours after administration of idarucizumab; consider resumption of anticoagulation as soon as medically appropriate. (See Thromboembolic Complications under Cautions.)

Special Populations

Renal Impairment

Dosage adjustment not required.

Hepatic Impairment

Safety and efficacy not established.

Cautions for Idarucizumab

Contraindications

• None.

Warnings/Precautions

Thromboembolic Complications

Patients receiving dabigatran usually have underlying conditions that predispose them to thromboembolism; reversal of anticoagulation by idarucizumab exposes patients to their underlying thrombotic risk. Consider resumption of anticoagulant therapy as soon as medically appropriate.

Re-elevation of Coagulation Parameters

Re-elevation of coagulation parameters following initial normalization with idarucizumab reported. May consider additional 5-g dose if patient has clinically relevant bleeding or requires a second urgent/emergency procedure.

Hereditary Fructose Intolerance

Recommended 5-g dose of idarucizumab contains 4 g of sorbitol as an excipient.

Serious adverse reactions, including death, reported in patients with hereditary fructose intolerance who received parenteral sorbitol. Minimum amount of sorbitol at which serious adverse reactions may occur not known.

Immunogenicity

Potential for immunogenicity with use of all therapeutic proteins, including idarucizumab. Preexisting antibodies with cross-reactivity to idarucizumab detected in some patients in clinical trials; however, clinically important effects not observed.

Sensitivity Reactions

Hypersensitivity

Additional clinical experience needed to fully determine immunogenic risk. Adverse events possibly indicative of hypersensitivity reactions (e.g., pyrexia, bronchospasm, rash, pruritus) reported.

Weigh anticipated benefits of idarucizumab against risk of hypersensitivity in patients with known hypersensitivity (e.g., anaphylactoid reaction) to the drug or other ingredients in formulation. Discontinue idarucizumab and initiate appropriate therapy if severe hypersensitivity reaction occurs.

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women. Animal reproductive and developmental studies lacking. Use during pregnancy only when clearly needed.

Safety and efficacy of idarucizumab during labor and delivery not established.

Lactation

Not known whether idarucizumab is distributed into human milk. Use with caution.

Consider known benefits of breast-feeding along with mother’s clinical need for idarucizumab and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy or safety between geriatric and younger patients; however, increased sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Does not affect dabigatran anticoagulation reversal effect of idarucizumab.

Hepatic Impairment

Pharmacokinetic data lacking.

Common Adverse Effects

Headache, constipation, nausea.

Drug Interactions

Specific Drugs

Idarucizumab Pharmacokinetics

Absorption

Bioavailability

No differences in idarucizumab plasma concentrations when the drug was administered alone or after pretreatment with dabigatran.

Onset

Rapidly binds to dabigatran; reverses anticoagulant effect of dabigatran within minutes.

Distribution

Extent

Limited extravascular distribution. Not known whether distributed into milk.

Elimination

Metabolism

Biodegraded into peptides and amino acids.

Elimination Route

Excreted in urine (32.1% within 6 hours after administration and <1% during next 18 hours); remainder of dose presumed eliminated via renal catabolism.

Half-life

Initial half-life 47 minutes; terminal half-life 10.3 hours.

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze or shake.

Vials protected from light in original package may be kept at room temperature (25°C) for ≤48 hours.

Vials not stored in original package and exposed to light may be kept at room temperature (25°C) for ≤6 hours.

Actions

• Recombinant IgG₁ monoclonal antibody fragment; binds specifically to unbound and thrombin-bound dabigatran and acylglucuronide metabolites.

• High affinity of idarucizumab for dabigatran causes rapid formation of idarucizumab-dabigatran complex, leaving thrombin uninhibited and capable of triggering clotting.

• Reversal of dabigatran-mediated anticoagulation observed within minutes.

• Structurally similar to thrombin; lacks thrombin-like activity. Does not exhibit intrinsic procoagulant or anticoagulant effects.

• Does not affect activity of factor Xa inhibitors (apixaban, edoxaban, rivaroxaban), direct thrombin inhibitors (argatroban and hirudin), vitamin K antagonists (warfarin), or heparin.

Advice to Patients

• Importance of informing patients of signs and symptoms of allergic hypersensitivity reactions (e.g., anaphylaxis) that may occur during or after administration of idarucizumab.

• Importance of informing patients that reversing dabigatran therapy exposes them to thromboembolic risk from their underlying disease. Clinicians should consider resuming anticoagulant therapy as soon as the patient is sufficiently stable.

• Importance of advising patients to seek immediate medical attention for any signs or symptoms of bleeding.

• Importance of informing patients with hereditary fructose intolerance that idarucizumab solution for injection contains sorbitol. Advise patients that parenteral sorbitol in patients with hereditary fructose intolerance is associated with reports of hypoglycemia, metabolic acidosis, increase in uric acid, acute liver failure with breakdown of hepatic excretory and synthetic function, and death; such effects may occur during or after administration of idarucizumab.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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