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Praxbind

Generic Name: Idarucizumab
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

Introduction

Specific reversal agent for anticoagulant effects of dabigatran etexilate mesylate (Pradaxa); recombinant humanized monoclonal antibody fragment capable of binding dabigatran.1 8 16

Uses for Praxbind

Urgent Reversal of Dabigatran Anticoagulation

Used for the urgent reversal of dabigatran anticoagulation in patients with life-threatening or uncontrolled bleeding or a need for emergency surgery/urgent procedures; designated an orphan drug by FDA for this use.1 2 3

Accelerated approval of idarucizumab for this indication based on reduction in unbound plasma dabigatran and normalization of coagulation parameters with idarucizumab treatment in healthy individuals; continued FDA approval for this indication may be contingent on results of ongoing cohort case series study.1 6

Specifically reverses dabigatran-induced anticoagulation; no impact on the effect of other anticoagulant or antithrombotic therapies.1 7 16

Can be used in conjunction with supportive measures (e.g., maintenance of adequate diuresis, mechanical compression, surgical hemostasis, volume replacement, blood products) as appropriate.1 17 18

Praxbind Dosage and Administration

General

  • Dabigatran therapy can be reinitiated 24 hours after administration of idarucizumab; consider resumption of anticoagulation as soon as medically appropriate.1 7 16 (See Thromboembolic Complications under Cautions.)

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.1 13

Once idarucizumab is withdrawn from vial, begin administration promptly or within 1 hour.1

Do not mix or administer with any other drug.1

May be administered through existing IV line; flush line with 0.9% sodium chloride injection prior to and at the end of idarucizumab infusion.1 19

Rate of Administration

IV infusion and rapid IV injection: Administer as rapidly as clinically feasible.19 Some clinicians state that infusion of each vial via syringe, infusion pump, or other appropriate equipment should take no longer than 5–10 minutes.16

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.1 16

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.1 16 Safety and efficacy of repeat treatment with idarucizumab not established.1

Special Populations

Renal Impairment

Dosage adjustment not required.1 13

Hepatic Impairment

Safety and efficacy not established. 1 13

Cautions for Praxbind

Contraindications

  • Manufacturer states none.1

Warnings/Precautions

Thromboembolic Complications

Patients receiving therapy with dabigatran usually have underlying conditions that predispose them to thromboembolism; reversal of anticoagulation by idarucizumab exposes patients to their underlying thrombotic risk.1 12 Consider resumption of anticoagulant therapy as soon as medically appropriate.1

Hereditary Fructose Intolerance

Recommended 5-g dose of idarucizumab contains 4 g of sorbitol as an excipient.1

Serious adverse reactions, including death, reported in patients with hereditary fructose intolerance who received parenteral sorbitol.1 Minimum amount of sorbitol at which serious adverse reactions may occur in such patients not known.1

Immunogenicity

Potential for immunogenicity with use of all therapeutic proteins, including idarucizumab.1 16 Preexisting antibodies with cross-reactivity to idarucizumab detected in some patients in clinical trials; however, clinically important effects not observed.1 5 7

Sensitivity Reactions

Hypersensitivity

Additional clinical experience needed to fully determine immunogenic risk.1 Adverse events possibly indicative of hypersensitivity reactions (e.g., pyrexia, bronchospasm, rash, pruritus) reported.1

Weigh anticipated benefits of idarucizumab against risk of hypersensitivity in patients with known hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or other ingredients in formulation.1 Discontinue idarucizumab and initiate appropriate therapy if severe hypersensitivity reaction occurs.1

Specific Populations

Pregnancy

No adequate and well-controlled studies of idarucizumab in pregnant women.1 13 Animal reproductive and developmental studies with idarucizumab lacking.1 Use during pregnancy only when clearly needed.1 Safety and efficacy of idarucizumab during labor and delivery not established.1

Lactation

Not known whether idarucizumab is distributed into human milk.1 Use with caution.1

Pediatric Use

Safety and efficacy not established.1 12

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.1 12

Renal Impairment

Does not affect dabigatran anticoagulation reversal effect of idarucizumab.1 13

Hepatic Impairment

Pharmacokinetic data lacking.1 13

Common Adverse Effects

Headache,1 hypokalemia,1 14 delirium,1 14 constipation,1 14 pyrexia.1 14

Interactions for Praxbind

Specific Drugs

Drug

Interaction

Coagulation factor concentrates (3- or 4- factor prothrombin complex concentrates [PCC], activated PCC, recombinant factor VIIa)

Inhibition of dabigatran anticoagulation not affected1

Volume-replacement preparations (crystalloids, colloids)

Neutralization of dabigatran not influenced by 50% hemodilution with volume-replacement therapies1 7 8

Praxbind Pharmacokinetics

Absorption

Bioavailability

No differences in idarucizumab plasma concentrations when the drug was administered alone or after pretreatment with dabigatran.1

Onset

Rapidly binds to dabigatran; reverses anticoagulant effect of dabigatran within minutes.3 7 16

Distribution

Extent

Limited extravascular distribution.1 Not known whether distributed into milk.1

Elimination

Metabolism

Biodegraded into peptides and amino acids.1

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.1 13 16

Half-life

Initial half-life 47 minutes; terminal half-life 10.3 hours.1

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze or shake.1

Unopened vials protected from light in original package may be kept at room temperature (25°C) for <48 hours.1

Unopened vials exposed to light may be kept at room temperature (25°C) for <6 hours.1

Actions

  • Recombinant IgG1 monoclonal antibody fragment; binds specifically to unbound and thrombin-bound dabigatran and acylglucuronide metabolites.1 8 14 16

  • High affinity of idarucizumab for dabigatran causes rapid formation of idarucizumab-dabigatran complex, leaving thrombin uninhibited and capable of triggering clotting.1 7 8 16 20

  • Reversal of dabigatran-mediated anticoagulation observed within minutes.3 7 16

  • Structurally similar to thrombin; lacks thrombin-like activity.8 9 16 20 Does not exhibit intrinsic procoagulant or anticoagulant effects.16

  • Does not affect activity of factor Xa inhibitors (apixaban, edoxaban, rivaroxaban), direct thrombin inhibitors (argatroban and hirudin), vitamin K antagonists (warfarin), or heparin.14

Advice to Patients

Importance of informing patients of signs and symptoms of allergic hypersensitivity reactions (e.g., anaphylaxis) that may occur during or after injection of idarucizumab.1

Importance of informing patients that reversing dabigatran therapy exposes them to thromboembolic risk of their underlying disease.1 Clinicians should consider resuming anticoagulant therapy as soon as the patient is sufficiently stable.1

Importance of advising patients to seek immediate medical attention for any signs or symptoms of bleeding.1

Importance of informing patients with hereditary fructose intolerance that idarucizumab solution for injection contains sorbitol.1 Importance of informing patients that parenteral sorbitol in patients with hereditary fructose intolerance 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 injection of idarucizumab.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

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.

Idarucizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

50 mg/mL (2.5 g)

Praxbind

Boehringer Ingelheim

AHFS DI Essentials. © Copyright 2016, Selected Revisions November 10, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Boehringer Ingelheim Pharmaceuticals, Inc. Praxbind (idarucizumab) injection prescribing information. Ridgefield, CT; 2015 Oct.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 Jan 28.

3. Pollack CV, Reilly PA, Eikelboom J et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015; 373:511-20. [PubMed 26095746]

4. Glund S, Stangier J, Schmohl M et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015; 386:680-90. [PubMed 26088268]

5. Glund S, Moschetti V, Norris S et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015; 113:943-51. [PubMed 25789661]

6. Pollack CV, Reilly PA, Bernstein R et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015; 114:198-205. [PubMed 26020620]

7. Miyares MA, Kuyumjian Y, Eaves S et al. Idarucizumab, a humanized, monoclonal antibody fragment for immediate reversal of dabigatran. J Pharm Pract. 2015; 28:548-54.

8. Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015; 35:198-207. [PubMed 25644580]

9. Das A, Liu D. Novel antidotes for target specific oral anticoagulants. Exp Hematol Oncol. 2015; 4:25. [PubMed 26380149]

10. Husted S, Verheugt FW, Comuth WJ. Reversal Strategies for NOACs: State of Development, Possible Clinical Applications and Future Perspectives. Drug Saf. 2016; 39:5-13. [PubMed 26519420]

11. Boehringer Ingelheim Pharmaceuticals, Inc. Pradaxa (dabigatran etexilate mesylate) capsules prescribing information. Ridgefield, CT; 2015 Nov.

12. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761025Orig1s000: medical review(s). From FDA website.

13. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761025Orig1s000: clinical pharmacology and biopharmaceutics review(s) . From FDA website.

14. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761025Orig1s000: summary review. From FDA website.

15. Food and Drug Administration. FDA news release: FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. 2015 Oct 16. From FDA website.

16. Eikelboom JW, Quinlan DJ, van Ryn J et al. Idarucizumab: The Antidote for Reversal of Dabigatran. Circulation. 2015; 132:2412-22. [PubMed 26700008]

17. van Ryn J, Stangier J, Haertter S et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010; 103:1116-27. [PubMed 20352166]

18. Boehringer Ingelheim Pharmaceuticals. Management of medical emergency. Ridgefield, CT: 2015. Available at: . Accessed 2016 Feb 5

19. Boehringer Ingelheim Pharmaceuticals,. Ridgefield, CT: Personal communication.

20. Schiele F, van Ryn J, Canada K et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013; 121:3554-62. [PubMed 23476049]

21. Food and Drug Administration. Compliance Policy Guides: CPG sec. 400.335 fructose-containing drugs. From FDA website.

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