Identification

Summary

Andexanet alfa is a recombinant Factor Xa used to reverse anticoagulation caused by rivaroxaban and apixaban.

Brand Names
Andexxa
Generic Name
Andexanet alfa
DrugBank Accession Number
DB14562
Background

Andexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan 1.

Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban 1. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited 7. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors 1. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways 5 and remains catalytically inactive due to structural modification 1. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex 5. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex 5. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin 5.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Blood factors
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
>Peptide sequence
ANSFLFWNKYKDGDQCETSPCQNQGKCKDGLGEYTCTCLEGFEGKNCELFTRKLCSLDNG
DCDQFCHEEQNSVVCSCARGYTLADNGKACIPTGPYPCGKQTLERRKRRKRIVGGQECKD
GECPWQALLINEENEGFCGGTILSEFYILTAAHCLYQAKRFKVRVGDRNTEQEEGGEAVH
EVEVVIKHNRFTKETYDFDIAVLRLKTPITFRMNVAPACLPERDWAESTLMTQKTGIVSG
FGRTHEKGRQSTRLKMLEVPYVDRNSCKLSSSFIITQNMFCAGYDTKQEDACQGDAGGPH
VTRFKDTYFVTGIVSWGEGCARKGKYGIYTKVTAFLKWIDRSMKTRGLPKAKSHAPEVIT
SSPLK
Download FASTA Format
Synonyms
  • Andexanet alfa
  • r-Antidote
  • rfXa Inhibitor Antidote
External IDs
  • PRT-4445
  • PRT064445

Pharmacology

Indication

Andexanet alfa is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding 7. Andexxa has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any Factor Xa inhibitors other than apixaban and rivaroxaban 7.

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

In vitro, andexanet alfa was shown to dose-dependently reverse the activity of apixaban, betrixaban, edoxaban, rivaroxaban, enoxaparin and fondaparinux on Factor Xa in human and rat plasma 1.

In a randomized placebo-controlled study of healthy elderly volunteers, co-administration of andexanet alfa bolus with 5 mg of apixaban twice daily resulted in a reduction of anti-factor Xa activity by 94% compared to 21% among those who received placebo, and thrombin generation was fully restored in 100% 2. The anti-factor Xa activity was reduced by 92% and thrombin generation was fully restored in 96% of the subjects upon andexanet alfa bolus administration in subjects receiving 20 mg of rivaroxaban daily 2. A multicenter, prospective, open-label, single-group study involving elderly patients with acute major bleeding within 18 hours after the administration of a factor Xa inhibitor was performed. In this study, the median anti-factor Xa activity in patients receiving rivaroxaban and apixaban was reduced by 89% and 93%, respectively, upon administration of andexanet alfa infusion 3.

In dose-ranging studies of healthy volunteers, the anti-FXa activity activity was observed within two minutes after the completion of the bolus administration. Elevation of Tissue Factor (TF)-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of andexanet alfa and was maintained throughout the duration of the continuous infusion 7. The anti-FXa activity returned to the placebo levels approximately 2 hours after completion of a bolus or continuous infusion 7. In contrast, TFPI activity in plasma was sustained for at least 22 hours following andexanet alfa administration 7.

Mechanism of action

Factor Xa inhibitors promote anticoagulation by binding to both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex. This ultimately leads to the blockade of thrombin generation or clot formation 4. Andexanet alfa is a factor Xa decoy that binds to factor Xa inhibitors such as apixaban and rivaroxaban with high affinity and prevents them from binding to endogenous factor Xa. It was also shown to sequester factor Xa inhibitors, leading to reversing their anticoagulant effects and restoring the activity of endogenous factor Xa 1. Andexanet alfa may also achieve procoagulation via binding and inhibiting the activity of Tissue Factor Pathway Inhibitor (TFPI), which is an endogenous inhibitor of Factor Xa 1. Inhibition of TFPI by andexanet alfa resulted in a transient increase in the level of prothrombin fragments 1 and 2, thrombin-antithrombin complex and D-dimer 1. Subsequently, this may result in increased tissue factor-initiated thrombin generation 7. Since it is a genetically modified variant of human factor Xa, andexanet alfa is not able to cleave and activate prothrombin nor assemble into the prothrombinase complex 1.

TargetActionsOrganism
ATissue factor pathway inhibitor
inhibitor
Humans
Absorption

Following intravenous administration of bolus doses > 30 mg in healthy subjects, the exposure of andexanet alfa increased in a dose-dependent manner.

Volume of distribution

The volume of distribution (Vd) for andexanet alfa is approximately equivalent to the blood volume of 5 L 7.

Protein binding

No information available.

Metabolism

There is limited information regarding the metabolism of andexanet alfa 5.

Route of elimination

There is limited information regarding the elimination of andexanet alfa 5.

Half-life

The elimination half-life ranges from 5 to 7 hours 7.

Clearance

Clearance for andexanet alfa is approximately 4.3 L/hr 7.

Adverse Effects
Adverseeffects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbciximabThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Abciximab.
AcenocoumarolThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Acenocoumarol.
Alpha-1-proteinase inhibitorAlpha-1-proteinase inhibitor may increase the thrombogenic activities of Andexanet alfa.
AlteplaseThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Alteplase.
Aminocaproic acidThe risk or severity of adverse effects can be increased when Aminocaproic acid is combined with Andexanet alfa.
AncrodThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Ancrod.
AnistreplaseThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Anistreplase.
Antithrombin AlfaThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Antithrombin Alfa.
Antithrombin III humanThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Antithrombin III human.
ApixabanThe therapeutic efficacy of Andexanet alfa can be decreased when used in combination with Apixaban.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AndexxaInjection, powder, lyophilized, for solution100 mg/10mLIntravenousAlexion Pharmaceuticals, Inc.2018-05-142020-10-31US flag
AndexxaInjection, powder, lyophilized, for solution200 mg/20mLIntravenousAlexion Pharmaceuticals, Inc.2019-01-08Not applicableUS flag
OndexxyaInjection, powder, for solution200 mgIntravenousAlexion Europe Sas2020-12-16Not applicableEU flag

Categories

ATC Codes
V03AB38 — Andexanet alfa
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
BI009E452R
CAS number
1262449-58-0

References

General References
  1. Heo YA: Andexanet Alfa: First Global Approval. Drugs. 2018 Jun 20. pii: 10.1007/s40265-018-0940-4. doi: 10.1007/s40265-018-0940-4. [Article]
  2. Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24. doi: 10.1056/NEJMoa1510991. Epub 2015 Nov 11. [Article]
  3. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J, Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B, Nakamya J, Lim WT, Crowther M: Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30. [Article]
  4. Cabral KP, Ansell JE: The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag. 2015 Jan 30;11:117-23. doi: 10.2147/VHRM.S39726. eCollection 2015. [Article]
  5. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG: Reversing factor Xa inhibitors - clinical utility of andexanet alfa. J Blood Med. 2017 Sep 13;8:141-149. doi: 10.2147/JBM.S121550. eCollection 2017. [Article]
  6. Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U: A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013 Apr;19(4):446-51. doi: 10.1038/nm.3102. Epub 2013 Mar 3. [Article]
  7. DailyMed Label: ANDEXXA- andexanet alfa injection, powder, lyophilized, for solution [Link]
  8. andexanet alfa | Ligand page | IUPHAR/BPS Guide to Pharmacology [Link]
RxNav
2045114
Wikipedia
Andexanet_alfa

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentAcute Intracranial Hemorrhage1
3CompletedOtherBleeding1
3CompletedTreatmentBleeding1
2CompletedTreatmentBleeding1
2CompletedTreatmentHealthy Subjects (HS)4
2RecruitingTreatmentSurgery1
2TerminatedTreatmentBleeding1
1CompletedOtherHealthy Subjects (HS)1
1CompletedTreatmentBleeding1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous100 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous200 mg/20mL
Injection, powder, for solutionIntravenous200 mg
Powder, for solutionIntravenous200 MG
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action...
Gene Name
TFPI
Uniprot ID
P10646
Uniprot Name
Tissue factor pathway inhibitor
Molecular Weight
35014.835 Da

Drug created at July 20, 2018 16:15 / Updated at August 17, 2021 04:16