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Betrixaban

Class: Direct Factor Xa Inhibitors
Chemical Name: N-(5-chloropyridin-2-yl)-2-[[4-(N,N-dimethylcarbamimidoyl)benzoyl]amino]-5-methoxybenzamide
Molecular Formula: C23H22ClN5O3
CAS Number: 330942-05-7
Brands: Bevyxxa

Medically reviewed by Drugs.com. Last updated on Oct 14, 2019.

Warning

    Spinal/Epidural Hematoma
  • Risk of epidural or spinal hematomas and neurologic injury, including long-term or permanent paralysis, in patients who are anticoagulated and also receiving neuraxial (spinal/epidural) anesthesia or spinal puncture.1

  • Risk increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis (e.g., NSAIAs, platelet-aggregation inhibitors, other anticoagulants).1 14

  • Monitor frequently for signs and symptoms of neurologic impairment and treat urgently if neurologic compromise noted.1

  • Consider potential benefits versus risks of spinal or epidural anesthesia or spinal puncture in patients receiving or being considered for anticoagulant therapy.1 (See Spinal/Epidural Hematoma under Cautions.)

Introduction

Anticoagulant; an oral, direct activated factor X (Xa) inhibitor.1 2 5 6 11

Uses for Betrixaban

Deep-Vein Thrombosis and Pulmonary Embolism

Thromboprophylaxis in Acute Medical Illness

Prevention of venous thromboembolism in patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderately or severely restricted mobility and other risk factors for venous thromboembolism.1 2 3 6

Pharmacologic thromboprophylaxis generally recommended in patients considered to be at high risk of venous thromboembolism.1001 Anticoagulant prophylaxis recommended by ACCP in acutely ill, hospitalized medical patients at increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding.1001 Such prophylaxis generally continued for 6–21 days until full mobility is restored or hospital discharge, whichever comes first; extended prophylaxis beyond these periods generally not recommended because of data suggesting unfavorable benefit-to-risk ratio for bleeding.6 15 16 1001

However, available data suggest benefit for extended-duration (35–42 days) betrixaban compared with standard-duration (6–14 days) enoxaparin for reducing risk of venous thromboembolism in hospitalized patients with acute medical illness and reduced mobility, at the cost of an increase in nonmajor but not major bleeding.1 2 3 6

Safety and efficacy of betrixaban not established in patients with prosthetic heart valves.1

Betrixaban Dosage and Administration

General

  • Routine monitoring of coagulation tests not required.7

  • May use anti-factor Xa assays to measure the effect of betrixaban on factor Xa activity.9 13 Coagulation tests such as PT, aPTT, dilute thrombin time (dTT) or thrombin time (TT) assays, or heparin-specific assays (e.g., activated clotting time [ACT]) not recommended.13

Administration

Oral Administration

Administer orally with food.1

If a dose is missed, take as soon as possible on the same day, then resume regular schedule the following day.1 14

Dosage

Adults

Deep-Vein Thrombosis and Pulmonary Embolism
Thromboprophylaxis in Acute Medical Illness
Oral

Initial loading dose of 160 mg, then 80 mg once daily.1

Recommended duration of therapy: 35–42 days.1

Special Populations

Hepatic Impairment

Avoid use in patients with hepatic impairment due to potential for intrinsic coagulation abnormalities in such patients.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Patients with Clcr >30 mL/minute: No dosage adjustment needed.1

Patients with Clcr 15–29 mL/minute: Initial loading dose of 80 mg, then 40 mg once daily.1

Patients Currently Receiving or Initiating P-glycoprotein (P-gp) Inhibitors

Initial loading dose of 80 mg, then 40 mg once daily.1 (See Drugs Affecting P-gp Transport under Interactions.)

Cautions for Betrixaban

Contraindications

  • Active pathologic bleeding.1

  • Severe hypersensitivity reaction to betrixaban.1

Warnings/Precautions

Warnings

Spinal/Epidural Hematoma

Epidural or spinal hematoma reported with concurrent use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures.1 Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis.1 (See Boxed Warning.)

Do not remove epidural catheters <72 hours after a dose of betrixaban; administer next dose ≥5 hours after catheter removal.1 If traumatic puncture occurs, delay betrixaban administration for 72 hours.1

Monitor frequently for signs of neurologic impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction).1 If spinal hematoma suspected, diagnose and treat immediately.1 Carefully consider potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis.1

Sensitivity Reactions

Hypersensitivity Reactions

At least one serious adverse reaction associated with moderate hypersensitivity to betrixaban reported.1 (See Contraindications under Cautions.)

Other Warnings and Precautions

Bleeding

Betrixaban increases risk of hemorrhage; can cause serious, sometimes fatal bleeding.1 2 5 Promptly evaluate any manifestations of bleeding and consider need for blood replacement.1 Discontinue if active pathologic hemorrhage occurs.1 (See Contraindications under Cautions.)

Risk of bleeding may be increased in patients with severe renal impairment (Clcr 15–29 mL/minute) and in those receiving concomitant therapy with drugs that affect hemostasis or with P-gp inhibitors.1 (See Interactions.)

No specific antidote or reversal agent for betrixaban; unknown if removed by hemodialysis.1 Protamine sulfate, vitamin K, and tranexamic acid not expected to reverse anticoagulant activity of betrixaban.1 Anticoagulant effect may persist for ≥72 hours after last dose.1

Specific Populations

Pregnancy

Adequate data lacking in pregnant women.1 In animal reproduction studies, betrixaban dosage of up to 44 times the recommended human dosage (80 mg once daily) was not associated with adverse fetal developmental effects; however, maternal toxicity (i.e., hemorrhage) was observed.1

Treatment with betrixaban likely to increase risk of hemorrhage during pregnancy and delivery.1 Consider risk of bleeding and stroke in pregnant women.1 Use only if potential benefit outweighs potential risk to the mother and fetus.1

Lactation

Data lacking on the presence of betrixaban in human milk, the effects on the breast-fed infant, or the effects on milk production.1 Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for betrixaban and any potential adverse effects on the breast-fed infant from betrixaban or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1 2

Geriatric Use

Of patients in APEX trial, 90% were ≥65 years of age and 68.6% were ≥75 years of age; no substantial differences in efficacy observed between older and younger adults.1

Hepatic Impairment

Safety and efficacy not established in patients with hepatic impairment.1 Due to potential for intrinsic coagulation abnormalities, use of betrixaban in patients with hepatic impairment not recommended.1

Renal Impairment

Betrixaban exposure increased in patients with renal impairment; risk of bleeding increased.1

Dosage adjustment recommended in patients with renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Bleeding.1

Interactions for Betrixaban

Minimally metabolized (<1%) by CYP isoenzymes 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4;1 11 neither an inducer nor an inhibitor of CYP isoenzymes.11

Drugs Affecting P-gp Transport

Inhibitors of P-gp transport protein may increase betrixaban exposure.1 Reduce betrixaban dosage to initial loading dose of 80 mg followed by 40 mg once daily in patients receiving concomitant P-gp inhibitor therapy.1

Drugs Affecting Hemostasis

Potential increased risk of hemorrhage.1 Promptly evaluate any manifestations of bleeding and consider need for blood replacement.1

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Possible increased betrixaban exposure1

Reduce betrixaban dosage to an initial loading dose of 80 mg, then 40 mg once daily1

Antacids (aluminum- or magnesium-containing)

No effect on betrixaban bioavailability or systemic exposure1 8

Anticoagulants

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

Azithromycin

Possible increased betrixaban exposure1

Reduce betrixaban dosage to an initial loading dose of 80 mg, then 40 mg once daily1

Digoxin

No effect on bioavailability or systemic exposure of either drug1 8 11

Esomeprazole

No effect on betrixaban bioavailability or systemic exposure1 8

Heparin

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

Ketoconazole

Increased betrixaban peak plasma concentration and AUC1 8

Reduce betrixaban dosage to an initial loading dose of 80 mg, then 40 mg once daily1

NSAIAs (e.g, aspirin)

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

Platelet-aggregation inhibitors

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

SNRIs

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

SSRIs

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

Thrombolytic agents

Potentially increased risk of hemorrhage1

Promptly evaluate if bleeding manifestations occur; consider need for blood replacement1

Verapamil

Increased betrixaban peak plasma concentration and AUC1 8

Reduce betrixaban dosage to an initial loading dose of 80 mg, then 40 mg once daily1

Betrixaban Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; bioavailability approximately 34%.1 11

Following oral administration, peak plasma concentrations occur within 3–4 hours; coincides with peak anticoagulant effect.1 11

Steady state achieved in 6 days when given without initial loading dose.1

Food

Food decreases peak concentration and systemic exposure to betrixaban by approximately 60%; effect of food on pharmacokinetics of betrixaban observed for up to 6 hours following a meal.1 11

Special Populations

In patients with mild (eGFR 60–89 mL/minute per 1.73 m2), moderate (eGFR 30–59 mL/minute per 1.73 m2), or severe (eGFR 15–29 mL/minute per 1.73 m2) renal impairment, betrixaban AUC increased by 1.89-, 2.27-, and 2.63-fold, respectively, compared with that in healthy individuals.1

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 60%.1

Elimination

Metabolism

Mainly metabolized by CYP-independent plasma hydrolysis.1 Unchanged betrixaban is the predominant form found in human plasma.1

Elimination Route

Approximately 85% of administered dose eliminated in feces, 11% in urine.1

Not known whether removed by hemodialysis.1

Half-life

Effective half-life: 19–27 hours.1

Terminal half-life: 37 hours.11

Stability

Storage

Oral

Tablet

20–25°C.1

Actions

  • Selectively blocks active site of factor Xa; inhibits both free and platelet-bound factor Xa within the prothrombinase complex.1 2 5 6 10 11

  • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.1 10 11

  • Unlike heparin and low molecular weight heparins, betrixaban binds directly to active site of factor Xa without the need for a cofactor (e.g., antithrombin III).10

  • Concentration-dependent increase in the QT interval corrected for rate (QTc) observed.1 A QTc prolongation of 4 msec predicted for an 80-mg dose of betrixaban and prolongation of 13 msec predicted for a supratherapeutic dose (4.7-fold increase in AUC).1

Advice to Patients

  • Importance of informing patients to take betrixaban with food.1

  • Importance of advising patients that if a dose is missed, it should be taken as soon as possible on the same day and the regular dosing schedule should be resumed the following day; the dose should not be doubled to replace a missed dose.1 14

  • Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required for bleeding to stop when taking betrixaban.1 Importance of informing clinicians about any unusual bleeding or bruising during therapy.1 Importance of patients informing clinicians immediately and of seeking emergency care if they experience signs and symptoms of blood loss.1

  • Importance of patients informing clinicians (e.g., physicians, dentists) about betrixaban therapy before any surgery or invasive procedures, including dental procedures, are scheduled.1

  • Importance of advising patients that the risk of bleeding is greater in people who have severe renal impairment.1

  • Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., numbness or weakness of the legs, bowel or bladder dysfunction); importance of immediately contacting a clinician if any of these symptoms occur.1

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

  • Importance of informing clinicians (e.g., physicians, dentists) of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.1

  • Importance of informing patients of other important precautionary information.1 (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.

Betrixaban Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

40 mg (of betrixaban)

Bevyxxa

Portola Pharmaceuticals

80 mg (of betrixaban)

Bevyxxa

Portola Pharmaceuticals

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 14, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Portola Pharmaceuticals, Inc. Bevyxxa (betrixaban) capsules prescribing information. South San Francisco, CA: 2017 Jun.

2. Cohen AT, Harrington RA, Goldhaber SZ et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016; 375:534-44. http://www.ncbi.nlm.nih.gov/pubmed/27232649?dopt=AbstractPlus

3. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 208383Orig1s000: summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000SumR.pdf

4. Gibson CM, Halaby R, Korjian S et al. The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial. Am Heart J. 2017; 185:93-100. http://www.ncbi.nlm.nih.gov/pubmed/28267480?dopt=AbstractPlus

5. . Betrixaban (Bevyxxa) for VTE prophylaxis in acute medical illness. Med Lett Drugs Ther. 2018; 60:4-5. http://www.ncbi.nlm.nih.gov/pubmed/29294463?dopt=AbstractPlus

6. Garland SG, DeRemer CE, Smith SM et al. Betrixaban: A new oral factor Xa inhibitor for extended venous thromboembolism prophylaxis in high-risk hospitalized patients. Ann Pharmacother. 2018; :1060028018754383. http://www.ncbi.nlm.nih.gov/pubmed/29338293?dopt=AbstractPlus

7. Aronis KN, Hylek EM. Evidence Gaps in the Era of Non-Vitamin K Oral Anticoagulants. J Am Heart Assoc. 2018; 7 http://www.ncbi.nlm.nih.gov/pubmed/29374049?dopt=AbstractPlus

8. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 208383Orig1s000: clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208383Orig1s000ClinPharmR.pdf

9. Samama MM, Amiral J, Guinet C et al. Monitoring plasma levels of factor Xa inhibitors: how, why and when?. Expert Rev Hematol. 2013; 6:155-64. http://www.ncbi.nlm.nih.gov/pubmed/23547865?dopt=AbstractPlus

10. Poulsen BK, Grove EL, Husted SE. New oral anticoagulants: a review of the literature with particular emphasis on patients with impaired renal function. Drugs. 2012; 72:1739-53. http://www.ncbi.nlm.nih.gov/pubmed/22931521?dopt=AbstractPlus

11. Chan NC, Hirsh J, Ginsberg JS et al. Betrixaban (PRT054021): pharmacology, dose selection and clinical studies. Future Cardiol. 2014; 10:43-52. http://www.ncbi.nlm.nih.gov/pubmed/24344662?dopt=AbstractPlus

12. Ageno W. Has time come for the use of direct oral anticoagulants in the extended prophylaxis of venous thromboembolism in acutely ill medical patients? Yes. Intern Emerg Med. 2017; http://www.ncbi.nlm.nih.gov/pubmed/28808888?dopt=AbstractPlus

13. Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol. 2018; http://www.ncbi.nlm.nih.gov/pubmed/29345686?dopt=AbstractPlus

14. Portola Pharmaceuticals, Inc. Bevyxxa (betrixaban) capsules medication guide. South San Francisco, CA: 2017 Jun.

15. Cohen AT, Spiro TE, Spyropoulos AC; MAGELLAN Steering Committee et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 May 16; 368(May 16):1945-6. http://www.ncbi.nlm.nih.gov/pubmed/23675665?dopt=AbstractPlus

16. Goldhaber SZ, Leizorovicz A, Kakkar AK; ADOPT Trial Investigators et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med. 2011; 365(Dec 8):2167-77. http://www.ncbi.nlm.nih.gov/pubmed/22077144?dopt=AbstractPlus

1001. Kahn SR, Lim W, Dunn AS et al. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl):e195S-226S.