Betrixaban

Dosage Forms

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

Capsule, Oral:

Bevyxxa: 40 mg, 80 mg

Pharmacology

Mechanism of Action

Inhibits fibrin clot formation via direct and selective inhibition of factor Xa (FXa). FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.

Pharmacokinetics/Pharmacodynamics

Absorption

C_max and AUC reduced by ~70% and 61% for low-fat and 50% and 48% for high-fat meal, respectively; effect of food observed for up to 6 hours.

Distribution

V_d: 32 L/kg

Metabolism

Minimal via CYP-independent hydrolysis to 2 major metabolites (inactive, accounting for 15% to 18% of parent compound); <1% of minor metabolites formed via CYP 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4; substrate of P-glycoprotein (P-gp).

Excretion

Feces (~85%); urine (11%)

Onset of Action

Peak effect: 3 to 4 hours

Time to Peak

3 to 4 hours

Duration of Action

≥72 hours

Half-Life Elimination

19 to 27 hours

Protein Binding

60% (in vitro)

Use in Specific Populations

Special Populations: Renal Function Impairment

Systemic exposure increased by 1.89-, 2.27-, and 2.63-fold in mild, moderate, and severe renal impairment, respectively, compared to healthy volunteers.

Special Populations: Hepatic Function Impairment

AUC increased ~30% and ~57% and C_max increased ~60% and ~119% in mild and moderate impairment, respectively, compared to normal hepatic function. Has not been evaluated in severe impairment.

Use: Labeled Indications

VTE (prophylaxis): Prophylaxis of VTE in adults hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.

Limitations of use: Safety and effectiveness have not been established in patients with prosthetic heart valves (has not been studied).

Contraindications

Severe hypersensitivity reaction to betrixaban or any component of the formulation; active pathological bleeding

Dosage and Administration

Dosing: Adult

VTE (prophylaxis): Oral: 160 mg as a single dose on day 1, followed by 80 mg once daily for 35 to 42 days

Dosage adjustment of betrixaban with concomitant medications: Reduce betrixaban dose (initial and maintenance) by 50% for patients receiving or starting P-glycoprotein inhibitors (eg, amiodarone, azithromycin, clarithromycin, ketoconazole, verapamil). If patient also has severe renal impairment, avoid use of betrixaban.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Obesity

The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of direct oral anticoagulants in patients with a BMI >40 kg/m² or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m² or weight >120 kg, ISTH suggests measuring peak and trough levels using an antifactor Xa assay or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of the direct oral anticoagulant (ISTH [Martin 2016]).

Administration

Oral: Administer with food at the same time each day.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Cobicistat: May increase the serum concentration of Betrixaban. Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Avoid combination

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). Consider therapy modification

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Betrixaban. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Adverse Reactions

1% to 10%:

Cardiovascular: Hypertension (2%)

Central nervous system: Headache (2%)

Endocrine & metabolic: Hypokalemia (3%)

Gastrointestinal: Constipation (3%), diarrhea (2%), nausea (2%)

Genitourinary: Urinary tract infection (3%), hematuria (2%)

Hematologic & oncologic: Hemorrhage (2%; clinically relevant non-major bleeding)

Respiratory: Epistaxis (2%)

<1%, postmarketing, and/or case reports: Hypersensitivity reaction, major hemorrhage (including gastrointestinal bleeding, intracranial hemorrhage, and intraocular bleeding)

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding; serious, potentially fatal bleeding may occur. Concomitant use of drugs that affect hemostasis increases the risk of bleeding. Monitor for signs and symptoms of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. No specific antidote exists for betrixaban reversal; it is unknown if hemodialysis removes betrixaban. Protamine, vitamin K, and tranexamic acid are not expected to reverse betrixaban.
• Thromboembolic events: Premature discontinuation of any oral anticoagulant, including betrixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If betrixaban must be discontinued for reasons other than bleeding or completion of a course of therapy, consider the use of another anticoagulant. Note: Anticoagulant effect may persist for at least 72 hours after discontinuing betrixaban.

Disease-related concerns:

• Hepatic impairment: Avoid use in patients with moderate or severe hepatic impairment or any hepatic disease associated with coagulopathy.
• Renal impairment: Systemic exposure increases with worsening renal function. Bleeding risk may be increased in severe renal impairment (CrCl 15 to 29 mL/minute); use with caution and reduce dose. If patient has severe renal impairment and is receiving a concomitant P-gp inhibitor, avoid use of betrixaban.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Spinal or epidural hematoma: [US Boxed Warning]: Epidural or spinal hematomas may occur in patients treated with betrixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. Risk may be increased by the use of in-dwelling epidural catheters or the concomitant use of medical products affecting hemostasis. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. In patients who receive both betrixaban and neuraxial anesthesia, avoid removal of epidural catheter for at least 72 hours following last betrixaban dose; avoid betrixaban administration for at least 5 hours following catheter removal. If traumatic puncture occurs, delay administration of betrixaban for at least 72 hours. Monitor frequently for signs of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction); if noted, prompt treatment is necessary.

Monitoring Parameters

Renal function prior to initiation and periodically as clinically indicated; signs/symptoms of bleeding.

Routine monitoring of coagulation tests is not required. Anti-FXa assay may be helpful (plasma concentrations and anti-FXa activity exhibit linear relationship) in guiding clinical decisions (Samama 2013).

Pregnancy

Pregnancy Considerations

Information related to the use of direct acting oral anticoagulants during pregnancy is limited and information specific to betrixaban has not been reported (Beyer-Westendorf 2016; Lameijer 2018). Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016b).

Data are insufficient to evaluate the safety of direct acting oral anticoagulants during pregnancy (Bates 2012) and use in pregnant females is not recommended (ESC [Regitz-Zagrosek 2018]). Agents other than betrixaban are preferred for VTE prophylaxis in pregnant patients (ESC [Regitz-Zagrosek 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct acting oral anticoagulant is continued (Cohen 2016b).

Until safety data are available, adequate contraception is recommended during therapy for females of childbearing potential. Females planning a pregnancy should be switched to alternative anticoagulants prior to conception (Cohen 2016b).

Patient Education

What is this drug used for?

• It is used to thin the blood so that clots will not form.

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

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes.
• Back pain
• Numbness or tingling
• Muscle weakness
• Paralysis
• Loss of bladder control
• Loss of bowel control
• Dizziness
• Passing out
• Loss of strength and energy
• Confusion
• Headache
• Joint pain
• Joint swelling
• 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.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.