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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis. If you are interested in helping the Publications Committee with creating a Pharmacist's Application to Practice, please contact Jeff Price at jprice@hoparx.org.

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June 23, 2017

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208383s000lbl.pdf

On June 23, 2017, the U.S. Food and Drug Administration approved betrixaban (BEVYXXA, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients 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.

Approval was based on data from APEX (NCT01583218), a randomized, double-blind, multinational clinical trial comparing extended duration betrixaban (35 to 42 days) to short duration of enoxaparin (6 to 14 days) in the prevention of VTE in an acutely medically ill hospitalized population with risk factors for VTE. The trial randomized 7,513 patients to either betrixaban or enoxaparin treatment. Patients on the betrixaban arm took an initial dose of 160 mg orally on day 1, then took 80 mg once daily for 35 to 42 days and received a placebo injection once daily for 6 to 14 days. Patients on the enoxaparin arm received 40 mg subcutaneously once daily for 6 to 14 days and took a placebo pill orally once daily for 35 to 42 days.

Efficacy was measured in 7,441 patients by a composite outcome score comprised of either the occurrence of asymptomatic or symptomatic proximal deep vein thrombosis, non-fatal pulmonary embolism, or VTE-related death. Fewer events were observed in patients receiving betrixaban (4.4%) compared with those taking enoxaparin (6%) (relative risk 0.75, 95% CI: 0.61, 0.91).

The most common adverse reactions (≥5%) with betrixaban were related to bleeding. Overall, 54% of patients receiving betrixaban experienced at least one adverse reaction compared with 52% taking enoxaparin. The frequency of patients reporting serious adverse reactions was similar between betrixaban (18%) and enoxaparin (17%). The most frequent reason for treatment discontinuation was bleeding, with an incidence rate for all bleeding episodes of 2.4% and 1.2% for betrixaban and enoxaparin, respectively. The incidence rate for major bleeding episodes was 0.67% and 0.57% for betrixaban and enoxaparin, respectively.

The recommended dose of betrixaban is an initial single dose of 160 mg starting on day 1, followed by 80 mg once daily taken for 35 to 42 days at the same time each day with food.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208383s000lbl.pdf.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Betrixaban (Bevyxxa) for Prophylaxis of Venous Thromboembolism in Adult Patients Hospitalized for an Acute Medical Illness

Author: Jordan Baskett, PharmD
Vanderbilt-Ingram Cancer Center
Nashville, TN

What is the potential role for betrixaban in the management of venous thromboembolism (VTE) prophylaxis?1-5

  • The 2012 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommend using low-dose parenteral anticoagulants in patients at high risk for thromboembolism for 6–14 days but advise stopping thromboprophylaxis at the time of the patient’s discharge from the hospital. However, the risk of pulmonary embolism (PE) and deep-vein thrombosis (DVT) remains increased for at least the first month after hospital discharge.
  • Betrixaban is the first and only oral anticoagulant approved for VTE prophylaxis in hospitalized adults at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. It is also the first oral anticoagulant approved for extended-duration prophylaxis (35–42 days) of VTE in this patient population.
  • In the phase 3 APEX study comparing extended-duration betrixaban to standard-duration enoxaparin, researchers investigated a primary outcome (a composite of asymptomatic proximal DVT between day 32 and day 47, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or death from VTE between day 1 and day 42) among three cohorts of patients.
    • In cohort 1 (patients with an elevated D-dimer level), the primary efficacy outcome occurred in 6.9% of the betrixaban group and in 8.5% of the enoxaparin group (relative risk in the betrixaban group, .81; 95% confidence interval [CI], .65–1.00, p = .054); the primary outcome did not reach statistical significance in this cohort.
    • In cohort 2 (patients with either an elevated D-dimer level or age 75 years or greater), the primary efficacy outcome occurred in 5.6% of the betrixaban group and in 7.1% of the enoxaparin group (relative risk, .80; 95% CI, .66–.98; p = .03).
    • In the overall population, the primary efficacy outcome occurred in 5.3% and 7% of the patients, respectively (relative risk, .76; 95% CI, .63–.92; p = .006).
  • The incidence rate for all bleeding episodes was 2.4% for betrixaban and 1.2% for enoxaparin; the incidence rate of major bleeding episodes was .67% and .57% for betrixaban and enoxaparin, respectively. In the overall population, major bleeding occurred in .7% of the betrixaban group and in .6% of the enoxaparin group (relative risk, 1.19; 95% CI, .67–2.12; p = .55).
  • When considering addition of this medication to the hospital formulary, providers must take into account study design, trial outcomes, and medication cost.
    • Researchers attempted to include only patients at increased risk for VTE on the basis of D-dimer level and advanced age, but this limited the study population and resulted in statistically insignificant findings.
    • The rationale for extended-duration versus standard-duration prophylaxis was based on the sustained risk of VTE after hospital discharge, but this resulted in a discrepancy among the treatment arms: one group received enoxaparin for 10 days and then received placebo for the remaining time, while the other group received active drug (betrixaban) for the entire study period. The primary outcome included all events up to day 42, regardless of treatment arm and active drug duration.
    • Enoxaparin is available as a generic medication that is administered to acutely ill hospitalized patients in order to reduce the risk of VTE. Betrixaban is not yet available as a generic medication, and thus the extended-duration prophylaxis may prove to be an economic barrier for patients at hospital discharge.

What role can the pharmacist play in the management of patients on betrixaban?3

  • Betrixaban is an oral agent that is administered in the hospital, and therefore pharmacists have numerous opportunities to provide patient counselling and monitor for adverse events.
  • Management of side effects and drug interactions is necessary to reduce a patient’s risk of bleeding.
    • Providers and patients should be cautioned about medications that increase bleeding risk, including aspirin, nonsteroidal anti-inflammatory drugs, and nonprescription products.
    • Patients on concomitant P-glycoprotein (P-pg) inhibitors may have an increased bleeding risk, and therefore it is important to reduce the dose of betrixaban in these patients.
  • Betrixaban should be used with caution in patients who have severe renal impairment (CrCl ≥15 ml/min to <30 ml/min, calculated by Cockcroft-Gault using actual body weight) because of an increased bleeding risk. (Providers should empirically reduce the dose of betrixaban in these patients and monitor closely for blood loss. Use should be avoided in patients who have severe renal impairment and are receiving concomitant P-gp inhibitors.
  • Betrixaban is not recommended in patients with hepatic impairment because these patients may have intrinsic coagulation abnormalities.

Clinical Pearls4,6

  • Results from the APEX trial should be considered exploratory. Trial investigators declared that if the between-group difference in any analysis among the three cohorts was not significant, the other analyses were considered to be exploratory. As such, the analysis of cohort 1 (patients with elevated D-dimer) failed to demonstrate statistical significance, despite a numeric benefit in favor of the betrixaban groups.
  • Although the primary end point did not reach statistical significance, the clinically relevant efficacy end points were in favor of betrixaban for all three cohorts.
  • In the case of an overdose, no specific reversal agent is available. There is no experience with hemodialysis, and protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban.
  • Betrixaban is available as 80 mg and 40 mg capsules, allowing for dose changes without the need for a new prescription.
  • The recommended dose of betrixaban is a single dose of 160 mg taken with food on day 1, followed by 80 mg once daily taken with food for 35–42 days.

References

  1. 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.
  2. Amin AN, Varker H, Princic N, et al. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7:231-238.
  3. Bevyxxa (Betrixaban) capsules [package insert]. South San Francisco, CA: Portola Pharmaceuticals, Inc.; June 2017.
  4. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375(6):534-544.
  5. U.S. Food & Drug Administration. FDA approved betrixaban (Bevyxxa, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients. 23 June 2017. Retrieved from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564422.htm. Accessed: July 31, 2017.
  6. Husten L. CardioBrief: Novel Xa Drug May Cut VTE in Medically Ill. 27 May 2016. Retrieved from: http://www.medpagetoday.com/cardiology/cardiobrief/58179. Accessed: July 31, 2017.
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