RX FOCUS Drug Interactions Betrixaban A Factor Xa Inhibitor BY JOHN R. HORN, PHARMD, FCCP AND PHILIP D. HANSTEN, PHARMD THE FDA RECENTLY APPROVED BETRIXABAN verapamil administrations both resulted in a nearly (Bevyxxa) as an oral anticoagulant (direct inhibi- 5-fold increase in betrixaban Cmax and a 3-fold tor of factor Xa).1 Inhibition of factor Xa leads to increase in its AUC. When patients receiving bet- reduced conversion of prothrombin to thrombin that rixaban and amiodarone were compared, patients is mediated by factor Xa. It has been approved for on amiodarone had betrixaban concentrations about the prophylaxis of venous thromboembolism in hos- 2-fold higher with concurrent amiodarone.2 Based on pitalized patients who are at risk of thromboembolic these studies, the betrixaban label recommends a 50% JOHN R. HORN, PHARMD, FCCP events. Investigators are studying betrixaban for use dose reduction if betrixaban is administered with P-gp in patients with atrial fibrillation and for thrombopro- inhibitors. Other drugs known to inhibit P-gp (eg, phylaxis after joint arthroplasty. itraconazole, cyclosporine, posaconazole, and tela- previr) would also be expected to interact with betrix- BETRIXABAN PHARMACOLOGY aban and produce elevated betrixaban plasma concen- The bioavailability of betrixaban is about 35%, with trations and an anticoagulant response. Betrixaban did peak plasma concentrations occurring 3 to 4 hours not alter the pharmacokinetics of digoxin.1 after dosing. The half-life of betrixaban has been Although no data are available regarding the effect PHILIP D. HANSTEN, PHARMD reported to range from 20 to 27 hours. To produce of P-gp inducers such as rifampin, doses of betrixaban a rapid clinical response, the labeling recommends will likely require an increase during concurrent P-gp AUTHOR BIOS a 160-mg loading dose, followed by 80 mg daily.1 inducer administration. Drs. Horn and Hansten Food (both high- and low-fat diets) reduces the are both professors mean bioavailability of betrixaban by 50% to 60%. Pharmacodynamic of pharmacy at the A minor portion of betrixaban is converted by amide As can occur with any anticoagulant alone, a com- University of Washington hydrolysis to inactive metabolites.1 Following intra- bination of 2 or more of these drugs (eg, warfarin, School of Pharmacy. For an electronic venous administration, about 17% of betrixaban is heparin, and enoxaparin) is likely to produce an version of this article, recovered unchanged in the urine. In subjects with increased risk of bleeding. The use of antiplatelet including references, visit renal dysfunction (creatinine clearance <60 mL/min), drugs (eg, nonsteroidal anti-inflammatories, clopido- hanstenandhorn.com. the betrixaban area under the concentration time grel, prasugrel, and ticagrelor) with betrixaban should curve (AUC) increased by about 2.5-fold. Labeling be carefully monitored for excess anticoagulation and recommends reducing the dose by 50% in patients evidence of bleeding. with severe renal impairment. Betrixaban appears to be a substrate for P-glycoprotein (P-gp). Betrixaban CLINICAL SIGNIFICANCE has not been demonstrated to inhibit or induce any Clinical experience is limited, but some potential cytochrome P450 enzyme. drug interactions with betrixaban are likely to alter the patient response. The anticoagulant response to DRUG INTERACTIONS betrixaban is related to its plasma concentration.1 P-glycoprotein–Based (see ONLINE TABLE) Patients stabilized on betrixaban should be monitored Although betrixaban is a substrate for P-gp, only a for an altered response, such as bleeding or loss of the few studies with drugs that affect P-gp have been anticoagulant effect, if P-gp inhibitors or inducers are reported. One study administered a single 40-mg added or removed from their drug regimen. If P-gp dose of betrixaban alone, following 5 days of keto- inhibitors are coadministered, consider cutting the conazole 200 mg twice daily. The maximum con- betrixaban dose to 40 mg daily. The administration centration (Cmax) and AUC of betrixaban increased of other anticoagulants or antiplatelet drugs would be by about 2.3-fold with ketoconazole pretreatment. expected to raise the risk of bleeding in patients who A single dose of betrixaban was administered alone take betrixaban. Patients with concurrent renal dys- FOR REFERENCES, GO TO PHARMACYTIMES.COM/ and on day 1 and day 14 of a 14-day regimen of ver- function may be particularly sensitive to drug interac- LINK/144. apamil (dose not stated). Single- and multiple-dose tion–induced reduction in betrixaban elimination. ® 28 OCTOBER 2017 PHARMACYTIMES.COM Pg 28 PT_1017_RxDrugInter-v3.indd 28 10/2/17 4:21 PM.