bleeding events. Reduce the BEVYXXA dose for patients with severe renal impairment. Monitor patients closely and promptly eva luate any signs or symptoms of blood loss in these patients [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.3), CLINICAL PHARMACOLOGY (12.3)]. No dose adjustment is needed for mild or moderate renal impairment (CrCl > 30 mL/min, computed by Cockcroft-Gault using actual body weight).
8.7 Hepatic Impairment
BEVYXXA has not been eva luated in patients with hepatic impairment, because these patients may have intrinsic coagulation abnormalities. Therefore, the use of BEVYXXA is not recommended in patients with hepatic impairment [see CLINICAL PHARMACOLOGY (12.3)].
10 OVERDOSAGE
Overdose of BEVYXXA increases the risk of bleeding [see WARNINGS AND PRECAUTIONS (5.1)].
A specific reversal agent for BEVYXXA is not available. There is no experience with hemodialysis in individuals receiving betrixaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of betrixaban.
11 DESCRIPTION
Betrixaban, a factor Xa (FXa) inhibitor, is chemically described as N-(5-chloropyridin-2-yl)-2-[4-(N,N-dimethylcarbamimidoyl)-benzoylamino]-5-methoxybenzamide maleate. Its molecular formula (as maleate salt) is C27H26ClN5O7, which corresponds to a molecular weight of 567.98. Betrixaban (maleate salt) has the following structural formula:
Chemical Structure
BEVYXXA capsules are available for oral administration in strengths of 80 mg and 40 mg of betrixaban with the following inactive ingredients: dextrose monohydrate, croscarmellose sodium, magnesium stearate, and a hard gelatin capsule.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Betrixaban is an oral FXa inhibitor that selectively blocks the active site of FXa and does not require a cofactor (such as Anti-thrombin III) for activity. Betrixaban inhibits free FXa and prothrombinase activity. By directly inhibiting FXa, betrixaban decreases thrombin generation (TG). Betrixaban has no direct effect on platelet aggregation.
12.2 Pharmacodynamics
Inhibition of FXa by betrixaban results in an inhibition of thrombin generation at clinically relevant concentrations, and the maximum inhibition of thrombin generation coincides with the time of peak betrixaban concentrations.
Cardiac Electrophysiology
In a study that eva luated the effect of betrixaban on the QT interval, a concentration-dependent increase in the QTc interval was observed. Based on the observed concentration-QTc relationship a mean (upper 95% CI) QTc prolongation of 4 ms (5 ms) is predicted for 80 mg betrixaban and 13 ms (16 ms) for a 4.7-fold increase in exposure [see CLINICAL PHARMACOLOGY (12.3)].
12.3 Pharmacokinetics
Within the anticipated therapeutic dose range a two-fold increase in dose resulted in a three-fold increase in exposure in the single ascending dose study. A two-fold increase in betrixaban exposure was observed after repeat dosing, and the time to steady-state is 6 days (without an initial loading dose).
Absorption
The oral bioavailability of betrixaban for an 80 mg dose is 34%, and peak concentrations occurred within 3 to 4 hours. Betrixaban is also a substrate of P-gp.
Effect of Food
When administered with a low-fat (900 calories, 20% fat) or high-fat (900 calories, 60% fat) meal, Cmax and AUC were reduced as compared to the fasting state by an average of 70% and 61% for low-fat and 50% and 48% for hi |
