Included as part of the "PRECAUTIONS" Section
Risk Of Bleeding
BEVYXXA increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss [see ADVERSE REACTIONS].
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see DRUG INTERACTIONS].
Advise patients of signs and symptoms of blood loss and to report them immediately and seek emergency care. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue BEVYXXA in patients with active pathological bleeding.
There is no established way to reverse the anticoagulant effect of BEVYXXA, which can be expected to persist for at least 72 hours after the last dose. It is unknown whether hemodialysis removes BEVYXXA. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of BEVYXXA.
Spinal/Epidural Anesthesia Or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
Do not remove an epidural catheter earlier than 72 hours after the last administration of BEVYXXA. Do not administer the next BEVYXXA dose earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of TRADENAME for 72 hours.
Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
Use In Patients With Severe Renal Impairment
Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) taking BEVYXXA may have an increased risk of bleeding events. Reduce dose of BEVYXXA, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients [see DOSAGE AND ADMINISTRATION, Risk Of Bleeding, ADVERSE REACTIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY].
Use In Patients On Concomitant P-Gp Inhibitors
Patients on concomitant P-gp inhibitors with BEVYXXA may have an increased risk of bleeding. Reduce dose of BEVYXXA in patients receiving or starting P-gp inhibitors. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients [see DOSAGE AND ADMINISTRATION, Risk Of Bleeding, ADVERSE REACTIONS, DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].
Avoid use of BEVYXXA in patients with severe renal impairment receiving concomitant P-gp inhibitors [see Use In Patients With Severe Renal Impairment].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Risk Of Bleeding
Advise patients that it might take longer than usual for bleeding to stop, and that they may bruise or bleed more easily when treated with BEVYXXA. Instruct patients to report any unusual bleeding to their physician [see WARNINGS AND PRECAUTIONS].
Instruct patients to tell their physicians and dentists that they are taking BEVYXXA, and/or any other products known to affect bleeding (including nonprescription products, such as aspirin or NSAIDs), before any surgery or medical or dental procedure is scheduled and before any new drug is taken [see WARNINGS AND PRECAUTIONS].
Use In Patients With Severe Renal Impairment
Advise patients that the risk of bleeding is higher in people who have severe kidney problems (severe renal impairment) [see WARNINGS AND PRECAUTIONS].
Advise patients having neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematomas, such as numbness or weakness of the legs, or bowel, or bladder dysfunction [see WARNINGS AND PRECAUTIONS]. Instruct patients to contact their physician immediately if any of these symptoms occur.
Pregnancy And Lactation
Advise female patients to inform their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with BEVYXXA [see Use In Specific Populations].
How To Take BEVYXXA
Instruct patients to take BEVYXXA with food, and instruct patients on what to do if a dose is missed [see DOSAGE AND ADMINISTRATION].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies with betrixaban have not been performed.
Betrixaban was not mutagenic in bacteria (Ames-Test) or clastogenic in Chinese hamster ovary cells in vitro or in the rat micronucleus test in vivo.
In a study to assess fertility and early embryonic development to implantation, oral doses of betrixaban were administered to male and female rats. There was no evidence that betrixaban up to 150 mg/kg/day adversely affected male or female fertility, reproductive performance, or embryo-fetal viability.
Use In Specific Populations
There are no data with the use of BEVYXXA in pregnant women, but treatment is likely to increase the risk of hemorrhage during pregnancy and delivery (see Clinical Considerations). Betrixaban was studied in reproductive and developmental toxicology studies in rats and rabbits during the period of organogenesis at exposures up to 44 times the recommended clinical dose of 80 mg daily. Although betrixaban was not associated with adverse developmental fetal outcomes in animals, maternal toxicity (i.e., hemorrhage) was identified in these studies (see Data). BEVYXXA should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no adverse embryofetal or teratogenic effects were seen when betrixaban was administered orally at doses up to 200 mg/kg/day, or 44 times the human dose of 80 mg/day when based on AUC. In rabbits, no adverse embryofetal or teratogenic effects were seen at doses up to 45 mg/kg/day, or 35 times the human exposure at a dose of 80 mg/day when based on AUC. Pregnant rabbits administered the highest dose of 150 mg/kg/day were terminated prematurely due to excessive maternal toxicities. Upon post-mortem examination, early and/or late resorptions and fetal deaths were observed at the 150 mg/kg dose, which may be linked to hemorrhage observed in various organs including the reproductive tract.
In a rat pre-and post-natal developmental study, betrixaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 200 mg/kg/day. Maternal toxicities (including decreased body weight gain and food consumption and red/brown perivaginal substance) were observed at 200 mg/kg/day, which is approximately 44 times the human exposure when based on AUC. At a maternal dose up to 200 mg/kg/day, betrixaban did not have adverse effects on sexual maturation, reproductive performance, and behavioral development of the F1 generation.
Maternal Adverse Reactions
Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Consider the risks of bleeding and of stroke in using BEVYXXA in this setting.
No data are available regarding the presence of betrixaban or its metabolites in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BEVYXXA and any potential adverse effects on the breast-fed child from BEVYXXA or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in the APEX clinical study 90% were 65 years and over, while 68.6% were greater than or equal to 75 years. No clinically significant differences in safety or effectiveness were observed between older and younger patients.
Patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min computed by Cockcroft-Gault using actual body weight) may have an increased risk of bleeding events. Reduce the BEVYXXA dose for patients with severe renal impairment. Monitor patients closely and promptly evaluate any signs or symptoms of blood loss in these patients [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]. No dose adjustment is needed for mild or moderate renal impairment (CrCl > 30 mL/min, computed by Cockcroft-Gault using actual body weight).
BEVYXXA has not been evaluated 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].