Bevyxxa

General

Betrixaban maleate is available in the following dosage form(s) and strength(s):

Capsules: 40 mg and 80 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

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

• Reduce dose for patients with severe renal impairment (CrCl ≥ 15 to < 30 mL/min, computed by Cockcroft-Gault using actual body weight).1 In such patients, the recommended dose of betrixaban maleate is an initial single dose of 80 mg, followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.1

• Reduce dose for patients on P-glycoprotein (P-gp) inhibitors.1 For patients receiving or starting concomitant P-gp inhibitors, the recommended dose of betrixaban maleate is an initial single dose of 80 mg, followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

• If you have an allergy to Bevyxxa or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Active bleeding or liver problems.
• If you have had a heart valve replaced.

This is not a list of all drugs or health problems that interact with Bevyxxa.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take Bevyxxa. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Do not run out of this medicine.
• You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
• Very bad and sometimes deadly bleeding problems have happened with Bevyxxa. Talk with the doctor.
• If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

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 evaluated 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)].

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 high-fat, respectively. The effect of food on betrixaban PK could be observed for up to 6 hours after meal intake.

Distribution

The apparent volume of distribution is 32 L/kg. In vitro plasma protein binding is 60%.

Elimination

The effective half-life of betrixaban is 19 to 27 hours.

Metabolism

Unchanged betrixaban is the predominant component found in human plasma. Two inactive major metabolites formed by CYP-independent hydrolysis comprise the other components in plasma, accounting for 15 to 18% of the circulating drug-related material. Less than 1% of the minor metabolites could be formed via metabolism by the following CYP enzymes; 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4.

Excretion

Following oral administration of radio-labeled betrixaban approximately 85% of the administered compound was recovered in the feces and 11% recovered in the urine. In a study of intravenous betrixaban a median value of 17.8% of the absorbed dose was observed as unchanged betrixaban in urine.

Specific Populations

Male and Female Patients

No clinically significant changes in betrixaban pharmacokinetics were observed between males and females.

Patients with Renal Impairment

In a dedicated renal impairment study mean AUC0-24 on day 8 was increased by 1.89, 2.27 and 2.63-fold in mild (eGFRMDRD ≥ 60 to < 90 mL/min/1.73 m2), moderate (eGFRMDRD ≥ 30 to < 60 mL/min/1.73 m2) and severe (eGFRMDRD ≥ 15 to < 30 mL/min/1.73 m2) renal impaired patients respectively compared to healthy volunteers [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Studies with betrixaban in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to betrixaban has not been evaluated [see Use in Specific Populations (8.7)].

Drug Interaction Studies

The effects of coadministered drugs on the pharmacokinetics of betrixaban exposure based on drug interaction studies are summarized in Figure 1.

Figure 1: Effect of Coadministered Drugs on the Pharmacokinetics of Betrixaban

How Supplied

Bevyxxa (betrixaban) capsules are available as listed below.

The 40 mg size 4 capsules are light grey with 40 printed in black, and have a light blue cap with PTLA printed in white.

• Bottles of 100 (NDC 69853-0202-1)

The 80 mg size 2 capsules are light grey with 80 printed in black, and have a blue cap with PTLA printed in white.

• Bottles of 100 (NDC 69853-0201-1)

Storage and Handling

Store at room temperature; 20°C to 25°C (68°F to 77°F).

NDC 69853-0202-1
Rx only

Bevyxxa®
(betrixaban) Capsules

40 mg

DISPENSE WITH MEDICATION GUIDE.

100 Capsules

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Many other drugs (including some over-the-counter medicines) can increase your risk of bleeding, or your risk of developing blood clots around the brain or spinal cord during a spinal tap or epidural. It is very important to tell your doctor about all medicines you have recently used, especially:

• ketoconazole;
• an antibiotic--azithromycin, clarithromycin, erythromycin;
• heart medication--amiodarone, quinidine, verapamil;
• an antidepressant, such as citalopram, duloxetine, escitalopram, fluoxetine (Prozac), fluvoxamine, paroxetine, sertraline (Zoloft), trazodone, venlafaxine, or vilazodone;
• an NSAID, such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib (Celebrex), diclofenac, indomethacin, or meloxicam; or
• other medicines to treat or prevent blood clots, such as dabigatran, dalteparin, enoxaparin, fondaparinux, heparin, or warfarin (Coumadin, Jantoven).

This list is not complete and many other drugs can interact with betrixaban. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Applies to betrixaban: oral capsule

General

The most common adverse events were related to bleeding.[Ref]

Hematologic

Common (1% to 10%): Clinically relevant non-major bleeding
Uncommon (0.1% to 1%): Major bleeding (gastrointestinal, intracranial, and fatal)

Cardiovascular

Common (1% to 10%): Hypertension[Ref]

Metabolic

Common (1% to 10%): Hypokalemia[Ref]

Gastrointestinal

Common (1% to 10%): Constipation, nausea, diarrhea[Ref]

Respiratory

Common (1% to 10%): Epistaxis[Ref]

Nervous system

Common (1% to 10%): Headache[Ref]

Hypersensitivity

Rare (less than 0.1%): Moderate hypersensitivity[Ref]

Some side effects of Bevyxxa may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.