APEX study design

APEX: a multinational pivotal trial of extended VTE prophylaxis in acutely ill medical patients (N=7513)1,*

Extended-duration Bevyxxa (35 to 42 days) vs enoxaparin (6 to 14 days) + placebo1

Apex study design chart
*Efficacy analyses were performed based on the modified Intent-to-Treat (mITT) population (N=7441), which included all patients who had taken at least one dose of Bevyxxa (N=3721) and who had follow-up assessment data on one or more primary or secondary efficacy outcome components. Patients taking a concomitant P-gp inhibitor received Bevyxxa 80-mg loading dose, then 40 mg once daily or enoxaparin 40 mg subcutaneously once daily for 6 to 14 days along with corresponding placebo.
R=randomization; SC=subcutaneous.

Primary efficacy analysis

Total VTE up to day 35—a composite of VTE-related death, symptomatic proximal or distal deep-vein thrombosis (DVT), nonfatal pulmonary embolism, and asymptomatic proximal DVT1

Principal safety outcome

Occurrence of major bleeding at any point until 7 days after the discontinuation of all study medications, defined as clinically overt bleeding that met one of the following criteria: a reduction in hemoglobin of at least 2 g/dL within 48 hours of bleeding event; requiring a transfusion of at least 2 units of whole blood or packed red blood cells; or, in a critical area1

Secondary safety outcome

Clinically relevant non-major bleeding, defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, cessation of the study treatment, or discomfort for the patient such as pain or impairment of daily activities1

APEX patients had multiple VTE risk factors

† Patients with severe renal impairment received reduced doses of study medications (Bevyxxa 80-mg loading dose, then 40 mg once daily or enoxaparin 20 mg once daily) along with corresponding placebo.1
‡ Moderate/severe immobilization.3
§ Patients were expected to be hospitalized for at least 3 days and moderately or severely immobilized for at least 24 hours.1

Baseline characteristics were well balanced between treatment arms2,3

apex trial baseline characteristics chart

CrCl=creatinine clearance; ULN=upper limit of normal.

INDICATION

Bevyxxa is indicated 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.

LIMITATIONS OF USE

The safety and effectiveness of Bevyxxa have not been established in patients with prosthetic heart valves because this population has not been studied.

SELECT IMPORTANT SAFETY INFORMATION

WARNING: SPINAL/EPIDURAL HEMATOMA
EPIDURAL OR SPINAL HEMATOMAS MAY OCCUR IN PATIENTS TREATED WITH BEVYXXA WHO ARE RECEIVING NEURAXIAL ANESTHESIA OR UNDERGOING SPINAL PUNCTURE. THE RISK OF THESE EVENTS MAY BE INCREASED BY THE USE OF IN-DWELLING EPIDURAL CATHETERS OR THE CONCOMITANT USE OF MEDICAL PRODUCTS AFFECTING HEMOSTASIS. THESE HEMATOMAS MAY RESULT IN LONG-TERM OR PERMANENT PARALYSIS. CONSIDER THESE RISKS WHEN SCHEDULING PATIENTS FOR SPINAL PROCEDURES.

CONTRAINDICATIONS

  • Active pathological bleeding
  • Severe hypersensitivity reaction to Bevyxxa

WARNINGS AND PRECAUTIONS

Risk of Bleeding

  • Bevyxxa increases the risk of bleeding and can cause serious and potentially fatal bleeding
  • 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)
  • Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room
  • 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. The next Bevyxxa dose is not to be administered earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of Bevyxxa 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) 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

Use in Patients on Concomitant P-glycoprotein (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 concomitant P-gp inhibitors, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients
  • Avoid use of Bevyxxa in patients with severe renal impairment receiving concomitant P-gp inhibitors

ADVERSE REACTIONS

  • The most common adverse reactions with Bevyxxa were related to bleeding (> 5%)

USE IN SPECIFIC POPULATIONS

Hepatic Impairment

  • Bevyxxa has not been evaluated in patients with hepatic impairment, because these patients may have intrinsic coagulation abnormalities
  • Bevyxxa is not recommended in patients with hepatic impairment

Please see full Prescribing Information and Important Safety Information, including Boxed Warning.

To report suspected adverse reactions or product complaints, contact Portola Pharmaceuticals (1.866.777.5947) or FDA (1.800.FDA.1088 or www.fda.gov/medwatch).

References: 1. Bevyxxa® (betrixaban) Prescribing Information. South San Francisco, CA: Portola Pharmaceuticals, Inc; 2017. 2. 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. 3. Data on file. Portola Pharmaceuticals, Inc.

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The Bevyxxa Co-Pay Savings Card

Terms and Conditions

  • The Bevyxxa® Co-Pay Savings Card (“Card”) can be used only by eligible residents of the United States, Puerto Rico, or United States territories at participating eligible retail or mail-order pharmacies in the United States, Puerto Rico, or United States territories. Product must originate in the United States, Puerto Rico, or United States territories.
  • You must be 18 years or older to use the Card for yourself or a minor.
  • The Card is limited to one per person and is not transferable. No substitutions are permitted.
  • The Card is available for each valid prescription. No other purchase necessary. The offer cannot be combined with any other coupon, free trial, discount, prescription savings card, or other offer.
  • The Card is not insurance and is not intended to substitute for insurance.
  • THE CARD IS VALID ONLY FOR PATIENTS WITH COMMERCIAL INSURANCE OR CASH-PAY PATIENTS AND IS NOT VALID FOR PRESCRIPTIONS THAT ARE ELIGIBLE TO BE REIMBURSED:
    • IN WHOLE OR PART, BY MEDICARE, MEDICAID OR A MEDICARE PART D PLAN, TRICARE, VA, DOD, PUERTO RICO GOVERNMENT HEALTH INSURANCE PLAN (“HEALTH CARE REFORM”), OR ANY OTHER FEDERAL OR STATE-FUNDED HEALTH CARE BENEFIT PROGRAM (COLLECTIVELY, “GOVERNMENT PROGRAMS”);
    • OR BY COMMERCIAL PLANS OR OTHER HEALTH OR PHARMACY BENEFIT PROGRAMS THAT REIMBURSE FOR THE ENTIRE COST OF PRESCRIPTION DRUGS.
  • Patients without insurance coverage or who have commercial insurance that does not cover Bevyxxa are considered “cash-pay” patients. Medicare Part D enrollees who are in the prescription drug coverage gap (the “donut hole”) are not considered cash-pay, and are not eligible for the Co-Pay Card. Patients who begin receiving prescription benefits from such Government programs at any time will no longer be eligible to use the Card. Void where prohibited by law, taxed, or restricted.
  • Patient, pharmacist, and prescriber agree not to seek reimbursement for all or any part of the benefit received by the patient through the offer. Both patient and pharmacist are each individually responsible for reporting receipt of coupon benefit to any insurer, health plan, or other third party who pays for or reimburses any part of the prescription filled using the Card, as required.
  • It is illegal to sell, purchase, trade, or counterfeit, or offer to sell, purchase, trade, or counterfeit the Card.
  • Certain information pertaining to your use of the Card will be shared with Portola, the sponsor of the Card, and its affiliates. The information disclosed will include the date the prescription is filled, the number of pills or product dispensed by the pharmacists, and the amount of your co-pay that will be paid for by using this Card. For more information, please click here to see the Portola Privacy Policy.
  • Portola reserves the right to terminate, rescind, revoke, or modify this Card at any time without notice.

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IMPORTANT SAFETY INFORMATION
WARNING: EPIDURAL OR SPINAL HEMATOMAS MAY OCCUR IN PATIENTS TREATED WITH BEVYXXA WHO ARE RECEIVING NEURAXIAL ANESTHESIA OR UNDERGOING SPINAL PUNCTURE. THE RISK OF THESE EVENTS MAY BE INCREASED BY THE USE OF IN-DWELLING EPIDURAL CATHETERS OR THE CONCOMITANT USE OF MEDICAL PRODUCTS AFFECTING HEMOSTASIS. THESE HEMATOMAS MAY RESULT IN LONG-TERM OR PERMANENT PARALYSIS. CONSIDER THESE RISKS WHEN SCHEDULING PATIENTS FOR SPINAL PROCEDURES.

IMPORTANT INFORMATION ABOUT BEVYXXA

Bevyxxa can cause serious side effects:

The most common side effect of Bevyxxa is bleeding

Bevyxxa can increase the risk of bleeding, which can be serious and may lead to death. This is because Bevyxxa is a blood thinner medicine that reduces blood clotting. The risk of bleeding is higher in people who have severe kidney problems (severe renal impairment).

INDICATION

Bevyxxa is indicated 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.

LIMITATIONS OF USE

The safety and effectiveness of Bevyxxa have not been established in patients with prosthetic heart valves because this population has not been studied.

SELECT IMPORTANT SAFETY INFORMATION

WARNING: SPINAL/EPIDURAL HEMATOMA EPIDURAL OR SPINAL HEMATOMAS MAY OCCUR IN PATIENTS TREATED WITH BEVYXXA WHO ARE RECEIVING NEURAXIAL ANESTHESIA OR UNDERGOING SPINAL PUNCTURE. THE RISK OF THESE EVENTS MAY BE INCREASED BY THE USE OF IN-DWELLING EPIDURAL CATHETERS OR THE CONCOMITANT USE OF MEDICAL PRODUCTS AFFECTING HEMOSTASIS. THESE HEMATOMAS MAY RESULT IN LONG-TERM OR PERMANENT PARALYSIS. CONSIDER THESE RISKS WHEN SCHEDULING PATIENTS FOR SPINAL PROCEDURES.
CONTRAINDICATIONS
  • Active pathological bleeding
  • Severe hypersensitivity reaction to Bevyxxa
WARNINGS AND PRECAUTIONS Risk of Bleeding
  • Bevyxxa increases the risk of bleeding and can cause serious and potentially fatal bleeding
  • 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)
  • Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room
  • 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. The next Bevyxxa dose is not to be administered earlier than 5 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of Bevyxxa 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) 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
Use in Patients on Concomitant P-glycoprotein (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 concomitant P-gp inhibitors, monitor patients closely, and promptly evaluate any signs or symptoms of blood loss in these patients
  • Avoid use of Bevyxxa in patients with severe renal impairment receiving concomitant P-gp inhibitors
ADVERSE REACTIONS
  • The most common adverse reactions with Bevyxxa were related to bleeding (> 5%)
USE IN SPECIFIC POPULATIONS Hepatic Impairment
  • Bevyxxa has not been evaluated in patients with hepatic impairment, because these patients may have intrinsic coagulation abnormalities
  • Bevyxxa is not recommended in patients with hepatic impairment

Please see full Prescribing Information and Important Safety Information, including Boxed Warning.

To report suspected adverse reactions or product complaints, contact Portola Pharmaceuticals (1.866.777.5947) or FDA (1.800.FDA.1088 or www.fda.gov/medwatch).

IMPORTANT INFORMATION ABOUT BEVYXXA

Bevyxxa can cause serious side effects:

The most common side effect of Bevyxxa is bleeding

Bevyxxa can increase the risk of bleeding, which can be serious and may lead to death. This is because Bevyxxa is a blood thinner medicine that reduces blood clotting. The risk of bleeding is higher in people who have severe kidney problems (severe renal impairment).

You may have a higher risk of bleeding if you take Bevyxxa and take other medicines that increase your risk of bleeding, including:

  • Aspirin or aspirin containing products
  • Long-term (chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)
  • Warfarin sodium (Coumadin®, Jantoven®)
  • Any medicine that contains heparin
  • Selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)
  • Other medicines to prevent or treat blood clots
  • P-glycoprotein (P-gp) inhibitors

Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider or pharmacist if you are not sure if your medicine is one listed above.

While taking Bevyxxa:

  • You may bruise more easily
  • It may take longer than usual for any bleeding to stop

Call your healthcare provider or get medical help right away if you have any of these signs or symptoms of bleeding when taking Bevyxxa:

  • Unexpected bleeding, or bleeding that lasts a long time such as:
    Unusual bleeding from the gums
    Nosebleeds that happen often
    Menstrual bleeding or vaginal bleeding that is heavier than normal
  • Bleeding that is severe or you cannot control
  • Red, pink, or brown urine
  • Red or black stools (looks like tar)
  • Cough up blood or blood clots
  • Vomit blood or your vomit looks like coffee grounds
  • Unexpected pain, swelling, or joint pain
  • Headaches, feeling dizzy or weak

Spinal or epidural blood clots (hematoma)

People who take a blood thinner medicine (anticoagulant) like Bevyxxa, and have medicine injected into their spinal and epidural area, or have a spinal puncture have a risk of forming a blood clot that can cause long-term or permanent loss of the ability to move (paralysis). Your risk of developing a spinal or epidural blood clot is higher if:

  • A thin tube called an epidural catheter is placed in your back to give you certain medicine
  • You take NSAIDs or a medicine to prevent blood from clotting
  • You have a history of difficult or repeated epidural or spinal punctures
  • You have a history of problems with your spine or have had surgery on your spine

If you take Bevyxxa and receive spinal anesthesia or have a spinal puncture, your healthcare provider should watch you closely for symptoms of spinal or epidural blood clots. Tell your healthcare provider right away if you have back pain, tingling, numbness (especially in your legs and feet), muscle weakness, or loss of control of the bowels or bladder (incontinence).

Do not take Bevyxxa if you:

  • Have bleeding problems. Tell your healthcare provider if you have, or are at risk for, bleeding problems
  • Are allergic to betrixaban or to any of the ingredients in Bevyxxa. See the Medication Guide for a complete list of ingredients in Bevyxxa

Before taking Bevyxxa, tell your healthcare provider about all your medical conditions, including if you:

  • Have liver or kidney problems
  • Have ever had bleeding problems
  • Have an artificial heart valve
  • Are pregnant or plan to become pregnant. It is not known if Bevyxxa will harm your unborn baby. Taking Bevyxxa may increase the risk of bleeding during pregnancy and delivery
  • Are breastfeeding or plan to breastfeed. It is not known if Bevyxxa passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take Bevyxxa

Tell all of your healthcare providers and dentists that you are taking Bevyxxa. Talk to the healthcare provider who prescribed Bevyxxa for you, before you have any surgery, medical, or dental procedure.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some of your other medicines may affect the way Bevyxxa works. Certain medicines may increase your risk of bleeding when taken with Bevyxxa. See “The most common side effect of Bevyxxa is bleeding” above.

How should I take Bevyxxa?

  • Take Bevyxxa exactly as prescribed by your healthcare provider
  • Take Bevyxxa 1 time a day with food
  • Your healthcare provider will decide how long you should take Bevyxxa. Do not change your dose or stop taking Bevyxxa unless your healthcare provider tells you to
  • If you miss a dose of Bevyxxa, take it as soon as you remember on the same day. Take your next dose at your usual time the next day. Do not take more than 1 dose of Bevyxxa at the same time to make up for a missed dose
  • If you take too much Bevyxxa, go to the nearest hospital emergency room or call your healthcare provider right away

Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you.

Call your doctor for medical advice about side effects. You are also encouraged to report side effects to Portola Pharmaceuticals (1.866.777.5947) or FDA (1.800.FDA.1088 or www.fda.gov/medwatch).

Please see full Prescribing Information and Medication Guide.