Apixaban

Name: Apixaban

How should this medicine be used?

Apixaban comes as a tablet to take by mouth. It is usually taken with or without food twice a day. When apixaban is taken to prevent DVT and PE after hip or knee replacement surgery, the first dose should be taken at least 12 to 24 hours after surgery. Apixaban is usually taken for 35 days after a hip replacement surgery and for 12 days after knee replacement surgery. Take apixaban at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take apixaban exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are unable to swallow the tablets, you can crush them and mix with water, apple juice, or applesauce. Swallow the mixture right after you prepare it. Apixaban can also be given in certain types of feeding tubes. Ask your doctor if you should take this medication in your feeding tube. Follow your doctor's directions carefully.

Continue to take apixaban even if you feel well. Do not stop taking apixaban without talking to your doctor. If you stop taking apixaban, your risk of a blood clot may increase.

What side effects can this medication cause?

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

  • bleeding gums
  • nosebleeds
  • heavy vaginal bleeding
  • red, pink, or brown urine
  • red or black, tarry stools
  • coughing up or vomiting blood or material that looks like coffee grounds
  • swelling or joint pain
  • headache
  • rash
  • chest pain or tightness
  • swelling of the face or tongue
  • trouble breathing
  • wheezing
  • feeling dizzy or faint

Apixaban prevents blood from clotting normally, so it may take longer than usual for you to stop bleeding if you are cut or injured. This medication may also cause you to bruise or bleed more easily. Call your doctor right away if bleeding or bruising is unusual, severe, or cannot be controlled.

Apixaban may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Is apixaban safe to take if I'm pregnant or breastfeeding?

  • There are no adequate studies in pregnant women. Use during pregnancy may increase the risk of bleeding during pregnancy and delivery. Apixaban should be avoided during pregnancy.
  • It is not known if apixaban is excreted in human milk. Nursing mothers should discontinue apixaban or discontinue nursing.

Adverse Effects

Bleeding (Aristotle Study)

Major (2.13%, warfarin 3.09%; P <0.0001)

GI (0.83%, warfarin 0.93%)

Intracranial (0.33%, warfarin 0.82%)

Intraocular (0.06%, warfarin 0.14%)

Fatal (0.06%, warfarin 0.24%)

Clinically relevant nonmajor bleeding (2.08%, warfarin 3.0%; P <0.0001)

Bleeding (Averroes Study)

Major (1.41%, aspirin 0.92%; P = 0.07)

Fatal (0.16%, aspirin 0.16%)

Intracranial (0.34%, aspirin 0.35%)

<1%

Hypersensitivity reactions (including skin rash and anaphylactic reactions such as allergic edema)

Syncope

Apixaban Overview

Apixaban is a prescription medication used to reduce the risk of stroke and systemic embolism (artery blockage). Apixaban belongs to a group of drugs called Xa inhibitor anticoagulants, which decrease the chance of a blood clot forming in the body. It is also used to treat deep vein thrombosis (DVT) and pulmonary embolism (PE) in some patients as well as prevent blood clots that travel throughout the body in patients who have been treated for these type of blood clots.

This medication comes in tablet form and is taken twice a day with or without food.

Common side effects are related to bleeding.

Apixaban Brand Names

Apixaban may be found in some form under the following brand names:

  • Eliquis

Apixaban Interactions

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

  • aspirin or aspirin-containing products
  • long-term (chronic) use of nonsteroidal 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 help prevent or treat blood clots

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

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking apixaban?

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

Grapefruit and grapefruit juice may interact with apixaban and lead to unwanted side effects. Discuss the use of grapefruit products with your doctor.

Apixaban side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Also seek emergency medical attention if you have symptoms of a spinal blood clot: back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

Call your doctor at once if you have:

  • easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), bleeding from wounds or needle injections, any bleeding that will not stop;

  • heavy menstrual periods;

  • headache, dizziness, weakness, feeling like you might pass out;

  • urine that looks red, pink, or brown; or

  • black or bloody stools, coughing up blood or vomit that looks like coffee grounds.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Introduction

Anticoagulant; an oral, reversible, direct activated factor X (factor Xa) inhibitor.1 3 5 8 9 28 31 32 33 35 39 42

Uses for Apixaban

Embolism Associated with Atrial Fibrillation

Reduction in the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 3 5 8 40 42 1007

More effective than aspirin or warfarin in reducing the risk of stroke and systemic embolism, major bleeding, and all-cause mortality in such patients.1 3 5 20 21 24 30

The American College of Chest Physicians (ACCP), American Stroke Association (ASA), ACC, AHA, and other experts currently recommend that antithrombotic therapy be given to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless contraindicated.80 81 82 989 990 999 1007 1017

Antithrombotic therapy in patients with atrial flutter generally managed in the same manner as in patients with atrial fibrillation.999 1007

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding.80 81 82 1007 In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke.7 80 81 82 988 989 990 999 1007 1017 Patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or CHF.7 80 81 82 990 999 1007 In addition, female sex is considered an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.1017

Apixaban is recommended by some experts as a useful alternative to warfarin in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin cannot be achieved; warfarin may still be preferred in patients who have well-controlled INRs and are compliant with regular laboratory monitoring.10 12 25 70 71 73

Relative efficacy and safety of apixaban and other non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban) remains to be fully elucidated.9 10 29 66 67 68 70 989 1017

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (Clcr <15 mL/minute),1038 lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).1017

When selecting an appropriate anticoagulant, consider factors such as individual patient's risks of stroke and bleeding; patient compliance, preference, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; availability of facilities to monitor INR; and degree of current INR control in patients already receiving warfarin.8 10 68 69 70 71 72 988 989 999 1007 1029 1030 1032

Manufacturer states that use not recommended in patients with prosthetic heart valves.1

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

Prevention of postoperative DVT, which may lead to PE, in patients who have undergone total hip- or knee-replacement surgery.1 8 9 31 32 33 34 35 36 37 38 39 40 42 1003

More effective than sub-Q enoxaparin sodium 40 mg once daily in reducing risk of venous thromboembolism with similar rates of bleeding.1 32 33 Noninferiority of apixaban (2.5 mg twice daily) and currently recommended US dosing regimen for sub-Q enoxaparin sodium in knee-replacement surgery (30 mg twice daily)47 not established.1 31

ACCP and other clinicians consider apixaban an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery;35 38 39 74 1003 however, a low molecular weight heparin (LMWH) generally is preferred.1003 Apixaban may be a reasonable choice when an LMWH is not available or cannot be used.1003

Data currently lacking on efficacy and safety of apixaban thromboprophylaxis in patients undergoing hip-fracture surgery†.74 1003

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.1003

Treatment and Secondary Prevention of DVT and/or PE

Treatment and reduction in the risk of recurrence (secondary prevention) of acute DVT and/or PE.1 43 44 45 46 48

For treatment of symptomatic acute DVT and/or PE, efficacy appears similar to conventional anticoagulant therapy (sub-Q enoxaparin followed by warfarin therapy adjusted to INR of 2–3 for 6 months) with lower incidence of major bleeding.1 43 44

For secondary prevention following 6–12 months of initial anticoagulant therapy (e.g., with apixaban or enoxaparin and warfarin therapy), extended therapy with apixaban reduced incidence of symptomatic recurrent venous thromboembolism without increasing rate of major bleeding.1 45 46

Limited data on efficacy and safety in patients with cancer, low body weight (<60 kg), or renal insufficiency (Clcr <50 mL/minute); additional study required.43 44 45 46

Not recommended as initial therapy (as an alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.1

Thromboprophylaxis in Acute Medical Illness

Current evidence in patients with acute medical illness† suggests that extended treatment with apixaban (2.5 mg twice daily for 30 days) is not superior to short-term sub-Q enoxaparin sodium (40 mg once daily for 6–14 days) and is associated with an increased risk of major bleeding.51

Acute Coronary Syndrome

Current evidence suggests that addition of apixaban to standard antiplatelet therapy (e.g., aspirin, clopidogrel) in patients with acute coronary syndrome† (ACS) is associated with an increased risk of major (sometimes fatal) bleeding without substantial reduction in recurrent ischemic events.49 50 75

Apixaban Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 50%.1 17 28

Following oral administration, peak plasma concentrations occur within approximately 3–4 hours.1 17 28

Absorption occurs throughout GI tract; about 55% of dose absorbed in distal small intestine and ascending colon.1

Following administration via nasogastric feeding tube of a single, crushed 5-mg tablet suspended in 60 mL of 5% dextrose in water, bioavailability of the drug is similar to that of a whole tablet taken orally.1

Food

Food does not appear to affect systemic exposure or peak plasma concentrations.1 17

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 87%.1 28

Elimination

Metabolism

Metabolized principally by CYP3A4/5 with minor contributions from CYP isoenzymes 1A2, 2C8, 2C9, and 2J2.1 15 No active circulating metabolites.1

Elimination Route

Eliminated via multiple pathways, including hepatic metabolism and intestinal, biliary, and renal excretion; approximately 25% of an administered dose is eliminated renally.1 15 16 42 77 Total clearance approximately 3.3 L/hour.1

Not expected to be removed by dialysis due to high plasma protein binding.1

Half-life

Clearance half-life approximately 6 hours, but apparent half-life longer (approximately 12 hours) following repeated administration because of prolonged absorption.1 17

Special Populations

Systemic exposure and peak plasma concentrations not substantially altered in patients with mild or moderate hepatic impairment.1

Systemic exposure and peak plasma concentrations not substantially altered in patients with mild, moderate, or severe renal impairment.1

Systemic exposure and peak plasma concentrations are similar in patients ≥65 years of age and younger adults (18–40 years of age).1

Peak plasma concentrations, half-life, and time to steady-state are similar among patients of different ethnic origins (e.g., Caucasian, Asian, African-American).1 8 42

Uses For apixaban

Apixaban is used to treat or prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. apixaban is used for several days after hip or knee replacement surgery while you are unable to walk. It is during this time that blood clots are most likely to form.

Apixaban is also used to prevent stroke and blood clots in patients with certain heart rhythm problem (eg, nonvalvular atrial fibrillation).

Apixaban is a factor Xa inhibitor, an anticoagulant. It works by decreasing the clotting ability of the blood and helps preventing harmful clots from forming in the blood vessels.

apixaban is available only with your doctor's prescription.

Proper Use of apixaban

Take apixaban exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. When your supply of apixaban is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of apixaban.

apixaban comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor if you have any questions.

If you are not able to swallow whole tablets, the tablets may be crushed, mixed in D5W, water, apple juice, or applesauce. Or, the crushed tablets may be mixed with 60 mL of water or D5W dose and given through a nasogastric tube (NGT).

If you are taking another medicine to thin the blood (eg, heparin, warfarin, Coumadin®, Jantoven®), your doctor will give you very specific instructions about how to switch to apixaban. Carefully follow the instructions and ask your doctor if you have any questions.

Dosing

The dose of apixaban will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of apixaban. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For prevention of deep venous thrombosis (hip replacement surgery):
      • Adults—2.5 milligrams (mg) two times a day, for 35 days. The first dose should be taken 12 to 24 hours after surgery.
      • Children—Use and dose must be determined by your doctor.
    • For prevention deep venous thrombosis (knee replacement surgery):
      • Adults—2.5 milligrams (mg) two times a day, for 12 days. The first dose should be taken 12 to 24 hours after surgery.
      • Children—Use and dose must be determined by your doctor.
    • For prevention of reoccurring deep venous thrombosis and pulmonary embolism:
      • Adults—2.5 milligrams (mg) two times a day, after at least 6 months of treatment for deep venous thrombosis or pulmonary embolism.
      • Children—Use and dose must be determined by your doctor.
    • For prevention of strokes and blood clots in patients with nonvalvular atrial fibrillation:
      • Adults—5 milligrams (mg) two times a day.
      • Adults with 2 of the following characteristics: 80 years of age and older, body weight of 60 kilograms (kg) or less, or kidney problems—2.5 mg two times a day.
      • Children—Use and dose must be determined by your doctor.
    • For treatment of deep venous thrombosis and pulmonary embolism:
      • Adults—At first, 10 milligrams (mg) two times a day, for the first 7 days. Then, your doctor may give you 5 mg two times a day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of apixaban, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Use Labeled Indications

Deep vein thrombosis: Treatment of deep vein thrombosis; to reduce the risk of recurrent deep vein thrombosis following initial therapy

Nonvalvular atrial fibrillation: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)

Note: The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of AF recommend oral anticoagulation for patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2. As an alternative to warfarin, apixaban may also be used for 3 weeks prior and 4 weeks after cardioversion in patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown (January 2014)

Postoperative venous thromboprophylaxis following hip or knee replacement surgery: Prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in patients who have undergone hip or knee replacement surgery

Pulmonary embolism: Treatment of pulmonary embolism; to reduce the risk of recurrent pulmonary embolism following initial therapy

Dosing Adult

Deep venous thrombosis: Oral:

Treatment: 10 mg twice daily for 7 days followed by 5 mg twice daily

Reduction in the risk of recurrence: 2.5 mg twice daily after at least 6 months of treatment for DVT

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral: 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, then reduce dose to 2.5 mg twice daily.

Postoperative venous thromboprophylaxis: Oral:

Hip replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 35 days

Knee replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 12 days

Pulmonary embolism (PE): Oral:

Treatment: 10 mg twice daily for 7 days followed by 5 mg twice daily

Reduction in the risk of recurrence: 2.5 mg twice daily after at least 6 months of treatment for PE

Conversion:

Conversion from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR is <2

Conversion from apixaban to warfarin: Note: Apixaban affects the INR; measuring the INR during coadministration with warfarin therapy may not be useful for determining an appropriate dose of warfarin

If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant with warfarin when the next dose of apixaban is due; discontinue parenteral anticoagulant when INR reaches an acceptable range. Alternatively, some recommend continuing apixaban during initiation of warfarin or other vitamin K antagonist (VKA) at usual starting doses until INR ≥2, then discontinue apixaban. During concomitant therapy, initiating INR testing on day 3 and just prior to each dose of apixaban is also recommended (Eliquis Canadian product labeling 2016).

Conversion from apixaban to other non-warfarin anticoagulants (oral or parenteral): Discontinue apixaban and begin taking the new non-warfarin anticoagulant at the usual time of the next scheduled dose of apixaban.

Conversion from other non-warfarin anticoagulants (oral or parenteral) to apixaban: Discontinue the other non-warfarin anticoagulant and begin taking apixaban at the usual time of the next scheduled dose of the other non-warfarin anticoagulant.

Dosage adjustment of apixaban with concomitant medications: For patients receiving dual strong CYP3A4 and P-glycoprotein inhibitors (eg, clarithromycin, ketoconazole, itraconazole, ritonavir) and apixaban doses >2.5 mg twice daily, reduce apixaban dose by 50%. Note: Avoid concomitant use with dual strong CYP3A4 and P-glycoprotein inhibitors if patient is already taking apixaban 2.5 mg twice daily or patient meets 2 of the following criteria: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Administration

Administer without regard to meals. After hip/knee replacement, initial dose should be administered 12 to 24 hours postoperatively. If patient unable to swallow whole tablets, may crush 5 mg or 2.5 mg tablets and suspend in 60 mL of water, D5W, or apple juice or mix with applesauce; administer immediately. For delivery through a nasogastric tube, crushed tablets may be suspended in 60 mL of water or D5W followed by immediate delivery. Crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

Pregnancy Risk Factor B Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Data are insufficient to evaluate the safety of oral factor Xa inhibitors during pregnancy; use during pregnancy should be avoided (Bates 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), dizziness, passing out, loss of strength and energy, confusion, headache, joint pain, angina, wheezing, or joint edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Usual Adult Dose for Pulmonary Embolism

Initial dose: 10 mg orally 2 times a day for 7 days
Maintenance dose: 5 mg orally 2 times a day

Use: Treatment of deep vein thrombosis and pulmonary embolism.

(web3)