Apixaban

Name: Apixaban

Eliquis Interactions

Tell your doctor about all prescription, nonprescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially those listed in the Eliquis Warnings section above, and the following:

  • Biaxin or Prevpac (clarithromycin)
  • Carbatrol, Epitol, Equetro, Tegretol, or Teril (carbamazepine)
  • Dilantin or Phenytek (phenytoin)
  • Nizoral (ketoconazole)
  • Norvir or Kaletra (ritonavir)
  • Onmel or Sporanox (itraconazole)
  • Rifadin, Rimactane, Rifadin, or Rifater (rifampin)
  • Selective serotonin reuptake inhibitors (SSRIs), such as Celexa (citalopram); Prozac, Sarafem, Selfemra, or Symbyax (fluoxetine); Luvox (fluvoxamine); Brisdelle, Paxil, or Pexeva (paroxetine); or Zoloft (sertraline)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as Cymbalta (duloxetine), Khedezla or Pristiq (desvenlafaxine), Fetzima or Savella (milnacipran), or Effexor (venlafaxine)
  • St. John's wort

Patient Handout

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Inform MD

Before you take apixaban, tell your doctor if you:

  • have kidney or liver problems
  • have any other medical condition
  • have ever had bleeding problems
  • will be having any surgery or procedure done in the future
  • are pregnant or plan to become pregnant. It is not known if apixaban will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if apixaban passes into your breast milk. You and your doctor should decide if you will take apixaban or breastfeed. You should not do both.

Tell all of your doctors and dentists that you are taking apixaban. They should talk to the doctor who prescribed apixaban for you, before you have any surgery, medical or dental procedure.

Tell your doctor 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 apixaban works. Certain medicines may increase your risk of bleeding or stroke when taken with apixaban.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

Apixaban Usage

  • Take apixaban exactly as prescribed by your doctor.
  • Take apixaban twice every day with or without food.
  • Do not change your dose or stop taking apixaban unless your doctor tells you to.
  • If you miss a dose of apixaban, take it as soon as you remember. Do not take more than one dose of apixaban at the same time to make up for a missed dose.
  • Your doctor will decide how long you should take apixaban. Do not stop taking it without first talking with your doctor. Stopping apixaban may increase your risk of having a stroke.
  • Do not run out of apixaban. Refill your prescription before you run out.
  • If you take too much apixaban, call your doctor or go to the nearest hospital emergency room right away.
  • Call your doctor or healthcare provider right away if you fall or injure yourself, especially if you hit your head. Your doctor or healthcare provider may need to check you.
  • Apixaban should be stopped at least 48 hours prior to surgery or procedures with a moderate or high risk of significant bleeding. Tell your doctor about any upcoming surgery or procedure before stopping this medication.
    • Apixaban should be stopped at least 24 hours before to surgery or procedures with a low risk of bleeding or where the bleeding would be non-critical and easily controlled. Tell your doctor about any upcoming surgery or procedure before stopping this medication.

Apixaban Dosage

The recommended dose of Eliquis (apixaban) for reducing the risk of stroke and blood clots in patients with atrial fibrillation is 5 mg taken orally twice daily. 

The recommended dose of Eliquis (apixaban) for preventing clots after hip or knee replacement surgery is 2.5 mg orally twice daily.

The recommended dose of Eliquis (apixaban) for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.

The recommended dose of Eliquis (apixaban) for reducing the risk of having another DVT and PE after being treated for these type of blood clots is 2.5 mg taken orally twice daily. 

Dose changes may be made according to your age, body weight, kidney function, and if you are taking other medications that may interact with apixaban.

Other Requirements

  • Store apixaban at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep apixaban and all medicines out of the reach of children.

Apixaban FDA Warning

WARNING: DISCONTINUING THIS MEDICATION IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE

Discontinuing apixaban places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following discontinuation of apixaban in clinical trials in patients with nonvalvular atrial fibrillation. If anticoagulation with apixaban must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be strongly considered.

What is the most important information I should know about apixaban?

You should not take apixaban if you have an artificial heart valve, or if you have any active bleeding from a surgery, injury, or other cause.

Apixaban can cause a very serious blood clot around your spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural), especially if you have a genetic spinal defect, if you have a spinal catheter in place, if you have a history of spinal surgery or repeated spinal taps, or if you are also using other drugs that can affect blood clotting. This type of blood clot can lead to long-term or permanent paralysis.

Get emergency medical help if you have symptoms of a spinal cord blood clot such as back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

Do not stop taking apixaban unless your doctor tells you to. Stopping suddenly can increase your risk of blood clot or stroke.

What happens if I miss a dose?

Take the missed dose on the same day you remember it. Take your next dose at the regular time and stay on your twice-daily schedule. Do not take extra medicine to make up the missed dose.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Binds selectively and with high affinity to active site of factor Xa; inhibits free and clot-bound factor Xa and prothrombinase activity.1 38 42

  • Inhibition of coagulation factor Xa prevents conversion of prothrombin to thrombin and subsequent thrombus formation.1 28 42

  • Unlike fondaparinux, heparin, and LMWHs, apixaban blocks factor Xa directly and does not require a cofactor (antithrombin III) to exert its anticoagulant activity.1 38 42

  • Inhibits factor Xa activity and prolongs PT, aPTT, and HepTest (an indirect measure of factor Xa activity) in a concentration-dependent manner.1 8 28

Advice to Patients

  • Importance of taking the drug exactly as prescribed and not discontinuing therapy without first consulting a clinician.1 2

  • Importance of advising patients that if a dose is missed, to take it as soon as possible on the same day and then resume the regular twice-daily dosing schedule; the missed dose should not be doubled.1 2

  • Importance of informing patients that they may bruise and/or bleed more easily and that a longer than normal time may be required to stop bleeding when taking apixaban; clinicians should advise patients on how to recognize signs and symptoms of bleeding.1 2 Importance of patients informing clinicians immediately about any unusual bleeding or bruising during therapy.1 2

  • Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., numbness or weakness in legs, bowel or bladder dysfunction), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors, or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1

  • Importance of patients informing clinicians (e.g., physicians, dentists) that they are receiving apixaban therapy before scheduling any surgery or invasive procedures, including dental procedures.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians (e.g., physicians, dentists) of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Precautions While Using apixaban

It is very important that your doctor check your progress at regular visits to make sure that apixaban is working properly and to decide if you should continue to take it. Blood tests may be needed to check for unwanted effects.

apixaban may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using apixaban.

Make sure any doctor who treats you knows that you are using apixaban. You may need to stop using apixaban for several days before having surgery, including dental procedures.

Do not suddenly stop using apixaban without asking your doctor. You might have a higher risk of stroke after you stop using apixaban.

You may bleed and bruise more easily while you are using apixaban. Be extra careful to avoid injuries. Stay away from rough sports or other situations where you could be bruised, cut, or injured. Gently brush and floss your teeth. Be careful when using sharp objects, including razors and fingernail clippers. Avoid picking your nose. If you need to blow your nose, blow it gently.

Check with your doctor right away if you have any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, headache, dizziness, or weakness, pain, swelling, or discomfort in a joint, pinpoint red spots on your skin, unusual nosebleeds, or unusual vaginal bleeding that is heavier than normal. These may be signs of bleeding problems.

apixaban may increase risk of blood clot in the spine or epidural area, which may lead to long-term or permanent paralysis. This is more likely to occur if you have an epidural catheter placed in your back, are taking NSAID or blood clotting medicine, a history of repeated epidural punctures or problems with your spine, or have had surgery on your spine. Tell your doctor right away if you have tingling, numbness, or muscle weakness, especially in your legs and feet.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal (eg, St. John's wort) or vitamin supplements.

How is this medicine (Apixaban) best taken?

Use apixaban as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food.
  • If you have trouble swallowing this medicine, it can be crushed and mixed in water, apple juice, or applesauce. If you crush and mix apixaban, take it within 4 hours of mixing.
  • To gain the most benefit, do not miss doses.
  • Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
  • Those who have feeding tubes may use apixaban. Use as you have been told. Flush the feeding tube after this medicine is given.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it on the same day you missed the dose.
  • Do not take 2 doses at the same time or extra doses.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Dosing Renal Impairment

Adults:

Deep vein thrombosis (DVT), pulmonary embolism (PE), reduction in the risk of recurrent DVT and PE: No dosage adjustment is recommended by the manufacturer. However, it should be noted that patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from the clinical trials (Agnelli 2013a; Agnelli 2013b).

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

Serum creatinine <1.5 mg/dL: No dosage adjustment necessary unless age ≥80 years and body weight ≤60 kg, then reduce dose to 2.5 mg twice daily (also refer to adult dosing).

Serum creatinine ≥1.5 mg/dL and either age ≥80 years or body weight ≤60 kg: 2.5 mg twice daily. Note: Patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from clinical trials (Connolly, 2011; Granger, 2011). In patients with severe or end-stage chronic kidney disease, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January, 2014]).

Postoperative (hip or knee replacement) venous thromboprophylaxis: No dosage adjustment is recommended by the manufacturer. However, it should be noted that patients with either clinically significant renal impairment (ADVANCE-1 [Lassen, 2009]), impaired renal function (ADVANCE-2 [Lassen, 2010b]), or CrCl <30 mL/minute (as determined by Cockcroft-Gault equation) (ADVANCE-3 [Lassen 2010a]) were excluded from the respective clinical trials.

ESRD requiring hemodialysis: Not dialyzable (Wang 2016) to minimal (AUC decreased by 14% over 4 hours) (NCS/SCCM [Frontera 2016]).

Deep vein thrombosis (DVT), pulmonary embolism (PE), reduction in the risk of recurrent DVT and PE: No dosage adjustment necessary.

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): No dosage adjustment necessary unless if age ≥80 years or body weight ≤60 kg, then reduce to 2.5 mg twice daily.

Postoperative (hip or knee replacement) venous thromboprophylaxis: No dosage adjustment necessary.

Note: The above recommendations are made solely on a single dose pharmacokinetic and pharmacodynamic (anti-factor Xa activity) study in only 8 patients (Wang 2016). Clinical efficacy and long-term safety studies have not been done in this population; therefore, use with caution. Further dosage adjustment may be necessary based on anti-factor Xa activity (Ikeda 2016). In one case, a probable relationship between apixaban exposure and GI bleeding has been reported (Kufel 2016). In patients with severe or end-stage chronic kidney disease and nonvalvular atrial fibrillation, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January 2014]).

Additional recommendations: Geriatric patients ≥65 years: CrCl <25 mL/minute: Avoid use due to increased risk of bleeding (Beers Criteria [AGS 2015]).

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding; serious, potentially fatal bleeding may occur. Concomitant use of drugs that affect hemostasis increases the risk of bleeding. Monitor for signs and symptoms of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. No specific antidote exists for apixaban reversal; hemodialysis does not appear to have a substantial impact on apixaban exposure. Although not evaluated in clinical trials, in the event of apixaban-related hemorrhage, the use of prothrombin complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa may be considered. A preclinical study evaluated the impact of different clotting factors in reversing actions of apixaban. A high concentration of apixaban (200 ng/mL) was added to blood from healthy donors in vitro and blood-clotting response was evaluated when prothrombin complex concentrates (PCCs; product not specified), activated prothrombin complex concentrates (aPCCs), and recombinant factor VII (rFVIIa) were added. PCC and aPCC seemed to be more efficient in restoring generation of thrombin, while rFVIIa was the quickest to produce a compact blood clot and most effective in studies with blood circulating through a damaged blood vessel. These lab tests indicate that these agents may reverse the effects of apixaban, but more studies are needed to determine their clinical impact (Escolar, 2012). The use of activated oral charcoal may be considered if ingestion occurred within 2 to 6 hours of presentation.

• Thromboembolic events: [US Boxed Warning]: Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. When used to prevent stroke in patients with nonvalvular atrial fibrillation, an increased risk of stroke was observed upon transition from apixaban to warfarin in clinical trials. If apixaban must be discontinued for reasons other than bleeding or completion of a course of therapy, consider the use of another anticoagulant.

Disease-related concerns:

• Acute coronary syndrome (ACS): In a clinical trial evaluating the use of apixaban in addition to standard antiplatelet therapy to reduce the risk of recurrent ischemic events post-ACS, an increased incidence of major bleeding (including intracranial and fatal bleeding) without any significant clinical benefit was observed (Alexander, 2011).

• Hepatic impairment: Use with caution in moderate impairment (Child-Pugh class B) as there is limited clinical experience in these patients; dosing recommendations cannot be provided. Use in severe hepatic impairment (Child-Pugh class C) is not recommended.

• Renal impairment: Systemic exposure increases with worsening renal function. Bleeding risk may be increased in severe renal impairment (CrCl <15 to 29 mL/minute); use with caution. Patients with significant renal impairment (eg, CrCl <30 mL/minute) were excluded from clinical trials. Hemodialysis does not appear to have a substantial impact in apixaban exposure; patients with ESRD with or without hemodialysis have not been studied. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation with a serum creatinine ≥1.5 mg/dL and are either ≥80 years of age or weigh ≤60 kg. Compared to warfarin, apixaban has been shown to be associated with less major bleeding among all ranges of estimated GFRs as determined by initial serum creatinine; however, patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from the analysis (Hohnloser, 2012).

• Valvular disease: Safety and efficacy have not been established in patients with prosthetic heart valves or significant rheumatic heart disease (eg, mitral stenosis); use is not recommended. Non-valvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valve (AHA/ACC/HRS [January, 2014]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Acutely ill medical patients: In acutely ill patients (eg, heart failure, respiratory failure) at risk for venous thromboembolism (VTE) receiving apixaban for extended VTE prophylaxis, an increased incidence of major bleeding without greater efficacy was observed with extended apixaban therapy (eg, 30 days) versus low molecular weight heparin (enoxaparin) therapy for 1 to 2 weeks (Goldhaber 2011).

• Elderly: Systemic exposure is increased ~32% in patients >65 years of age; however, dose reductions are not required. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation who are ≥80 years of age and either weigh ≤60 kg or with a serum creatinine ≥1.5 mg/dL.

Other warnings/precautions:

• Appropriate use: In hemodynamically unstable patients with acute PE or patients with PE requiring thrombolysis or pulmonary embolectomy, the use of apixaban is not recommended as an alternative to unfractionated heparin for initial treatment.

• Body weight: Systemic exposure may be increased by 20% to 30% in patients <50 kg and decreased by 20% to 30% in patients >120 kg; dosage reduction is recommended for patients with nonvalvular atrial fibrillation weighing ≤60 kg and either ≥80 years of age or with a serum creatinine ≥1.5 mg/dL.

• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas resulting in long-term or permanent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal/epidural puncture; the risk is increased by the use of indwelling epidural catheters with concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, a history of spinal deformity or surgery, or if optimal timing between the administration of apixaban and neuraxial procedures is not known. Consider the potential benefit versus risk prior to neuraxial intervention in patients who are anticoagulated or scheduled to be anticoagulated for thromboprophylaxis. In patients who receive both apixaban and neuraxial anesthesia, avoid removal of epidural or intrathecal catheter for at least 24 hours following last apixaban dose; avoid apixaban administration for at least 5 hours following catheter removal. If traumatic puncture occurs, delay administration of apixaban for at least 48 hours. Monitor frequently for signs of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction). If neurologic impairment is noted, prompt treatment is necessary.

• Surgery and invasive procedures: Discontinue apixaban at least 48 hours prior to elective surgery or invasive procedures with a moderate-to-high risk of unacceptable or clinically significant bleeding. Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where bleeding would not be in a critical location and easily controlled. Anticoagulation bridging during the 24 to 48 hours apixaban is interrupted and prior to the intervention is not generally required. Reinitiate apixaban when adequate hemostasis has been achieved unless oral therapy cannot be administered, then consider administration of a parenteral anticoagulant.

Usual Adult Dose for Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery

DEEP VEIN THROMBOSIS (DVT) PROPHYLAXIS FOLLOWING HIP OR KNEE REPLACEMENT SURGERY:
2.5 mg orally twice a day

Duration of therapy:
-Hip replacement: 35 days
-Knee replacement: 12 days

Comments: The initial dose should be taken 12 to 24 hours after surgery.

Use: Prophylaxis of DVT, which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.


RECURRENT DVT AND PE RISK REDUCTION:
2.5 mg orally twice a day

Use: Reduction in the risk of recurrence of DVT and PE after at least 6 months of treatment for DVT or PE.

Liver Dose Adjustments

Mild liver impairment (Child-Pugh A): No adjustment recommended

Moderate liver impairment (Child-Pugh B): These patients may have intrinsic coagulation abnormalities and there is limited experience with apixaban in these patients; therefore, data is not available.

Severe liver impairment (Child-Pugh C): Not recommended

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