Additional Dosing Information:

Dosing considerations in NVAF patients with renal impairment

Renal impairment No dose adjustment
Mild
Moderate
Severe

No dose adjustment for renal impairment alone in patients with NVAF, except for NVAF patients who meet the criteria for dosage adjustment as described above.1

  • Recommended dose for patients with at least 2 of the following:
    1. age ≥80 years
    2. body weight ≤60 kg
    3. serum creatinine ≥1.5 mg/dL
  • OR
  • For patients taking drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (eg, ketoconazole, itraconazole, ritonavir, clarithromycin)

Note: In patients already taking 2.5 mg twice daily, coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp should be avoided.

Patients with end-stage renal disease (ESRD) on dialysis:

  • Clinical efficacy and safety studies with ELIQUIS® (apixaban) did not enroll patients with ESRD on dialysis
  • In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study
  • It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as were seen in ARISTOTLE

Adjust ELIQUIS dose for patients taking drugs that are strong dual inhibitors of CYP3A4 and P-gp.

Dosing considerations in patients with renal impairment for all other ELIQUIS indications

No dose adjustment is recommended for patients with renal impairment, including those with ESRD on dialysis

Clinical efficacy and safety studies with ELIQUIS did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; therefore, dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in subjects with ESRD maintained on dialysis.

ELIQUIS elimination

Renal excretion accounts for about 27% of total clearance1

ELIQUIS is eliminated in both urine and feces. Biliary and direct intestinal excretion contributes to elimination of ELIQUIS in the feces1

Mild
hepatic impairment
(Child-Pugh class A)
No dose adjustment required1
Moderate
hepatic impairment
(Child-Pugh class B)
There is limited clinical experience with ELIQUIS® (apixaban) in patients with moderate hepatic impairment; dosing recommendation cannot be provided1
Severe
hepatic impairment
(Child-Pugh class C)
ELIQUIS is not recommended1

Adjust ELIQUIS dose for patients taking drugs that are strong dual inhibitors of CYP3A4
and P-gp.

For patients receiving doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS® (apixaban) by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (eg, ketoconazole, itraconazole, ritonavir, clarithromycin).1

In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp.1

Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (eg, rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban.

If a dose of ELIQUIS® (apixaban) is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.1

Bleeding risk with elective surgery or invasive procedures Recommendation1
Moderate or high risk of unacceptable or clinically significant bleeding Discontinue ELIQUIS® (apixaban) at least 48 hours prior
Low risk or noncritical site and easily controlled Discontinue ELIQUIS at least
24 hours prior
  • Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after surgical or other procedures as soon as adequate hemostasis has been established
Recommendation
SWITCHING
from warfarin to ELIQUIS® (apixaban)
Discontinue warfarin and start ELIQUIS when international normalized ratio (INR) is <2.0
SWITCHING
from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS
Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual time of the next dose of the anticoagulant other than warfarin
SWITCHING
from ELIQUIS to anticoagulants other than warfarin (oral or parenteral)
Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the usual time of the next dose of ELIQUIS
SWITCHING
from ELIQUIS to warfarin

ELIQUIS affects INR, so that initial INR measurements during transition to warfarin may not be useful for determining the appropriate dose of warfarin.

One approach is to discontinue ELIQUIS and begin both parenteral anticoagulant and warfarin at the time the next dose would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
  • For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS® (apixaban) tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally1
  • Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube1
  • Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours1
Drug Categories/
Examples
Key Considerations
Drugs affecting hemostasis1
  • Aspirin and other antiplatelet agents
  • Other anticoagulants
  • Heparin
  • Thrombolytic agents
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Serotonin norepinephrine reuptake inhibitors (SNRIs)
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), when used chronically
  • Fibrinolytics
Coadministration with these drugs increases the risk of bleeding
Strong dual inhibitors of CYP3A4 and P-gp1
  • Ketoconazole
  • Itraconazole
  • Ritonavir
  • Clarithromycin
Reduce the dose by 50%: For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily when coadministered with strong dual inhibitors of CYP3A4 and P-gp

In patients already taking ELIQUIS at a dose of 2.5 mg twice daily: Avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp

These drugs increase exposure to ELIQUIS and increase the risk of bleeding
Strong dual inducers of CYP3A4 and P-gp1
  • Rifampin
  • Carbamazepine
  • Phenytoin
  • St John’s wort
Avoid concomitant use

These drugs decrease exposure to ELIQUIS and increase the risk of thromboembolic events

  • Apixaban is a substrate of both CYP3A4 and P-gp.
  • Famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of ELIQUIS® (apixaban) in healthy subjects
  • ELIQUIS did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid in healthy subjects
  • APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo
  • For diltiazem, no dose adjustment of ELIQUIS is required4
  • This chart contains examples of drugs in each of the categories described. These examples reflect those in the ELIQUIS Full Prescribing Information, but do not represent an all-inclusive list.

A specific antidote for ELIQUIS® (apixaban) is not available

  • The apparent half-life of ELIQUIS is approximately 12 hours following oral administration
  • The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, ie, for about 2 drug half-lives
There is no established way to reverse bleeding in patients taking ELIQUIS The use of procoagulant reversal agents may be considered but has not been evaluated in clinical studies
  • Hemodialysis does not appear to have a substantial impact on ELIQUIS exposure
  • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of ELIQUIS
  • There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving ELIQUIS
  • There is no experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban, and they are not expected to be effective as a reversal agent
  • Prothrombin complex concentrate (PCC)
  • Activated prothrombin complex concentrate
  • Recombinant factor VIIa
  • When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended
  • Activated oral charcoal reduces absorption of ELIQUIS, thereby lowering ELIQUIS plasma concentration

aPTT = activated partial thromboplastin time; PT = Prothrombin time.

IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

(B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

  • use of indwelling epidural catheters
  • concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
  • a history of traumatic or repeated epidural or spinal punctures
  • a history of spinal deformity or spinal surgery
  • optimal timing between the administration of ELIQUIS and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

CONTRAINDICATIONS

  • Active pathological bleeding
  • Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions)

WARNINGS AND PRECAUTIONS

  • Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
  • Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.

    • Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
    • Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.
    • There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). A specific antidote for ELIQUIS is not available.
  • Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis.

    The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours.

    Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients.

  • Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients.
  • Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

ADVERSE REACTIONS

  • The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.

TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS

  • ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.

DRUG INTERACTIONS

  • Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with strong dual inhibitors of CYP3A4 and P-gp.
  • Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.
  • Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo.

PREGNANCY CATEGORY B

  • There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
INDICATIONS

ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.

ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy.

Please see U.S. FULL PRESCRIBING INFORMATION including Boxed WARNINGS, and MEDICATION GUIDE.

ELIQUIS is available in 2.5 mg and 5 mg tablets.

References

1. ELIQUIS® (apixaban) Package Insert. Bristol-Myers Squibb Company, Princeton, NJ, and Pfizer Inc, New York, NY.

2. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817.

3. Granger CB, Alexander JH, McMurray JJV, et al; for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.

4. Data on File. APIX075. Bristol-Myers Squibb Company, Princeton, NJ.

SELECTED IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS,(B) SPINAL/EPIDURAL HEMATOMA

(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

See Full Boxed WARNINGS

ELIQUIS® and the ELIQUIS logo are trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.
© Bristol-Myers Squibb Company.