Dosing and uses of Eliquis (apixaban)
Adult dosage forms and strengths
tablet
- 2.5mg
- 5mg
Stroke Prophylaxis with Atrial Fibrillation
Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation
5 mg PO BId
Postoperative Prophylaxis of DVT/PE
Indicated following hip or knee replacement surgery
Initial: Give 2.5 mg PO 12-24 hr after surgery
Duration of therapy (hip replacement): 2.5 mg PO BID for 35 days
Duration of therapy (knee replacement): 2.5 mg PO BID for 12 days
Renal impairment, including with ESRD on dialysis
- Deep Vein Thrombosis: No dose adjustment recommended; clinical efficacy and safety studies did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in study subjects with ESRD maintained on dialysis
DVT or PE Treatment
Indicated for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE)
10 mg PO BID x 7 days, then 5 mg BId
Reduce risk for recurrent DVT or Pe
- Indicated to reduce the risk of recurrent DVT and PE following initial 6 months treatment for DVT and/or PE
- 2.5 mg PO BID
Renal impairment, including with ESRd
- No dose adjustment recommended; clinical efficacy and safety studies did not enroll patients with ESRD on dialysis or patients with a CrCl <15 mL/min; dosing recommendations are based on pharmacokinetic and pharmacodynamic (anti-FXa activity) data in study subjects with ESRD maintained on dialysis
Dosage modifications
Coadministration with dual inhibitors of CYP3A4 and P-gp
- If taking >2.5 PO BID, decrease dose by 50%
- If taking 2.5 mg BID, avoid coadministration with strong dual inhibitors
Nonvalvular atrial fibrillation
- Decrease dose to 2.5 mg PO BID in patients with any 2 of the following characteristics:
- Age ≥80 years
- Weight ≤60 kg
- Serum creatinine ≥1.5 mg/dL
Renal impairment (nonvalvular atrial fibrillation)
- Mild-to-moderate: No dosage adjustment required
- Serum creatinine ≥1.5 mg/dL: Decrease dose to 2.5 mg BID if patient has 1 additional characteristic of age ≥80 years or weight ≤60 kg
- ESRD maintained on hemodialysis: 5 mg BID; decrease dose to 2.5 mg BID if 1 additional characteristic of age ≥80 years or weight ≤60 kg is present
Hepatic impairment
- Mild: No dosage adjustment required
- Moderate: Patients may have intrinsic coagulation abnormalities; data are limited and no recommendations are available
- Severe: Not recommended
Dosing Considerations
Switching between apixaban and anticoagulants other than warfarin: Discontinue one being taken, and begin the other at the next scheduled dose
Switching from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR <2.0
Switching from apixaban to warfarin
- Apixaban affects INR, so measurements during coadministration with warfarin may not determine appropriate warfarin dose
- If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken
- Discontinue parenteral anticoagulant when INR reaches an acceptable level
Surgery/procedures
- Discontinue at least 48 hr before elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding
- Discontinue at least 24 hr before elective surgery or invasive procedures with a low risk of unacceptable or where the bleeding would be noncritical in location and easily controlled
Administration
May take with or without food
Missed dose: If 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; do not double the dose to make up for a missed dose
For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally; alternatively, tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube; crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hr
Pediatric dosage forms and strengths
Safety and efficacy not established
Eliquis (apixaban) adverse (side) 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
Warnings
Black box warnings
Discontinuing in patients with nonvalvular atrial fibrillation
- Premature discontinuation of any oral anticoagulant, including, apixaban, increases risk of thrombotic events; consider using another anticoagulant if anticoagulation with apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy
- 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 (see Dosing Considerations)
Spinal/epidural hematoma
- Increased risk of epidural or spinal hematoma when used with neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture (can result in long-term or permanent paralysis)
- Risk increased with indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis (eg, NSAIDs, platelet aggregation inhibitors, other anticoagulants)
- Risk also increased by traumatic or repeated epidural or spinal puncture; if this occurs, delay apixaban administration for 48 hr
- Monitor patients for signs and symptoms of neurologic impairment; if neurologic compromise is noted, urgent treatment is necessary
- Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hr after the last administration of apixaban; the next apixaban dose should not be administered earlier than 5 hr after the removal of the catheter
- Consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis
Contraindications
Severe hypersensitivity (ie, anaphylactic reactions)
Active pathological bleeding
Cautions
Discontinuing apixaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events (see Black box warnings)
Risk of epidural or spinal hematoma when used with neuraxial anesthesia (see Black box warnings)
Safety and efficacy has not been studied in patients with prosthetic heart valves; therefore, use of is not recommended in these patients
Not recommended as an alternative to unfractionated heparin for the initial treatment of PE in patients who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy
Coadministration with strong dual inhibitors of CYP3A4 and P-gp (see Dosage modifications)
Avoid coadministration with strong dual inducers of CYP3A4 and P-gp; such drugs decrease apixaban’s systemic exposure
Increases the risk of bleeding and can cause serious, potentially fatal, bleeding
Coadministration with other drugs that affect hemostasis increases bleeding risk (eg, aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, NSAIDs)
Prolongs PT and aPTT; however, changes are small and highly variable and are not useful for monitoring anticoagulation effect of apixaban
Reversing apixaban effect
- No specific antidote is available to reverse anticoagulant effect, which is expected to persist for about 24 hr after the last dose (~2 half-lives)
- Because of high plasma protein binding, apixaban is not expected to be dialyzable
- Protamine sulfate and vitamin K would not be expected to affect the anticoagulant activity of apixaban
- There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban
- There is neither scientific rationale for reversal nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving apixaban
- Use of procoagulant reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa) may be considered but has not been evaluated in clinical studies
- Activated oral charcoal reduces absorption of apixaban, thereby lowering plasma concentration
Pregnancy and lactation
Pregnancy category: B; increased incidence of maternal bleeding, primarily during gestation when studied in rats
Lactation: Unknown whether distributed in human breast milk; rats excreted apixaban in milk (12% of the maternal dose)
Women should be instructed either to discontinue breastfeeding or to discontinue apixaban therapy, taking into account the importance of the drug to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Eliquis (apixaban)
Mechanism of action
Factor Xa inhibitor; that inhibits platelet activation by selectively and reversibly blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity
Inhibits free and clot-bound factor Xa, and prothrombinase activity; no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin
Blood coagulation cascade is dependent on the activation of factor X to Factor Xa via the intrinsic and extrinsic pathways plays a central role in the blood coagulation cascade
Absorption
Bioavailability: Displays prolonged absorption Peak Plasma Concentration: 3-4 hr
Distribution
Protein Bound: 87%
Vdss: 21 L
Metabolism
Metabolized mainly by CYP3A4
Metabolized with minor contributions from CYP1A2, 2C8, 2C9, 2C19 and 2J2
Major sites of biotransformation: O-demethylation and hydroxylation at the 3-oxopirperidinyl moiety
Metabolites: No active circulating metabolites Substrate of P-gp and BCRp
Elimination
Half-life: 5-6 hr (dominant); 12 hr (apparent half-life with repeated dosing)
Dialyzable: No
Renal clearance: 27%
Excretion: 25% in urine and feces as metabolites; renal excretion accounts for 27% of total clearance; biliary and direct intestinal excretion contributes to elimination in feces
