apixaban (Rx)

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

Postmarketing Reports

Blood and lymphatic system disorders: Thrombocytopenia (including platelet count decreases)

Vascular disorders: Hypotension (including procedural hypotension)

Respiratory, thoracic, and mediastinal disorders: Epistaxis

Gastrointestinal disorders: Gastrointestinal hemorrhage (including hematemesis and melena), hematochezia

Hepatobiliary disorders: Liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased

Renal and urinary disorders: Hematuria (including respective laboratory parameters)

Injury, poisoning, and procedural complications: Wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage

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; advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room; discontinue therapy in patients with active pathological hemorrhage

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

Direct-acting oral anticoagulants (DOACs), are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS); for patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2- glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy

Reversing apixaban effect

• Anticoagulant effect is expected to persist for about 24 hr after the last dose (~2 half-lives)
• Coagulation factor Xa recombinant, inactivated-zhzo is commercially available for reversal of the anticoagulant effect of apixaban when reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding
• 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

There are no adequate and well-controlled studies in pregnant women

Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery

Use of anticoagulants, during pregnancy, may increase risk of bleeding in fetus and neonate

Pregnancy confers an increased risk of thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions

Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy

Therapy should be administered during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus

Animal studies

• Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban, but was not associated with increased risk for fetal malformations or toxicity

Labor and delivery

• All patients receiving anticoagulants, including pregnant women, are at risk for bleeding; use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas; consider use of a shorter acting anticoagulant as delivery approaches
• Consider the risks of bleeding and of stroke in this setting

Females of reproductive potential

• Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician
• The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants should be assessed in females of reproductive potential and those with abnormal uterine bleeding

Lactation

There are no data on presence of drug metabolites in human milk, effects on breastfed child, or the effects on milk production; the drug and/or its metabolites were present in milk of rats

Rats excrete apixaban in milk (12% of the maternal dose)

Because human exposure through milk is unknown, instruct women to either 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.

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, which play 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

Oral 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

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