WARNING: (A) PREMATUREDISCONTINUATION OF APIXABAN TABLETSINCREASES THE RISK OF THROMBOTICEVENTS (B) SPINAL/EPIDURAL HEMATOMA (A) PREMATURE DISCONTINUATION OF APIXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS Premature discontinuation of any oral anticoagulant, including apixaban tablets, increases the risk of thrombotic events. If anticoagulation with apixaban tablets is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 ), and Clinical Studies ( 14.1 )]. (B) SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients treated with apixaban tablets 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 apixaban tablets and neuraxial procedures is not known [see Warnings and Precautions ( 5.3 )] Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions ( 5.3 )]. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated [see Warnings and Precautions ( 5.3 )]. WARNING: (A) PREMATURE DISCONTINUATION OF APIXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS (B) SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. (A) PREMATURE DISCONTINUATION OF APIXABAN TABLETS INCREASES THE RISK OF THROMBOTIC EVENTS: Premature discontinuation of any oral anticoagulant, including apixaban tablets, increases the risk of thrombotic events. To reduce this risk, consider coverage with another anticoagulant if apixaban tablets are discontinued for a reason other than pathological bleeding or completion of a course of therapy. ( 2.5 , 5.1 , 14.1 ) (B) SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas may occur in patients treated with apixaban tablets 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. ( 5.3 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Apixaban tablets can cause serious, potentially fatal, bleeding. Promptly evaluate signs and symptoms of blood loss. An agent to reverse the anti-factor Xa activity of apixaban is available. ( 5.2 ) • Prosthetic heart valves: Apixaban tablets use not recommended. ( 5.4 ) • Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Apixaban tablets use not recommended. ( 5.6 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including apixaban tablets, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban tablets to warfarin in clinical trials in atrial fibrillation patients. If apixaban tablets is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration ( 2.5 ) and Clinical Studies ( 14.1 )]. 5.2 Bleeding Apixaban tablets increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration ( 2.1 ) and Adverse Reactions ( 6.1 )]. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions ( 7.3 )]. Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue apixaban tablets in patients with active pathological hemorrhage. Reversal of Anticoagulant Effect The pharmacodynamic effect of apixaban tablets can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies [see Clinical Pharmacology ( 12.2 )] . When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or a PTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration [see Overdosage ( 10 )]. Hemodialysis does not appear to have a substantial impact on apixaban exposure [see Clinical Pharmacology ( 12.3 )]. Protamine sulfate and vitamin K are not 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 no experience with systemic hemostatics (desmopressin) in individuals receiving apixaban tablets and they are not expected to be effective as a reversal agent. 5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing 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 apixaban tablets. The next dose of apixaban tablets 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 apixaban tablets for 48 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, or bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. No data are available on the timing of the placement or removal of neuraxial catheters in pediatric patients while on apixaban tablets. In such cases, discontinue apixaban tablets and consider a short acting parenteral anticoagulant. 5.4 Patients with Prosthetic Heart Valves The safety and efficacy of apixaban tablets have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban tablets is not recommended in these patients. 5.5 Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy Initiation of apixaban tablets 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. 5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including apixaban tablets, 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.