APIXABAN Drug Interactions: What You Need to Know

INTERACTIONS

• Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce ELIQUIS dose or avoid coadministration. ( 2.6 , 7.1 , 12.3)
• Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blood levels of apixaban: Avoid concomitant use. (7.2 , 12.3)

7.1 Combined P-gp and Strong CYP3A4 Inhibitors For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be decreased by 50% when coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span> . For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span> . Concomitant administration of combined P-gp and strong CYP3A4 inhibitors has not been studied in pediatric patients. Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors increases exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> which increases the risk for bleeding.

Clarithromycin

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS [see Clinical Pharmacology (12.3) ] .

7.2 Combined P-gp and Strong CYP3A4 Inducers Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inducers decreases exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> which increases the risk for stroke and other thromboembolic events.

7.3 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 ELIQUIS 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 ELIQUIS compared to placebo. The rate of ISTH major bleeding was 2.8% per year with ELIQUIS versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with ELIQUIS versus 2.5% per year with placebo in those receiving dual antiplatelet therapy. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.

7.1 Combined P-gp and Strong CYP3A4 Inhibitors For patients receiving ELIQUIS 5 mg or 10 mg twice daily, the dose of ELIQUIS should be decreased by 50% when coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span> . For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ]</span> . Concomitant administration of combined P-gp and strong CYP3A4 inhibitors has not been studied in pediatric patients. Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors increases exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> which increases the risk for bleeding.

Clarithromycin

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS [see Clinical Pharmacology (12.3) ] .

7.2 Combined P-gp and Strong CYP3A4 Inducers Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Apixaban is a substrate of both CYP3A4 and P-gp. Concomitant use with drugs that are combined P-gp and strong CYP3A4 inducers decreases exposure to apixaban <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> which increases the risk for stroke and other thromboembolic events.

7.3 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 ELIQUIS 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 ELIQUIS compared to placebo. The rate of ISTH major bleeding was 2.8% per year with ELIQUIS versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with ELIQUIS versus 2.5% per year with placebo in those receiving dual antiplatelet therapy. In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with ELIQUIS.

Apixaban tablets are contraindicated in patients with the following conditions:

• Active pathological bleeding [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )]
• Severe hypersensitivity reaction to apixaban tablets (e.g., anaphylactic reactions) [see Adverse Reactions ( 6.1 )]
• Active pathological bleeding ( 4 )
• Severe hypersensitivity to apixaban tablets ( 4 )

AND PRECAUTIONS

• ELIQUIS 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: ELIQUIS use not recommended. (5.4)
• Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: ELIQUIS use not recommended. (5.6)

5.1 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Clinical Studies (14.1) ]</span> .

5.2 Bleeding ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Adverse Reactions (6.1) ]</span> . 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . 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. Reversal of Anticoagulant Effect A specific reversal agent (andexanet alfa) antagonizing the pharmacodynamic effect of apixaban is available for adults. However, its safety and efficacy have not been established in pediatric patients (refer to the USPI of andexanet alfa). The pharmacodynamic effect of ELIQUIS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 apixaban, thereby lowering apixaban plasma concentration <span class="opacity-50 text-xs">[see Overdosage (10)]</span> . Hemodialysis does not appear to have a substantial impact on apixaban exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 ELIQUIS, 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 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 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 ELIQUIS. In such cases, discontinue ELIQUIS and consider a short acting parenteral anticoagulant.

5.4 Patients with Prosthetic Heart Valves The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these patients.

5.5 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.

5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including ELIQUIS, 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.

5.1 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Clinical Studies (14.1) ]</span> .

5.2 Bleeding ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) and Adverse Reactions (6.1) ]</span> . 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> . 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. Reversal of Anticoagulant Effect A specific reversal agent (andexanet alfa) antagonizing the pharmacodynamic effect of apixaban is available for adults. However, its safety and efficacy have not been established in pediatric patients (refer to the USPI of andexanet alfa). The pharmacodynamic effect of ELIQUIS 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 apixaban, thereby lowering apixaban plasma concentration <span class="opacity-50 text-xs">[see Overdosage (10)]</span> . Hemodialysis does not appear to have a substantial impact on apixaban exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 ELIQUIS, and they are not expected to be effective as a reversal agent.

5.4 Patients with Prosthetic Heart Valves The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these patients.