ELIQUIS (apixaban), a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide. Its molecular formula is C 25 H 25 N 5 O 4 , which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula: Apixaban is a white to pale-yellow powder. At physiological pH (1.2-6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL. ELIQUIS tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). Apixaban Chemical Structure

ELIQUIS is a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 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. for the treatment of DVT and PE, and for the reduction in the risk of recurrent DVT and PE following initial therapy. (1.3 , 1.4 , 1.5) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery 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

Treatment of Deep Vein Thrombosis ELIQUIS is indicated for the treatment of DVT

Treatment of Pulmonary Embolism ELIQUIS is indicated for the treatment of PE

Reduction in the Risk of Recurrence of DVT and PE ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.

2.5 mg, yellow, round, biconvex, film-coated tablets with “893” debossed on one side and “2½” on the other side. 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one side and “5” on the other side. Tablets: 2.5 mg and 5 mg

Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation: The recommended dose is 5 mg orally twice daily. In patients with at least 2 of the following characteristics: age greater than or equal to 80 years, body weight less than or equal to 60 kg, or serum creatinine greater than or equal to 1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily. Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2.5 mg taken orally twice daily

Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of the following characteristics: age greater than or equal to 80 years body weight less than or equal to 60 kg serum creatinine greater than or equal to 1.5 mg/dL Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days. Treatment of DVT and PE The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE

Missed Dose If a dose of ELIQUIS 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

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 non-critical 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

Converting from or to ELIQUIS Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started when the international normalized ratio (INR) is below 2.0. Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements during the transition to warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken, discontinuing the parenteral anticoagulant when INR reaches an acceptable range. 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 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

Combined P-gp and Strong CYP3A4 Inhibitors For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose by 50% when ELIQUIS is coadministered with drugs that are combined P-glycoprotein (P-gp) and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, itraconazole, ritonavir) . In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors

Administration Options For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS 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, ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube . Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

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. Prosthetic heart valves: ELIQUIS use not recommended. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: ELIQUIS use not recommended. 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

Bleeding ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding . 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) . 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 An agent to reverse the anti-factor Xa activity of apixaban is available. 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 . 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 . Hemodialysis does not appear to have a substantial impact on apixaban exposure . 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

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

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

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

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.

Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. Combined P-gp and strong CYP3A4 inhibitors increase blood levels of apixaban. Reduce ELIQUIS dose or avoid coadministration. (2.5 , 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) . For patients receiving ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration with combined P-gp and strong CYP3A4 inhibitors . 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

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

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.