Apixaban: uses, appearance and warnings

Apixaban tablets are a factor Xa inhibitor indicated: to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. (1.1) 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. (1.2) 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 Apixaban tablets are indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Apixaban tablets are 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. 1.3 Treatment of Deep Vein Thrombosis Apixaban tablets are indicated for the treatment of DVT. 1.4 Treatment of Pulmonary Embolism Apixaban tablets are indicated for the treatment of PE. 1.5 Reduction in the Risk of Recurrence of DVT and PE Apixaban tablets are indicated to reduce the risk of recurrent DVT and PE following initial therapy.

2.5 mg, yellow, round, biconvex, film-coated tablets debossed with “M” on one side and “2.5” on other side. 5 mg, pink, oval, biconvex, film-coated tablets debossed with “M” on one side and “5” on other side. Tablets: 2.5 mg and 5 mg. (3)

How Supplied Apixaban tablets are available as listed in the table below. Tablet Strength Tablet Color/Shape Tablet Markings Package Size NDC Code 2.5 mg Yellow, round, biconvex Debossed with “M” on one side and “2.5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1721-13 0115-1721-03 0115-1721-01 5 mg Pink, oval, biconvex Debossed with “M” on one side and “5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1722-13 0115-1722-03 0115-1722-01 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. How Supplied Apixaban tablets are available as listed in the table below. Tablet Strength Tablet Color/Shape Tablet Markings Package Size NDC Code 2.5 mg Yellow, round, biconvex Debossed with “M” on one side and “2.5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1721-13 0115-1721-03 0115-1721-01 5 mg Pink, oval, biconvex Debossed with “M” on one side and “5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1722-13 0115-1722-03 0115-1722-01 How Supplied Apixaban tablets are available as listed in the table below. Tablet Strength Tablet Color/Shape Tablet Markings Package Size NDC Code 2.5 mg Yellow, round, biconvex Debossed with “M” on one side and “2.5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1721-13 0115-1721-03 0115-1721-01 5 mg Pink, oval, biconvex Debossed with “M” on one side and “5” on the other side Bottles of 60 Bottles of 1000 Hospital Unit-Dose Blister Package of 100 0115-1722-13 0115-1722-03 0115-1722-01

Apixaban is 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 (e.g., anaphylactic reactions) [see Adverse Reactions (6.1) ] Active pathological bleeding. (4) Severe hypersensitivity to apixaban. (4)

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 use not recommended. (5.4) Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome: Apixaban use not recommended. ( 5.6 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including apixaban, 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 to warfarin in clinical trials in atrial fibrillation patients. If apixaban 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 (2.4) and Clinical Studies (14.1) ] . 5.2 Bleeding Apixaban 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 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 apixaban 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 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 [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, 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. The next dose of apixaban 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 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. 5.4 Patients with Prosthetic Heart Valves The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban 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 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, 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 apixaban, 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 to warfarin in clinical trials in atrial fibrillation patients. …

The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information. Increased Risk of Thrombotic Events After Premature Discontinuation [see Warnings and Precautions (5.1) ]. Bleeding [see Warnings and Precautions (5.2) ]. Spinal/Epidural Anesthesia or Puncture [see Warnings and Precautions (5.3) ]. Most common adverse reactions (>1%) are related to bleeding. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Impax Laboratories, Inc. at 1-800-934-6729 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. …

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 apixaban 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. …