Axibel Special Precautions

Hemorrhage risk: As with other anticoagulants, patients taking apixaban are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of hemorrhage, such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery. Apixaban is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Apixaban administration should be discontinued if severe hemorrhage occurs (see Adverse Reactions and Overdosage).
In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical hemostasis or the transfusion of fresh frozen plasma, should be considered. If life-threatening bleeding cannot be controlled by the previously mentioned measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of Apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received Apixaban. Currently, there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban.
Temporary discontinuation of Apixaban: Discontinuing anticoagulants, including Apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with Apixaban must be temporarily discontinued for any reason, restart therapy as soon as possible.
Renal impairment: Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥1.5 mg/dL (133 micromole/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of apixaban 2.5 mg twice daily (see Dosage & Administration).
In patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Apixaban is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (See Hepatic impairment under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Interaction with strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): Apixaban can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold (see Interactions).
Interaction with Strong inducers of both CYP3A4 and P-gp: Prevention of VTE: elective hip or knee replacement surgery: The concomitant use of apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. Use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Prevention of stroke and systemic embolism: NVAF: The concomitant use of apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. Use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Treatment of VTE: The concomitant use of apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. For the treatment of DVT or PE, Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (see Interactions). For prevention of recurrent DVT and PE, use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Interaction with other medicinal products affecting hemostasis: The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with Apixaban following surgery (see Interactions).
In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Apixaban. In a clinical study of patients with atrial fibrillation, concomitant use of ASA increased the major bleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk on warfarin from 2.7% per year to 4.6% per year.
In this clinical study, there was limited (2.3%) use of concomitant dual antiplatelet therapy with Apixaban.
A clinical study enrolled patients with atrial fibrillation with who had acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI) and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. The risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding was significantly lower in apixaban-treated subjects (24.7 per year) as compared to VKA-treated subjects (35.8% per year). Concomitant use of ASA increased the risk of ISTH major or CRNM bleeding from 21.0% per year to 40.5% per year when added to anticoagulation (either apixaban or VKA) on top of P2Y12 inhibitor. Specifically, concomitant use of ASA increased the risk of major or CRNM bleeding in apixaban-treated subjects from 16.4% per year to 33.1% per year and increased the bleeding risk in VKA-treated subjects from 26.1% per year to 48.4% per year.
In a clinical study of high-risk post-acute coronary syndrome patients without atrial fibrillation, characterized by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in bleeding risk was reported for apixaban compared to placebo.
Spinal/epidural anesthesia or puncture: Prevention of VTE: elective hip or knee replacement surgery: 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 post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Apixaban. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, 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.
Hip fracture surgery: Prevention of VTE: elective hip or knee replacement surgery: Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, Apixaban is not recommended in these patients.
Patients with prosthetic heart valves: Safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of apixaban is not recommended in this setting.
Acute PE in Hemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy: Treatment of VTE: 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.
Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (APS). In particular for patients who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. The efficacy and safety of Apixaban in patients with APS have not been established.
Effects on ability to drive and use machines: Apixaban has no or negligible influence on the ability to drive and use machines.
Use in Children: The efficacy and safety of Apixaban in children below age 18 have not been established. No data are available.