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Haemorrhage risk: As with other anticoagulants, patients taking XALIQUIS are to be carefully observed for signs of bleeding.
XALIQUIS is recommended to be used with caution in conditions with increased risk of haemorrhage, 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. XALIQUIS administration should be discontinued if severe haemorrhage occurs (see Overdosage).
Although treatment with Apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see Pharmacology: Pharmacodynamics under Actions).
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 XALIQUIS 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 XALIQUIS. Currently, there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban.
Temporary discontinuation of XALIQUIS: Discontinuing anticoagulants, including XALIQUIS, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with XALIQUIS must be temporarily discontinued for any reason, restart therapy as soon as possible.
Renal impairment: Prevention of VTE: elective hip or knee replacement surgery.
Because there is limited clinical experience in patients with creatinine clearance <15 mL/min, apixaban is not recommended in these patients (see Pharmacology: Pharmacodynamics under Actions).
Treatment of VTE: Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients (see Pharmacology: Pharmacodynamics under Actions).
Prevention of stroke: 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: Pharmacodynamics under Actions).
Body weight: Low body weight (<60 kg) may increase haemorrhagic risk (see Pharmacology: Pharmacodynamics under Actions).
Hepatic impairment: XALIQUIS is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see Contraindications).
XALIQUIS is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacodynamics under Actions).
XALIQUIS may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see Pharmacology: Pharmacodynamics under Actions).
Interaction with strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): The use of XALIQUIS is not recommended 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), or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment).
Interaction with strong inducers of both CYP3A4 and P-gp: The concomitant use of XALIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were observed with co-administration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone. In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp the following recommendations apply (see Interactions): for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke in patients with NVAF and for the prevention of recurrent DVT and PE, apixaban should be used with caution; for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be compromised.
For the treatment of DVT or PE, XALIQUIS 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 XALIQUIS with strong inducers of both CYP3A4 and P-gp (see Interactions).
Interaction with other medicinal products affecting haemostasis: Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation inhibitors or other antithrombotic agents (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 XALIQUIS.
Concomitant use of ASA increased the major bleeding risk on apixaban in patients with atrial fibrillation.
Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) 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 haematoma 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 haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of XALIQUIS. 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.
There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case of such need and based on pharmacokinetic data, a time interval of 20-30 hours (i.e., twice the half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant drugs, experience with neuraxial blockade is limited and extreme caution is therefore, recommended when using apixaban in the presence of neuraxial blockade.
Hip fracture surgery: Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, XALIQUIS is not recommended in these patients.
Patients with prosthetic heart valves: Safety and efficacy of XALIQUIS have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of XALIQUIS is not recommended in this setting.
Information about excipients: XALIQUIS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Acute PE in hemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy: Treatment of VTE: Initiation of XALIQUIS 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 active cancer: Patients with active cancer can be at high risk of both venous thromboembolism and bleeding events. When apixaban is considered for DVT or PE treatment in cancer patients, a careful assesment of the benefits against the risks should be made (see also Contraindications).
Patients with antiphospholipid syndrome: Direct acting oral anticoagulants (DOACs), including XALIQUIS, 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 XALIQUIS in patients with APS have not been established.
Effects on ability to drive and use machines: XALIQUIS has no or negligible influence on the ability to drive and use machines.
Use in the Elderly: Increasing age may increase haemorrhagic risk (see Pharmacology: Pharmacodynamics under Actions).
Also, the co-administration of XALIQUIS with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.
