Safety Warnings and Precautions for APIXABAN Use

Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated except under specific circumstances– please see Section 4.3 of the ELIQUIS SmPC.

The concomitant use of ELIQUIS with antiplatelet agents increases the risk of bleeding.

Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin.

Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with ELIQUIS.

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 ELIQUIS.

Further information on interactions with other medicinal products is available in the ELIQUIS SmPC.

There is very limited experience with the use of thrombolytic agents for the treatment of acute ischaemic stroke in patients who are administered ELIQUIS.

Safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves – with or without atrial fibrillation. Therefore, the use of ELIQUIS is not recommended in this setting.

Direct acting Oral Anticoagulants (DOACs), including ELIQUIS, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that 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.

ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable.

ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled.

If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

ELIQUIS should be restarted after the invasive procedure or surgical intervention as soon as possible, provided the clinical situation allows and that adequate haemostasis has been established.

Discontinuing anticoagulants – including ELIQUIS, for active bleeding, elective surgery, or invasive procedures – places patients at an increased risk of thrombosis.

Lapses in therapy should be avoided and if anticoagulation with ELIQUIS must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.

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 post-operative 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 ELIQUIS. 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 ELIQUIS with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20–30 hours (i.e., 2 x half-life) between the last dose of ELIQUIS and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of ELIQUIS may be given at least 5 hours after catheter removal. As with all new anticoagulant medicinal products, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using ELIQUIS in the presence of neuraxial blockade.

ELIQUIS is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy, as the safety and efficacy of ELIQUIS have not been established in these clinical situations.

Efficacy and safety of ELIQUIS in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in patients with active cancer have not been established.

Limited clinical data indicate that ELIQUIS 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 prevention of VTE in elective hip or knee replacement surgery, for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, ELIQUIS is to be used with caution in patients with severe renal impairment (creatinine clearance 15–29 ml/min).

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 µmol/L) associated with age ≥80 years or body weight ≤60 kg should receive the lower dose of ELIQUIS 2.5 mg twice daily.

In patients with creatinine clearance <15 ml/min, or in patients undergoing dialysis, there is no clinical experience; therefore, ELIQUIS is not recommended.

For further information on use of ELIQUIS in patients with renal impairment, click here.

Increasing age may increase haemorrhagic risk.

Also, the co-administration of ELIQUIS with aspirin in elderly patients should be used cautiously because of a potentially higher bleeding risk.

For further information on use of ELIQUIS in older patients, click here.

Low body weight (<60 kg) may increase haemorrhagic risk.

For further information on use of ELIQUIS in patients with low body weight, click here.

ELIQUIS is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

It is not recommended in patients with severe hepatic impairment.

It should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh A or B).

Patients with elevated liver enzymes ALT / AST >2 x ULN or total bilirubin ≥1.5 x ULN were excluded in clinical trials. Therefore, ELIQUIS should be used cautiously in this population. Prior to initiating ELIQUIS, liver function testing should be performed.

For further information on use of ELIQUIS in patients with hepatic impairment, click here.

The use of ELIQUIS 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 ELIQUIS exposure by 2-fold or greater in the presence of additional factors that increase ELIQUIS exposure (e.g. severe renal impairment).

The concomitant use of ELIQUIS 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 ELIQUIS exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher risk of bleeding were observed with co-administration of ELIQUIS with strong inducers of both CYP3A4 and P-gp, compared with using ELIQUIS alone.

In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, the following recommendations apply:

• For the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, ELIQUIS should be used with caution
• For the treatment of DVT and treatment of PE, ELIQUIS should not be used, as efficacy may be compromised

ELIQUIS has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, it is not recommended in these patients.

Clotting tests (e.g. prothrombin time [PT], INR, and activated partial thromboplastin time [aPTT]) are affected as expected by the mechanism of action of ELIQUIS. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability.

ELIQUIS contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.