Genexiban Special Precautions

Haemorrhage 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 haemorrhage. Apixaban administration should be discontinued if severe haemorrhage occurs (see Adverse Reactions and 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).
An agent to reverse the anti-factor Xa activity of apixaban is available.
Interaction with other medicinal products affecting haemostasis: Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see Contraindications).
The concomitant use of apixaban with antiplatelet agents increases the risk of bleeding (see Interactions).
Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or nonsteroidal anti-inflammatory medicinal products (NSAIDs), including acetylsalicylic acid.
Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with apixaban (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 Genexiban.
Concomitant use of ASA increased the major bleeding risk on apixaban and increased the bleeding risk on warfarin.
Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated patients.
A significant increase in risk of ISTH major bleeding was reported for apixaban.
Use of thrombolytic agents for the treatment of acute ischemic stroke: There is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban (see Interactions).
Patients with prosthetic heart valves: There is available data for use of Apixaban in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of apixaban is not recommended in this setting.
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. 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.
Surgery and invasive procedures: Apixaban 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.
Apixaban 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.
Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established (for cardioversion see Dosage & Administration).
For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to be interrupted (see Dosage & Administration, Contraindications and Interactions).
Temporary discontinuation: Discontinuing anticoagulants, including apixaban, 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 apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy Apixaban 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 since the safety and efficacy of apixaban have not been established in these clinical situations.
Patients with active cancer: Efficacy and safety of apixaban in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established.
Body weight: Low body weight (<60 kg) may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).
Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): The use of apixaban 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 inducers of both CYP3A4 and P-gp: 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. Diminished efficacy and a higher risk of bleeding were observed with coadministration 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 stroke and systemic embolism 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.
Laboratory parameters: Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see Pharmacology: Pharmacodynamics under Actions).
Information about excipients Genexiban contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effect on ability to drive and use machines: Genexiban has no or negligible influence on the ability to drive and use machines.
Patients with 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).
Patients with hepatic impairment: Apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see Contraindications).
It is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Patients with elevated liver enzymes ALT/AST >2 x ULN or total bilirubin ≥1.5 x ULN were excluded in clinical studies. Therefore, apixaban should be used cautiously in this population (see Pharmacology: Pharmacokinetics under Actions). Prior to initiating apixaban, liver function testing should be performed.
Use in the Elderly: Increasing age may increase haemorrhagic risk (see Pharmacology: Pharmacokinetics under Actions).
Also, the co-administration of apixaban with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk.