Appendix IV - Prescribing Guidance for Apixaban Patient Factors Dose of Apixaban If your patient has any of the following MAJOR risk factors: Hypersensitivity to the active substance or to any of the excipients Clinically significant active bleeding Hepatic disease associated with coagulopathy and clinically relevant bleeding risk or severe liver impairment Lesion or condition at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities Concomitant treatment with any other anticoagulant agent e.g. UFH, LMWH, heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under the circumstances of switching therapy to or from apixaban or when UFH is given at doses necessary to maintain a patent central venous or arterial catheter Patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir) are not recommended to use apixaban High risk of falls that are likely to cause injury and contraindicate the use of anticoagulation Breastfeeding and pregnancy CrCl < 15 ml/min, or in patients undergoing dialysis CrCl 15-29 ml/min (This is not a licensed contraindication but high risk so should avoid) Avoid as contra -indicated If your patient has any of the following increased bleeding risk factors: Age >80 years old Age 75-80 years when thromboembolic risk is low and bleeding risk high Weigh <60kg Serum creatinine 133 micromole And all MAJOR risk factors have been excluded. Use with caution and initiate reduced dose of apixaban at 2.5mg twice daily If your patient is: Age 18-79 years egfr or CrCl>30mls/min Does not have 2 characteristics as outlined above for dose reduction And all major and additional risk factors for bleeding have been excluded as per contraindications Initiate standard dose of apixaban at 5mg twice daily Switching anticoagulants
Table to show switching Apixaban Required Switch in Therapy Recommendation Apixaban treatment to parenteral anticoagulant Parenteral anticoagulants to apixaban Apixaban treatment to Vitamin K antagonists (VKA) e.g. warfarin. VKA to apixaban Switching treatment from apixaban to parenteral anticoagulants can be done at the next scheduled dose Switching treatment from parenteral anticoagulants to apixaban can be done at the next scheduled dose Converting from apixaban to VKA therapy, continue administration of apixaban for at least 2 days after beginning VKA therapy. After 2 days of coadministration of apixaban with VKA therapy, obtain an INR prior to the next scheduled dose of apixaban. Continue coadministration of apixaban and VKA therapy until the INR is 2.0. When converting patients from Vitamin K antagonist (VKA) therapy to apixaban, discontinue warfarin or other VKA therapy and start apixaban when the international normalized ratio (INR) is < 2.0. Monitoring There is no routine anticoagulant monitoring for apixaban. Apixaban is a factor Xa inhibitor and as a result, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aptt). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. These tests are not recommended to assess the pharmacodynamic effects of apixaban. Rotachrom anti-fxa assay has been used in some studies but is not available in routine laboratory testing locally. Apixaban is a black triangle drug. ANY adverse effects must be reported to the Committee on Safety of Medicines (CSM). http://yellowcard.mhra.gov.uk/ Renal Function Renal excretion of apixaban accounts for approximately 27% of total clearance. As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients. Although apixaban is licenced for use in patients with an egfr of 15-30mls/min the data is limited so the European Cardiac Society advises against this. If it is necessary to use apixaban in this scenario it will require great caution. Whilst on treatment, renal function should be assessed in certain clinical situations when it is suspected that renal function could decline or deteriorate (such as hypovolaemia, dehydration, and with certain co-mediations e.g. high dose diuretics). The dose of apixaban should be reviewed in these circumstances. Bleeding Risk
As with all anticoagulants, apixaban should be used with caution in conditions with an increased risk of bleeding. Bleeding may occur at any site during therapy with apixaban. An unexplained fall in haemaglobin and/or haematocrit, blood pressure or other clinical features suggestive of bleeding should lead to further investigation. Close clinical supervision is recommended throughout the treatment period, especially if risk factors are combined. Interactions with Apixaban Interacting Drug Strong inhibitors of both CYP3A4 and P- gp e.g., azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). Strong inducers of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, eg. diltiazem, amiodarone, verapamil, quinidine Anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc). Platelet aggregation inhibitors and NSAIDs Agents associated with serious bleeding e.g. thrombolytic agents, GPIIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone. Activated Charcoal Digoxin Beta blockers Advice Avoid co-prescribing. These medicinal products may increase apixaban exposure by 2-fold or greater in the presence of additional factors that increase apixaban exposure (e.g., severe renal impairment). Use with caution. Can 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 coadministration of apixaban with strong inducers of both CYP3A4 and P-gp compared with using apixaban alone. No dose adjustment for apixaban is required when co-administered with less potent inhibitors of CYP3A4 and/or P-gp. They are expected to increase apixaban plasma concentration to a lesser extent. Avoid co-prescribing contraindicated Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except when switching therapy to or from apixaban, or with the use of unfractionated heparin for maintenance of venous or arterial catheter patency. Use with caution. May increase the risk of bleeding. A significant increase in bleeding risk was reported with the triple combination of apixaban, ASA and clopidogrel in a clinical study in patients with acute coronary syndrome Not recommended The risk of bleeding may be increased when apixaban is co-prescribed with these drugs. Administration of activated charcoal reduces apixaban exposure. No interactions reported to date. No interactions reported to date.
Acutely unwell patients While on treatment with apixaban, renal function should be assessed in clinical situations where it is suspected that renal function could decline or deteriorate. Consider temporarily substituting apixaban with prophylactic LMWH in patients who are admitted to hospital with sepsis, acute kidney injury, hypovolaemia, dehydration or who are started on high dose diuretics where patients may have severe renal impairment. Compliance Aids Apixaban tablets may be dispensed in a compliance aid. Swallowing difficulties There is no safety data or pharmacokinetic studies available on crushing apixaban tablets therefore this should be avoided. Management of Overdose and Bleeding with apixaban There is no specific antidote to apixaban. Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment should be as per Trust guidelines on Management Of Bleeding In Patients Taking a Newer Oral Anticoagulant (NOAC). Apixaban is a factor Xa inhibitor and as a result, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aptt). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. These tests are not recommended to assess the pharmacodynamic effects of apixaban. Surgery If a patient is admitted to hospital and requires emergency surgery then if possible try to delay surgery until at least 24 hours after the last dose of apixaban. More time may be required if the patient has renal impairment. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention. Please consult with haematology.
Management of new oral anticoagulants in patients undergoing surgery. CrCl / egfr >15ms/min PRE PROCEDURE Miss 4 doses (two days) POST PROCEDURE Do not restart medication until haemostasis has been achieved (24-72 hours) and epidural has been removed (See note 1). Note 1. If a patient has spinal/epidural anaesthesia they should not have apixaban restarted until at least 6 hours after the removal of the catheter. References Stroke and systemic embolism (prevention, non-valvular atrial fibrillation) Apixaban NICE TA275 (February 2013). Available from http://guidance.nice.org.uk/ta275 Summary of product characteristics for Eliquis available online at www.medicines.org.uk British National Formulary 65, March 2013