Medicines and Healthcare products Regulatory Agency (MHRA) announces that use of direct-acting oral anticoagulants (DOACs) increases the risk of bleeding and can cause serious, potentially fatal, bleeds. MHRA continues to receive reports of bleeds, often life-threatening or fatal, in association with DOACs in patients in the United Kingdom. In many reported cases, patients have underlying factors that suggest they are at increased risk of bleeding events. Available DOACs include the direct factor Xa inhibitors apixaban (Eliquis), edoxaban (Lixiana▼), and rivaroxaban (Xarelto▼) and the direct thrombin inhibitor dabigatran etexilate (Pradaxa).
For this reason, DOACs should be used with caution in patients at increased risk of bleeding such as older people and patients with low body weight or renal impairment. Although routine anticoagulant monitoring is not required for DOACs as it is for vitamin K antagonists, patients (particularly those with an increased bleeding risk) should be made aware of the risk of bleeding and be routinely examined clinically for signs of bleeding or anaemia. Bleeding can occur at any site during treatment with DOACs. Treatment with DOACs should be discontinued if severe bleeding occurs.
DOACs interact with a number of medicines, some of which increase bleeding risk. Refer to product information for advice on use of DOACs with other medicines. Of note, DOACs should not be taken with other anticoagulants. Strong inhibitors of P-glycoprotein or CYP3A4 (or both) increase circulating levels of DOACs therefore may be not recommended or may require DOAC dose reduction.
Exposure to DOACs is increased in patients with renal impairment and it is therefore important that patients receive an appropriate dose depending on renal function. Calculate creatinine clearance (CrCl) in order to determine renal function for dosing of DOACs. Estimated glomerular filtration rate (eGFR) can overestimate renal function and increase the risk of bleeding events. Dose adjustment may be necessary if renal function significantly changes during treatment. The product information for dabigatran and edoxaban advises to assess renal function if a decline in function is suspected during treatment (for example, due to hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products). DOACs can be used in patients with moderate renal impairment (creatinine clearance of 30ml/min or higher) but a reduced dose may be required depending on the indication. In patients with severe renal impairment (creatinine clearance of lower than 30ml/min) use of dabigatran is contraindicated, while other DOACs should be used with caution or at a reduced dose.
The product information for DOACs includes guidance on the management of bleeds and bleeding complications. Specific reversal agents are available for dabigatran (Praxbind▼, idarucizumab) and apixaban and rivaroxaban (Ondexxya▼, andexanet alfa) but there is currently no specific authorised reversal agent available for edoxaban.
A calibrated quantitative anti-Factor Xa (anti-FXa) assay may help to inform clinical decisions in exceptional situations about use of apixaban, edoxaban, or rivaroxaban, for example in overdose and emergency surgery. However, use of anti-FXa assays should not be used to measure the effectiveness of andexanet alfa as the results may not be reliable. Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (achievement of haemostasis), lack of efficacy (re-bleeding), and adverse events (thromboembolic events).
Healthcare professionals are advised:
- Use caution if prescribing DOACs to patients at increased risk of bleeding (for example, older people or people with renal impairment).
- Remain vigilant for signs and symptoms of bleeding complications during treatment, especially patients with increased bleeding risk.
- Remind patients of the signs and symptoms of bleeding and encourage them to always read the patient information leaflet that accompanies their medicines.
- Ensure patients with renal impairment receive an appropriate dose and monitor renal function during treatment to ensure dose remains appropriate.
- Specific DOAC reversal agents are available for dabigatran, apixaban, and rivaroxaban.
- Monitor the reversal effects of andexanet alfa using clinical parameters; anti-FXa assays should not be used to measure the effectiveness of andexanet alfa as the results may not be reliable.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/direct-acting-oral-anticoagulants-doacs-reminder-of-bleeding-risk-including-availability-of-reversal-agents
In Hong Kong, there are registered pharmaceutical products containing apixaban (2 products), dabigatran etexilate (3 products), edoxaban (3 products) and rivaroxaban (7 products), and all products are prescription-only medicines. So far, the Department of Health (DH) has received cases of adverse drug reaction related to apixaban (30 cases), dabigatran etexilate (12 cases), edoxaban (18 cases) and rivaroxaban (19 cases). These cases include bleeding.
Related news on the bleeding risk of various direct-acting oral anticoagulants was previously issued by overseas drug regulatory authorities, and was posted on the Drug Office website since 2011, with the latest update posted on 4 Jun 2015. Letters to inform local healthcare professionals were issued by the DH on 19 Aug 2011, 4 Nov 2011 and 25 Sep 2013. The risk of bleeding and precautions associated with the use of apixaban, dabigatran etexilate, edoxaban and rivaroxaban is documented in overseas reputable drug references such as the “Martindale: The Complete Drug Reference”. The DH will remain vigilant on safety update of the drugs issued by other overseas drug regulatory authorities.
Ends/Tuesday, Jun 30, 2020
Issued at HKT 16:00
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