Medicines Healthcare Products Regulatory Agency
Advice for healthcare professionals:
- for paediatric use of these medicines, counsel parents and caregivers about the reconstitution and dosing of dabigatran granules and rivaroxaban granules to reduce the risk of medication errors; highlight the new instructions for use and other educational materials to support safe use in children
- ensure all patients with renal impairment receive an appropriate DOAC dose and monitor renal function during treatment to ensure dose remains appropriate
- report suspected adverse drug reactions associated with DOACs on a Yellow Card, including thromboembolic or haemorrhagic events
Advice for healthcare professionals to give to patients and carers:
- DOACs are a group of medicines that help to prevent blood clots from forming they are used to prevent strokes, heart attacks and other issues associated with blood clots
- parents and caregivers of children and adolescents prescribed these medicines should read and follow the Instructions for Use (IFU) booklet provided for instructions on how to prepare and administer these medicines
- all patients with renal impairment who are taking DOACs will be reviewed regularly to make sure they are taking the correct dose
- if patients or carers have any concerns about these medicines, they should talk to their healthcare professional
Availability of paediatric-specific formulations
Direct-acting oral anticoagulants (DOACs) are approved for a variety of uses related to anticoagulation (see full indications in further information section). Available DOACs include the direct factor Xa inhibitors apixaban (Eliquis), edoxaban (Lixiana), and rivaroxaban (Xarelto), and the direct thrombin inhibitor dabigatran etexilate (Pradaxa). Risk minimisation materials in the form of a prescriber guide and a patient alert card are in place for all DOACs.
Rivaroxaban and dabigatran are indicated for the treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in patients younger than 18 years. For rivaroxaban, granules for oral suspension are available for children weighing up to 30kg. For dabigatran, a paediatric-specific formulation is available in Northern Ireland.
All parents and caregivers of children and adolescents prescribed these medicines should be advised to read and follow the Instructions for Use (IFU) provided in the carton (rivaroxaban and dabigatran in Northern Ireland). This shows how to prepare and take these formulations. In addition, an educational video showing how to prepare and administer rivaroxaban can be accessed via the patient alert card for rivaroxaban granules for oral suspension (video online).
Dosing and restrictions to the use of DOACs by renal function
Advice relating to paediatrics
Dosing of DOACs for children is based on body weight. For use of rivaroxaban in children aged younger than 1 year, renal function should be determined using serum creatinine. Rivaroxaban is not recommended in children younger than 1 year with serum creatinine results above 97.5th percentile (refer to the product information).
For all other children, the glomerular filtration rate should be determined (see BNF for Children resources on Prescribing in renal impairment). In paediatric patients with a glomerular filtration rate lower than 50mL/min/1.73m2 treatment with rivaroxaban is not recommended (1 year and older) and use of dabigatran is contraindicated.
Advice relating to adults
Exposure to DOACs is increased in patients with renal impairment and it is therefore important that patients receive an appropriate dose adjusted for renal function.
Renal function in adults should be assessed by calculating creatinine clearance (CrCl) using the Cockcroft-Gault formula. See BNF resources on Prescribing in renal impairment.
Patients with renal impairment should be reviewed regularly to ensure ongoing efficacy and safety, with dosing adjusted as required.
Recommendations for use of DOACs in patients with renal impairment were published in the June 2020 issue of Drug Safety Update. Following queries from healthcare professionals, an updated table for adults is included below, which provides further clarity on dose adjustment in various indications and in patients with different severities of renal impairment.
Table 1 - Recommendations for DOACs in adults with renal impairment
| Severity of renal impairment (creatinine clearance (CrCl)) | Dabigatran | Apixaban | Edoxaban | Rivaroxaban |
|---|---|---|---|---|
| End stage (CrCl less than 15 mL per minute) | Contraindicated | Not recommended | Not recommended | Not recommended |
| Severe (CrCl 15 to 29 mL per minute)** | Contraindicated | To be used with caution in VTEp and VTEt; dose reduction is recommended in SPAF | Dose reduction recommended in all indications | Use with caution in all indications Dose adjustment is recommended in SPAF and should be considered in VTEt |
| Moderate (CrCl 30 to 49 mL per minute)** | Dose adjustment recommended in VTEp and should be considered in SPAF and VTEt | Dose reduction is required in SPAF in some patients* | Dose reduction recommended in all indications | Dose adjustment recommended in SPAF and should be considered in VTEt |
| Mild (CrCl 50 to 80 mL per minute)** | No dose adjustment required | Dose reduction is required in SPAF in some patients* | No dose adjustment required*** | No dose adjustment required |
CrCl = creatinine clearance. SPAF = prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). VTEp = prevention of VTE (venous thromboembolism) in elective hip or knee replacement surgery. VTEt = treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent VTE events.
*In patients with serum creatinine ?1.5mg/dL (133 micromole/L) associated with age 80 years or older or body weight 60kg or lower.
**For edoxaban moderate to severe renal impairment is defined as CrCl 15 to 50 mL/min.
***For patients with non-valvular atrial fibrillation (NVAF) and high creatinine clearance, in clinical trials there was a trend towards decreasing efficacy with increasing creatinine clearance observed for edoxaban versus well-managed warfarin, therefore edoxaban should be used in patients with NVAF and high CrCl only after a careful evaluation of the individual thromboembolic and bleeding risk.
Further information about DOACs
DOACs are oral anticoagulants. DOACs are indicated for:
- prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age of 75 years and older, diabetes mellitus, prior stroke or transient ischaemic attack (all DOACs)
- treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent events in adults (all DOACs)
- prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery (dabigatran, apixaban and rivaroxaban)
- treatment of venous thromboembolic events (VTE) and prevention of recurrent VTE in paediatric patients from birth to less than 18 years of age (dabigatran and rivaroxaban)
- prevention of atherothrombotic events in adult patients after an acute coronary syndrome with elevated cardiac biomarkers when co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine (2.5mg rivaroxaban only) *prevention of atherothrombotic events in adult patients with coronary artery disease or symptomatic peripheral artery disease at high risk of ischaemic events when co-administered with ASA (2.5mg rivaroxaban only)
DOACs are not recommended in patients with antiphospholipid syndrome. Dabigatran is contraindicated and other DOACs are not recommended in patients with prosthet