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Summary
A warning about anticoagulant-related nephropathy (ARN) has been added to the Product Information (PI) for all oral anticoagulants.
This is a rare but serious adverse event resulting from profuse glomerular bleeding. It has the potential to cause irreversible kidney damage and death. Although rare, ARN is likely to be underdiagnosed as a cause of acute kidney injury.
Early detection and intervention of ARN is critical to minimising its associated morbidity and mortality. Therefore, awareness of this adverse event among health professionals is important.
What’s new in this article
There have been reports of ARN in patients taking oral anticoagulants, mainly from overseas.[1,2,3] We investigated this safety signal. We also sought expert advice from the Advisory Committee on Medicines (ACM) about mitigating the risk of harm in Australia.
The ACM noted this adverse event is now well documented in the medical literature with warfarin and there is growing evidence for other oral anticoagulants. The ACM supported a class-wide warning being added to the PI for all oral anticoagulants. This is because these medicines are widely used, and this adverse event is serious.
Read the ACM’s statement on this safety issue for more information.
The ACM do not consider a warning for parenteral anticoagulants is needed at this stage. This is because they are mainly used in hospitals and for a shorter duration.
What should health professionals do
It is important that you are aware of this side effect, as early detection and treatment is critical to reducing permanent kidney damage and death.
Although anticoagulant-related nephropathy is rare, it is likely underdiagnosed. This is because kidney biopsy is required for a definitive diagnosis but is rarely performed in people taking anticoagulants. Also, many patients who develop ARN have comorbidities that may explain their acute kidney injury presentation.
If you are treating patients taking oral anticoagulants, talk to them about the risk of anticoagulant-related nephropathy.
Close monitoring, including renal testing, is recommended for those with excessive anticoagulation (or supratherapeutic INR for those on warfarin) and haematuria. Monitoring is also recommended for patients with compromised renal function who are taking apixaban (Eliquis), dabigatran (Pradaxa) or rivaroxaban (Xarelto).
Be aware that ARN has been reported in patients who do not have pre-existing kidney disease.
The TGA has also published a safety advisory on the risk of kidney damage with oral anticoagulants for the general public.
Background
Oral anticoagulants are widely used in Australia to prevent and treat thromboembolic conditions. They are often taken for long periods.
Medicines in this class include:
- factor Xa inhibitors - apixaban (Eliquis) and rivaroxaban (Xarelto)
- direct thrombin inhibitors - dabigatran (Pradaxa)
- vitamin K antagonists - warfarin (Coumadin, Marevan).
Adverse events reported to the TGA
As of 24 April 2023, one case of anticoagulant-related nephropathy had been reported to the TGA, where the sole suspect was warfarin. The patient was taking concomitant amoxicillin. The case describes resolution of the adverse event one month after warfarin was stopped.[4]
PI updates
The following warnings are now included in the prescribing information for apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto):
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Anticoagulant-related nephropathy
There have been post-marketing reports of anticoagulant-related nephropathy (ARN) following anticoagulant use, presenting as acute kidney injury.
In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur, possibly in relation to episodes of excessive anticoagulation and haematuria. A few cases have been reported in patients with no pre-existing kidney disease. Close monitoring including renal function evaluation is advised in patients with excessive anticoagulation, compromised renal function and haematuria (including microscopic).
4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
System organ class: Renal and urinary disorders, Frequency: Not known, Anticoagulant-related nephropathy (see section 4.4), haematuria.
Similar warnings have been included in the prescribing information for warfarin (Coumadin, Marevan). However, close monitoring is specifically advised in patients with a supratherapeutic INR and haematuria (including microscopic).
Please consult the full PI of individual products for exact wording.
References
| [1] | Mikič TB, et al. Management of Anticoagulant-Related Nephropathy: A Single Center Experience. J Clin Med 2021. 16:796. doi.org/10.3390/jcm10040796 |
|---|---|
| [2] | De Aquino Moura KB, et al. Anticoagulant-related nephropathy: systematic review and meta-analysis. Clinical Kidney Journal 2019; 12:400-407 |
| [3] | Brodsky S, et al. Anticoagulant-Related Nephropathy. J Am Soc Nephrol 2018; 29: 2787–2793. doi: 10.1681/ASN.2018070741 |
| [4] | Chamberlain AJ, et al. Anticoagulant-related nephropathy: a common complication hiding in plain sight. Internal Medicine Journal 2020;50(10):1295-1296 |
What to report? You don't need to be certain, just suspicious!
The TGA encourages the reporting of all suspected adverse reactions to medicines, including vaccines, over-the-counter medicines, herbal, traditional or alternative remedies.
We particularly request reports of:
- all suspected reactions to new medicines (look for the Black Triangle ▼ in PI and CMI documents – this symbol identifies medicines that are new or being used differently)
- all suspected medicines interactions
- suspected reactions causing death, admission to hospital or prolongation of hospitalisation, increased investigations or treatment, or birth defects.
To report a suspected side effect or for more information about reporting, go to our ‘Report problem or side effect’ webpage or contact the TGA's Pharmacovigilance Branch ADR.Reports@health.gov.au.
Disclaimer
Medicines Safety Update is aimed at health professionals. It is intended to provide practical information to health professionals on medicine safety, including emerging safety issues. The information in Medicines Safety Update is necessarily general and is not intended to be a substitute for a health professional's judgment in each case, taking into account the individual circumstances of their patients. Reasonable care has been taken to ensure that the information is accurate and complete at the time of publication. The Australian Government gives no warranty that the information in this document is accurate or complete, and shall not be liable for any loss whatsoever due to negligence or otherwise arising from the use of or reliance on this document.
© Commonwealth of Australia 2022
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For correspondence or further information about Medicines Safety Update, contact the TGA's Pharmacovigilance Branch at ADR.Reports@health.gov.au.
Medicines Safety Update is written by staff from the Pharmacovigilance Branch.
Editor: Elspeth Kay
Deputy Editor: Fiona Mackinnon
Contributors: Sarah May, Gilbert Yeap, Rebecca Mathews and Angela Gowland