Prescribing medicines in renal impairment: using the appropriate estimate of renal function to avoid the risk of adverse drug reactions

For most patients and most medicines, estimated Glomerular Filtration Rate (eGFR) is an appropriate measure of renal function for determining dosage adjustments in renal impairment; however, in some circumstances, the Cockcroft-Gault formula should be used to calculate creatinine clearance (CrCl).

From:
Medicines and Healthcare products Regulatory Agency
Published
18 October 2019
Therapeutic area:
Haematology, Urology and nephrology

Advice for healthcare professionals:

  • MHRA has received reports and queries related to the choice of renal function estimate used when prescribing medicines for patients with renal impairment
  • for most drugs and for most adult patients of average build and height, estimated Glomerular Filtration Rate (eGFR) should be used to determine dosage adjustments
  • creatinine clearance (CrCl) should be calculated using the Cockcroft-Gault formula (see below) to determine dosage adjustments for:
    • direct-acting oral anticoagulants (DOACs)
    • patients taking nephrotoxic drugs (examples include vancomycin and amphotericin B)
    • elderly patients (aged 75 years and older)
    • patients at extremes of muscle mass (BMI <18 kg/m2 or >40 kg/m2)
    • patients taking medicines that are largely renally excreted and have a narrow therapeutic index, such as digoxin and sotalol
  • when dose adjustment based on CrCl is important and no advice is provided in the relevant BNF monograph, consult the Summary of Product Characteristics
  • reassess renal function and drug dosing in situations where eGFR and/or CrCl change rapidly, such as in patients with acute kidney injury (AKI)

Background

Estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCl) are two estimates of renal function available to prescribers. Clinical laboratories routinely report renal function in adults based on eGFR normalised to a body surface area of 1.73 m2. For most drugs and most situations, eGFR is an acceptable estimate of renal function.

However, eGFR can overestimate renal function compared with CrCL in some patient groups or clinical situations. This overestimation can result in patients receiving higher than recommended doses of their medicine in relation to their renal function.

When to use estimated creatinine clearance

Existing guidance from the BNF advises prescribers to use calculated CrCl rather than eGFR when initiating or adjusting dose in people taking nephrotoxic drugs, elderly patients, and patients at extremes of muscle mass.

CrCl should also be considered for dosage adjustment of medicines that are substantially renally excreted and have a narrow therapeutic index. In particular, CrCl should always be used to guide dose adjustment for direct-acting oral anticoagulants (DOACs; apixaban, dabigatran etexilate, edoxaban▼, and rivaroxaban▼). Use of eGFR for dosing of DOACs is known to increase risk of bleeding events as a consequence of overestimating renal function.

Other medicines that are largely renally excreted and have a narrow therapeutic index include digoxin and sotalol.

Calculation of creatinine clearance

It is normal to calculate CrCl based on the Cockcroft-Gault formula rather than measuring it via 24-hour urine collection. Applications such as MDCalc provide the ability to use adjusted body weight, ideal body weight, or actual bodyweight as appropriate when calculating the Cockcroft-Gault CrCl value.

MHRA has received reports and queries concerning suspected adverse drug reactions related to the use of eGFR rather than calculated CrCl when prescribing in patients with renal impairment. For example, we have received a Yellow Card report that provided sufficient detail to outline that the initial dosing of a DOAC in an elderly patient was based on eGFR values. The suspected adverse drug reaction was a significant bleeding event. Retrospective review of the renal function in terms of CrCl identified that the dose initiated was too high for the patient.

In addition, a recent cross-sectional study of data from 80 general practices in the UK[footnote 1] reviewed the application of prescribing recommendations in older people with reduced kidney function. Prescribing of drugs outside recommendations for use in patients with reduced kidney function was widespread for the 8 drugs analysed. The prescribed dose was too high for kidney function in up to 40% of people aged 65 years and older, and up to 80% of people aged 85 years and older. Use of eGFR overestimated kidney function for up to 28% of those aged 65 years and older, and up to 58% of those aged 85 years and older.

Report suspected adverse drug reactions on a Yellow Card

Please continue to report relevant suspected adverse drug reactions (ADRs) on a Yellow Card. Reporting suspected ADRs, even those known to occur in association with the medicine, adds to knowledge about the frequency and severity of these reactions and can be used to identify patients who are most at risk. Your report helps the safer use of medicines.

Healthcare professionals, patients, and caregivers can report suspected ADRs via the Yellow Card website or via the Yellow Card app. Download the app via iTunes Yellow Card for iOS devices or via PlayStore Yellow Card for Android devices.

Further information and resources

Article citation: Drug Safety Update volume 13, issue 3: October 2019: 3.

  1. Wood S, et al. Application of prescribing recommendations in older people with reduced kidney function: a cross-sectional study in general practice. Br J Gen Pract 2018; 68: e378–e387 ↩

Published 18 October 2019
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