Using the appropriate estimate of renal function to avoid the risk of adverse drug reactions

The MHRA has issued guidance on the prescribing of medicines in renal impairment: using the appropriate estimate of renal function to avoid the risk of adverse drug reactions (MHRA Drug Safety Update, October 2019).

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).

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.

Reporting suspected adverse drug reactions

The MHRA Safety Update includes examples of harm related to incorrect renal impairment calculations. Suspected adverse drug reactions can be reported via the MHRA Yellow Card Scheme.