Macrobid (Nitrofurantoin) in Chronic Kidney Disease
Nitrofurantoin should be avoided in patients with CKD when eGFR is below 30 mL/min (CKD stages 4-5), and is generally contraindicated or not recommended when eGFR is below 60 mL/min according to current FDA labeling, though the evidence supporting this cutoff is weak. 1, 2
Current Contraindication and Its Evidence Base
The FDA-approved product labeling currently contraindicates nitrofurantoin when creatinine clearance is below 60 mL/min, though this contraindication appeared sometime between 1988 and 2003 without clear clinical evidence 2
The original 1988 Macrodantin labeling indicated a CrCl cutoff of 40 mL/min, but this was changed to <60 mL/min in the 2003 Macrobid labeling without transparent justification 2
The evidence supporting this contraindication is severely limited and based primarily on a 1968 study by Sachs showing reduced urinary drug recovery below 60 mL/min CrCl—but this study measured urinary excretion amounts rather than urinary concentrations and lacked clinical efficacy endpoints 2
Pharmacokinetic Considerations
Nitrofurantoin requires adequate urinary concentrations to be effective, and these concentrations become inadequate when unilateral creatinine clearance falls below 20 mL/min 3
For each kidney, peak urinary drug concentration is directly proportional to creatinine clearance and drug dosage 3
The drug is eliminated primarily by the kidneys, making it one of the top-ranked medications that pharmacists should adjust or avoid in advanced CKD 1
Practical Recommendations by CKD Stage
CKD Stage 3a (eGFR 45-59 mL/min):
- Use with caution; standard dosing may be considered but monitor closely 4
- The 60 mL/min cutoff lacks strong evidence, and limited data suggest the drug may be effective at CrCl ≥40 mL/min 2
CKD Stage 3b (eGFR 30-44 mL/min):
- Avoid nitrofurantoin; the risk of inadequate urinary concentrations and accumulation-related toxicity outweighs potential benefits 4, 1
- If absolutely necessary and no alternatives exist, consider use only with CrCl ≥40 mL/min and close monitoring 2
CKD Stages 4-5 (eGFR <30 mL/min):
- Nitrofurantoin is contraindicated and should not be used 1, 5
- Expert consensus identifies this as a top medication to avoid in advanced CKD 1
Safety Concerns in Renal Impairment
Serious adverse reactions (pulmonary toxicity, peripheral neuropathy, hepatotoxicity) are linked to prolonged treatment and may be more common with reduced renal function, though the exact relationship to renal impairment versus treatment duration remains unclear 2
Renal function should be monitored before and during treatment in any patient with CKD receiving nitrofurantoin 4
Common Prescribing Errors
Nitrofurantoin dosing errors are exceedingly common in CKD care, with studies showing it was prescribed 169 times to patients with advanced CKD despite contraindication 5
Even after implementation of eGFR reporting in laboratories, prescribing errors for contraindicated antibiotics like nitrofurantoin did not decrease 5
In one study, 64-68% of antibiotic prescriptions requiring dose adjustment in CKD were dosed excessively 5
Alternative Considerations
For urinary tract infections in patients with CKD stages 3b-5, consider alternative antibiotics such as cephalexin or sulfamethizole, which maintain adequate urinary concentrations even at lower creatinine clearances (as low as 4-11 mL/min) 3
Antibiotic selection should account for the accuracy of renal function assessment and take advantage of the pharmacodynamic profile of the chosen agent 6