How Ranolazine Affects Kidney Function
Ranolazine does not directly damage the kidneys but requires significant dose adjustment in renal impairment because kidney dysfunction substantially increases drug exposure, raising plasma levels by 50-100% and increasing the risk of adverse effects including QT prolongation and neurologic toxicity. 1, 2, 3
Pharmacokinetic Impact of Renal Impairment
Ranolazine plasma concentrations increase progressively with worsening kidney function:
- In mild renal impairment, ranolazine AUC increases by approximately 72% compared to normal kidney function 4
- In moderate renal impairment, AUC increases by approximately 80% 4
- In severe renal impairment, AUC increases by approximately 97% (nearly double) 4, 5
- This occurs despite less than 7% of ranolazine being excreted unchanged in urine, suggesting factors beyond reduced glomerular filtration contribute to drug accumulation 4
Metabolism and Excretion
Ranolazine undergoes extensive hepatic metabolism but kidney excretion of metabolites is critical:
- Ranolazine is primarily metabolized by CYP3A enzymes and to a lesser extent by CYP2D6 3, 5
- Following oral administration, 73% of the dose is excreted in urine (though <5% as unchanged drug) 5
- The kidney's role in clearing active metabolites explains why renal impairment significantly affects drug levels 4, 5
Dosing Restrictions and Contraindications
The FDA and major cardiology societies provide clear guidance on ranolazine use in renal impairment:
- Maximum dose is 500 mg twice daily in severe renal impairment (CrCl <30 mL/min) 2, 3
- Both ranolazine and its comparator trimetazidine are contraindicated when GFR is <30 mL/min/1.73 m² 1
- Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min) 3
- If acute renal failure develops during treatment, discontinue ranolazine immediately 3
Clinical Safety Concerns in Renal Impairment
Higher ranolazine levels in renal impairment amplify known adverse effects:
- QT prolongation risk increases with elevated drug levels, particularly concerning in patients with renal dysfunction who may have electrolyte abnormalities 2, 3
- Neurologic adverse effects (dysarthria, dysmetria, hallucinations, tremors, word-finding difficulty) have been reported in elderly patients with renal impairment receiving doses >500 mg twice daily 6
- A case report documented bradycardia, hyperkalemia, and acute kidney injury in an elderly patient on ranolazine, representing a variant of BRASH syndrome 7
Monitoring Algorithm for Patients with Renal Impairment
When prescribing ranolazine to patients with any degree of kidney dysfunction:
- Measure baseline creatinine clearance before initiating therapy 3
- Limit dose to 500 mg twice daily if CrCl <60 mL/min 2, 3
- Avoid ranolazine entirely if CrCl <30 mL/min 1, 3
- Monitor renal function periodically during treatment, especially in elderly patients (>80 years) 3, 6
- Perform ECG monitoring for QT prolongation in patients with renal impairment, particularly when combined with other QT-prolonging drugs 2
- Watch for neurologic symptoms (confusion, tremor, speech difficulties) which may indicate drug accumulation 6
Special Consideration: Elderly Patients
Age compounds the risk of ranolazine toxicity in renal impairment:
- Avoid doses greater than 500 mg twice daily in patients older than 80 years, even with mild renal impairment 6
- Elderly patients with baseline neurologic disease are at particularly high risk for neurologic adverse effects 6
- The combination of advanced age, renal impairment, and high doses creates a perfect storm for toxicity 6
Drug Interactions Affecting Renal Patients
Ranolazine's interaction profile becomes more critical in renal impairment:
- Ranolazine increases digoxin levels by 40-60% through P-glycoprotein inhibition; this effect is magnified when both drugs accumulate in renal dysfunction 1, 2, 3
- Monitor digoxin levels closely if co-administration is necessary in patients with kidney disease 2
- Limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily, though this high ranolazine dose should be avoided in renal impairment 3