How Ranolazine Affects Kidney Function
Ranolazine does not directly damage the kidneys but requires significant dose adjustment or avoidance in patients with renal impairment because it is primarily excreted by the kidneys, leading to 50-97% increases in drug plasma levels as kidney function declines. 1, 2
Pharmacokinetic Impact of Renal Impairment
Ranolazine undergoes extensive hepatic metabolism by cytochrome P450 enzymes but is primarily excreted by the kidney. 1 The drug's exposure increases progressively with worsening renal function:
- Mild renal impairment (CrCl 60-90 mL/min): Ranolazine AUC increases by approximately 72% compared to normal kidney function 2
- Moderate renal impairment (CrCl 30-60 mL/min): Ranolazine AUC increases by approximately 80% 2
- Severe renal impairment (CrCl <30 mL/min): Ranolazine AUC increases by approximately 97% 2
Importantly, less than 7% of the administered dose is excreted unchanged in urine, indicating that factors beyond reduced glomerular filtration rate contribute to increased ranolazine concentrations in renal impairment. 2 This suggests that renal dysfunction affects both excretion and possibly metabolism of the drug.
Dosing Recommendations Based on Kidney Function
The National Kidney Foundation recommends limiting ranolazine to 500 mg twice daily in patients with severe renal impairment (CrCl <30 mL/min) due to increased risk of adverse effects. 3
Both the FDA label and expert consensus guidelines state that ranolazine should not be prescribed when glomerular filtration rate is <30 mL/min/1.73 m². 1, 4, 5
Monitoring Requirements
The FDA recommends monitoring renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min). 5 If acute renal failure develops during treatment, ranolazine should be discontinued immediately. 5
Risk of Adverse Effects in Renal Impairment
The accumulation of ranolazine in patients with kidney disease substantially increases the risk of adverse effects:
- Neurologic toxicity: A case report documented severe neurologic adverse effects (dysarthria, dysmetria, hallucinations, worsening tremors, word-finding difficulty) in an 81-year-old woman with renal impairment receiving ranolazine, which resolved within 2 days of discontinuation 6
- QT prolongation: The dose-dependent QT interval prolongation caused by ranolazine becomes more pronounced with drug accumulation in renal impairment 3
- Drug interactions: Ranolazine's inhibition of P-glycoprotein and CYP3A can lead to dangerous accumulation of other medications (particularly tacrolimus in transplant patients) when renal function is compromised 7
Clinical Outcomes in CKD Patients
In the MERLIN-TIMI 36 trial, patients with chronic kidney disease following non-ST-elevation ACS had significantly worse cardiovascular outcomes regardless of ranolazine treatment. 8 Those with GFR <30 vs ≥90 mL/min/1.73 m² had a 3.24-fold increased risk of cardiovascular death or MI through 7 days and a 2.12-fold increased risk through 1 year. 8 Importantly, the effect of ranolazine versus placebo on clinical outcomes was similar among those with and without CKD, suggesting the drug neither improves nor worsens kidney-related cardiovascular risk. 8
Critical Pitfalls to Avoid
- Never exceed 500 mg twice daily in patients with CrCl <30 mL/min 3
- Avoid ranolazine entirely in patients on dialysis (this was an exclusion criterion in major trials) 8
- In elderly patients (>80 years) with any degree of renal impairment, avoid doses greater than 500 mg twice daily due to compounded risk of neurologic adverse effects 6
- Monitor tacrolimus levels closely in transplant patients with renal impairment when initiating ranolazine, as the combination with diltiazem can cause severe tacrolimus toxicity and acute kidney injury 7