Ranolazine Use in End-Stage Renal Disease on Hemodialysis
Ranolazine cannot be safely recommended for patients with end-stage renal disease on maintenance hemodialysis due to significant safety concerns, unpredictable pharmacokinetics, and lack of established dosing guidelines.
Critical Safety Concerns
The FDA label explicitly documents that a pharmacokinetic study in severe renal impairment (CrCL<30 mL/min) was prematurely stopped when 2 of 4 subjects developed acute renal failure after receiving ranolazine 500 mg twice daily for 5 days followed by 1000 mg twice daily 1. Three subjects experienced increases in creatinine, BUN, and potassium during the 500 mg phase, with one requiring hemodialysis 1. The FDA label states: "Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue Ranolazine Extended-Release Tablets if acute renal failure develops" 1.
Pharmacokinetic Challenges in Hemodialysis
Unpredictable Drug Removal
Research demonstrates that ranolazine exhibits highly variable hemodialytic clearance, with mean percent reduction ratios of 52.3 ± 8.1% for 500 mg doses and 69.2 ± 37.6% for 1000 mg doses 2. This substantial variability makes consistent therapeutic dosing nearly impossible 2.
Altered Drug Exposure
- Plasma concentrations increase 40-50% in renal impairment regardless of severity, with AUC increases of 1.72-fold in mild, 1.80-fold in moderate, and 1.97-fold in severe renal impairment 1, 3
- The FDA notes that pharmacokinetics have not been assessed in patients on dialysis 1
- Time to maximum concentration ranges widely from 2 to 18 hours in hemodialysis patients, making timing of administration problematic 2
Neurologic Toxicity Risk
A case report documented severe neurologic adverse effects (dysarthria, dysmetria, hallucinations, worsening tremors, word-finding difficulty) in an 81-year-old patient with renal impairment receiving ranolazine 4. These symptoms resolved 2 days after discontinuation 4. The FDA label warns that health care practitioners should avoid doses greater than 500 mg twice daily in patients with creatinine clearance less than 30 mL/minute 4.
Lack of Evidence-Based Dosing
The single pharmacokinetic study in hemodialysis patients concluded that "neither 500 mg nor 1000 mg can be recommended as a starting dose in patients receiving maintenance hemodialysis" due to extensive pharmacokinetic variability 2. The authors explicitly state that further multi-dose clinical trials are needed to optimize therapeutic outcomes 2.
Clinical Recommendation Algorithm
If ranolazine is being considered despite these risks:
- Contraindication assessment: Ranolazine is contraindicated in liver cirrhosis 1
- Risk-benefit discussion: Document that standard dosing cannot be recommended and acute renal failure has occurred in clinical studies 1, 2
- If proceeding (not recommended):
- Start with the lowest possible dose (significantly below 500 mg twice daily)
- Administer after hemodialysis sessions to prevent premature drug removal 5, 6, 7
- Monitor renal function, electrolytes (especially potassium), and neurologic status closely 1, 4
- Discontinue immediately if acute renal failure develops 1
Common Pitfalls to Avoid
- Do not assume that standard renal dosing adjustments apply—the FDA study was stopped due to safety concerns, not completed 1
- Do not use doses of 500 mg or higher as starting doses in ESRD patients 2, 4
- Do not overlook the high degree of inter-patient variability in drug clearance during hemodialysis 2
- Do not ignore early signs of neurologic toxicity, which may indicate supratherapeutic concentrations 4
Alternative Considerations
Given the cardiovascular disease burden in ESRD patients on hemodialysis 8, consider alternative antianginal therapies with established safety profiles in this population rather than ranolazine, which lacks adequate safety and efficacy data for dialysis-dependent patients 1, 2.