Can ranolazine (antianginal medication) worsen impaired renal function?

Ranolazine Does Not Directly Worsen Kidney Function, But Accumulates Dangerously in Renal Impairment

Ranolazine itself does not cause kidney damage, but patients with severe renal impairment (CrCl <30 mL/min or GFR <30 mL/min/1.73 m²) are at risk of acute renal failure and should not receive this medication. 1, 2

Pharmacokinetic Concerns in Renal Impairment

The primary issue is drug accumulation rather than nephrotoxicity:

• Ranolazine undergoes extensive hepatic metabolism via CYP450 enzymes but is primarily excreted by the kidney, leading to plasma level increases of 50-97% as kidney function declines 3, 4
• In patients with mild to severe renal impairment, ranolazine AUC increases 1.72-fold to 1.97-fold compared to those with normal kidney function 5
• Less than 7% of the administered dose is excreted unchanged in urine, indicating that factors beyond reduced glomerular filtration (likely reduced metabolite clearance) contribute to drug accumulation 5

Guideline-Based Contraindications and Dosing Restrictions

Expert consensus and FDA labeling provide clear thresholds:

• Ranolazine should NOT be prescribed when GFR is <30 mL/min/1.73 m² 1, 3
• The FDA warns that patients with severe renal impairment may be at risk of renal failure while on ranolazine 2
• For moderate renal impairment (CrCl 30-60 mL/min), limit the dose to 500 mg twice daily due to increased risk of adverse effects 3, 6

Mechanism of Renal Risk

The danger stems from complications of drug accumulation rather than direct kidney toxicity:

• QT prolongation becomes more pronounced with drug accumulation in renal impairment, creating a dose-dependent arrhythmia risk 3
• Case reports document ranolazine-associated acute renal failure, hyperkalemia, and bradycardia (a BRASH syndrome variant) in patients with baseline renal dysfunction 7
• The combination of bradycardia, renal dysfunction, and electrolyte abnormalities can create a dangerous feedback loop 7

Monitoring Requirements

For patients with moderate renal impairment (CrCl 30-60 mL/min) who are prescribed ranolazine:

• Monitor renal function after initiation and periodically throughout treatment 2
• If acute renal failure develops, discontinue ranolazine immediately 2
• Monitor ECG for QT prolongation, as this risk increases with drug accumulation 3, 6
• Be vigilant for signs of drug accumulation: dizziness, bradycardia, or electrolyte disturbances 7

Critical Drug Interactions in Renal Impairment

P-glycoprotein substrates pose particular risk:

• Ranolazine inhibits P-glycoprotein, increasing digoxin levels by 40-60% 4, 6
• In a case report, the combination of dabigatran (a P-gp substrate) and ranolazine in a patient with renal failure resulted in dangerous anticoagulation (INR 7.03) 8
• Avoid combining ranolazine with P-gp substrates in patients with any degree of renal impairment 8

Clinical Algorithm

For patients with chronic angina and renal impairment:

1. CrCl or GFR <30 mL/min/1.73 m²: Ranolazine is contraindicated—choose alternative antianginal agents (calcium channel blockers, nitrates, or beta-blockers if tolerated) 1, 3

2. CrCl 30-60 mL/min: Maximum dose 500 mg twice daily with close monitoring of renal function and ECG 3, 6

3. CrCl >60 mL/min: Standard dosing (500-1000 mg twice daily) is appropriate 2

Alternative Antianginal Options in Renal Disease

When ranolazine is contraindicated or risky:

• Calcium channel blockers and nitrates have no renal contraindications and are preferred in chronic kidney disease 1
• Trimetazidine shares the same renal limitations as ranolazine (contraindicated when GFR <30 mL/min/1.73 m²) 1, 9
• Beta-selective blockers (bisoprolol) or ivabradine can be used for heart rate control without renal dose adjustment concerns 1