How should ranolazine be dosed and what are the contraindications, dose adjustments for hepatic or renal impairment, and drug interactions in an adult with chronic stable angina refractory to optimal therapy?

Ranolazine Dosing and Management in Chronic Stable Angina

Initial Dosing

Start ranolazine at 500 mg orally twice daily and escalate to 1000 mg twice daily after one week if symptoms persist and the drug is well-tolerated. 1, 2

• The maximum recommended dose is 1000 mg twice daily 1
• Tablets should be swallowed whole and may be taken with or without food 1
• If a dose is missed, take the next scheduled dose without doubling 1

Absolute Contraindications

Ranolazine is absolutely contraindicated in patients with liver cirrhosis or significant hepatic impairment. 1, 2, 3

Additional absolute contraindications include:

• Concurrent use of strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) 1
• Concurrent use of CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine) 1

Dose Adjustments for Organ Impairment

Hepatic Impairment

Do not use ranolazine in any degree of hepatic impairment or cirrhosis. 1, 4

• Plasma levels increase 50-60% in moderate hepatic impairment 4
• The drug undergoes extensive hepatic metabolism via CYP3A 4

Renal Impairment

Avoid ranolazine when glomerular filtration rate is <30 mL/min/1.73 m² due to marked accumulation and risk of acute renal failure. 4, 2, 1

• Plasma levels increase 50-97% as kidney function declines 4
• Acute renal failure has been observed in severe renal impairment (CrCL <30 mL/min) 1
• If acute renal failure develops (marked creatinine increase with elevated BUN), discontinue ranolazine immediately 1

Critical Drug Interactions Requiring Dose Adjustment

Moderate CYP3A Inhibitors

Limit ranolazine to a maximum of 500 mg twice daily when combined with moderate CYP3A inhibitors. 1

This applies to:

• Diltiazem 1
• Verapamil 1
• Erythromycin 1

P-glycoprotein Inhibitors

Titrate ranolazine dose based on clinical response when combined with P-gp inhibitors like cyclosporine, as they increase ranolazine exposure. 1

Digoxin

Exercise caution and monitor digoxin levels closely, as ranolazine increases digoxin plasma concentrations requiring dose adjustment of digoxin. 3

Important Safety Considerations

QTc Prolongation

• Ranolazine causes dose-dependent QTc interval prolongation 1, 2
• However, torsades de pointes has not been observed at therapeutic doses 2, 3
• Limited experience exists with high doses (>1000 mg twice daily), congenital long QT syndrome, or combination with other QT-prolonging drugs 1

Hemodynamic Profile

• Ranolazine does not significantly affect heart rate or blood pressure 3, 2
• This makes it particularly useful in patients with bradycardia or hypotension 3, 4

Special Population Considerations

Diabetes Mellitus

Ranolazine should be the preferred antianginal agent in patients with type 2 diabetes and chronic stable angina. 4

• It significantly reduces HbA1c levels, fasting glucose, and 2-hour postprandial glucose 4
• Simultaneously reduces angina pain and increases exercise tolerance 4

Chronic Kidney Disease (Non-Severe)

• Monitor renal function closely in patients with moderate renal impairment 4
• Consider dose reduction or alternative agents if CrCL approaches 30 mL/min 4

Atrial Fibrillation

• Ranolazine can be added to beta-blockers in patients with both chronic stable angina and atrial fibrillation 4
• It has been shown to suppress supraventricular arrhythmias 4

Common Pitfalls to Avoid

• Do not confuse ranolazine with prognostic medications: It provides symptom relief only and does not reduce cardiovascular death, myocardial infarction, or mortality 2, 5
• Do not use in hepatic impairment of any degree: Even moderate impairment significantly increases plasma levels 4, 1
• Do not combine with strong CYP3A inhibitors or inducers: This is an absolute contraindication 1
• Monitor for drug interactions: Pay particular attention to digoxin, statins, and metformin when co-prescribing 3
• Do not crush, break, or chew tablets: The extended-release formulation must remain intact 1