How should ranolazine (Ranexa) be dosed and what are its contraindications, major drug interactions, and precautions for treating chronic stable angina?

Ranolazine (Ranexa) Dosing and Clinical Management

Dosing Recommendations

Start ranolazine at 500 mg orally twice daily and titrate to 1000 mg twice daily based on clinical response and tolerability. 1

• The initial dose of 500 mg twice daily should be escalated as needed to the maximum dose of 1000 mg twice daily for optimal symptom control 2, 1
• Dosing is independent of meals and should be administered at 12-hour intervals 1

Absolute Contraindications

Ranolazine is absolutely contraindicated in three specific situations:

• Liver cirrhosis or hepatic impairment - due to dose-dependent QTc prolongation and significantly increased plasma levels (50-60% elevation in moderate hepatic impairment) 2, 3, 1
• Concurrent use with strong CYP3A inhibitors (ketoconazole, clarithromycin, nelfinavir, ritonavir) - these dramatically increase ranolazine levels and arrhythmia risk 1
• Concurrent use with CYP3A inducers (rifampin, phenobarbital, St. John's wort, carbamazepine) - these reduce ranolazine efficacy to subtherapeutic levels 1

Major Drug Interactions Requiring Dose Adjustments

Moderate CYP3A inhibitors require limiting ranolazine to 500 mg twice daily:

• Diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice all necessitate dose reduction to prevent excessive drug accumulation 1, 4

Ranolazine increases levels of multiple medications requiring their dose reductions:

• Simvastatin must be limited to 20 mg daily when combined with ranolazine 1
• Metformin should be limited to 1700 mg daily when used with ranolazine 1000 mg twice daily 1
• Digoxin levels increase significantly - use cautiously with monitoring as ranolazine inhibits P-glycoprotein transport 2, 3, 1
• Other sensitive CYP3A substrates (lovastatin, cyclosporine, tacrolimus, sirolimus) and CYP2D6 substrates (tricyclic antidepressants) may require dose reductions 1

Clinical Positioning in Treatment Algorithm

Ranolazine is a second-line or add-on agent, not first-line therapy for chronic stable angina:

• Beta-blockers remain the initial therapy for symptom relief in stable ischemic heart disease (Class I B recommendation) 5
• Ranolazine can be substituted for beta-blockers when they cause unacceptable side effects, are ineffective, or are contraindicated (Class IIa B recommendation) 5
• Ranolazine combined with beta-blockers is most appropriate when initial beta-blocker therapy fails to control symptoms (Class IIa A recommendation) 5, 2
• The European Society of Cardiology recommends ranolazine as add-on therapy when symptoms persist despite beta-blockers and/or calcium channel blockers (Class IIa, Level B) 2

Important Precautions and Monitoring

QT interval prolongation occurs in a dose-dependent manner:

• Ranolazine causes modest QTc prolongation, though torsades de pointes has not been observed at therapeutic doses 2, 1
• Avoid in patients with congenital long QT syndrome, family history of long QT, or concurrent use of other QT-prolonging medications 1
• Limited data exists on safety with high doses, prolonged exposure, or in patients with potassium channel variants 1

Renal function monitoring is essential:

• Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min) 1
• Plasma levels increase 50-97% as kidney function declines 2
• Discontinue ranolazine if acute renal failure develops 1
• Avoid when GFR is <30 mL/min/1.73 m² 2

Unique Clinical Advantages

Ranolazine has a neutral hemodynamic profile making it particularly valuable in specific populations:

• No significant effect on heart rate or blood pressure, unlike beta-blockers, calcium channel blockers, or nitrates 2, 3, 6
• Preferred in patients with bradycardia or hypotension where traditional antianginals would be problematic 2, 3
• Particularly useful in diabetic patients with chronic stable angina - reduces HbA1c, fasting glucose, and 2-hour postprandial glucose while treating angina 2
• May be added to beta-blockers in patients with both chronic stable angina and atrial fibrillation, as it suppresses supraventricular arrhythmias 2
• Can be added without concern for excessive blood pressure lowering in hypertensive patients 2

Critical Limitation: No Mortality or Morbidity Benefit

Ranolazine provides only symptomatic relief and does not improve cardiovascular outcomes:

• Does not reduce cardiovascular death, myocardial infarction, or recurrent ischemia (HR 0.92,95% CI 0.83-1.02) 7, 3
• Does not reduce major cardiovascular events in non-ST-elevation acute coronary syndrome 2
• This is purely symptomatic therapy, not prognostic therapy - unlike aspirin, beta-blockers, or statins which improve survival 7
• Does not improve outcomes regardless of ventricular function 2

Common Adverse Effects

The most frequent side effects (>4% and more common than placebo) include:

• Dizziness, headache, constipation, and nausea 1, 8
• These are generally mild and do not require discontinuation in most patients 6, 4

Mechanism of Action Context

Ranolazine works through inhibition of late sodium current (late INa):

• Prevents intracellular calcium overload during ischemia by blocking sodium-dependent calcium accumulation 2
• Reduces oxygen demand and left ventricular wall tension without affecting myocardial perfusion 2
• Exerts antianginal effects without significantly affecting heart rate, blood pressure, or coronary blood flow 2, 6

Common Pitfall to Avoid

Do not reflexively continue ranolazine indefinitely without reassessing need:

• If a patient becomes asymptomatic, consider whether ranolazine is still necessary, as it has no prognostic benefit 7
• The drug has a 7-hour half-life and clears within 24-48 hours, so there is no risk of rebound ischemia from discontinuation 7
• Optimize standard antianginal therapy (beta-blockers, calcium channel blockers, nitrates) before restarting ranolazine if symptoms recur 7