What is the recommended use and dosage of Ranexa (ranolazine) for patients with chronic angina?

Recommended Use and Dosage of Ranolazine for Chronic Angina

Ranolazine should be used as add-on therapy at an initial dose of 500 mg twice daily, which can be increased to 1000 mg twice daily based on clinical response, when angina symptoms are inadequately controlled with first-line agents (beta-blockers and/or calcium channel blockers). 1

Indications and Placement in Therapy

Ranolazine is an antianginal medication specifically indicated for the treatment of chronic angina 2. The treatment algorithm for chronic angina follows this hierarchy:

1. First-line therapy: Beta-blockers and/or calcium channel blockers 1
2. Second-line therapy: Ranolazine as add-on when symptoms persist despite first-line therapy 1, 3
3. Alternative use: When beta-blockers and calcium channel blockers are contraindicated or poorly tolerated 1

Ranolazine offers a unique advantage as it does not significantly affect heart rate or blood pressure, making it particularly suitable for patients with bradycardia or hypotension 1.

Dosing Recommendations

• Starting dose: 500 mg orally twice daily 1, 2
• Maximum dose: Can be uptitrated to 1000 mg orally twice daily based on clinical response 1, 2
• Dose adjustments:
  • Limit to 500 mg twice daily when used with moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) 2
  • Dose adjustment needed in patients with significant renal dysfunction 1
  • Not recommended with strong CYP3A inhibitors or inducers 1, 2

Contraindications

Ranolazine is contraindicated in:

• Patients taking strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) 2
• Patients taking CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) 2
• Patients with liver cirrhosis 1, 2
• Patients with pre-existing QT prolongation or long QT syndrome 1

Drug Interactions

Ranolazine has significant potential for drug interactions:

• Dose adjustments required when used with:
  • P-gp inhibitors (e.g., cyclosporine) 2
  • CYP3A substrates (limit simvastatin to 20 mg) 2
  • OCT2 substrates (limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily) 2
  • Digoxin (increased concentrations through P-glycoprotein inhibition) 1, 2

Monitoring Requirements

• Baseline assessment:

  • ECG to evaluate QTc interval (ranolazine can prolong QT interval in a dose-dependent manner) 1
  • Renal function tests 1
  • Hepatic function tests 1
  • Medication review for potential interactions 1

• Follow-up monitoring:

  • ECG after dose adjustments 1
  • Periodic renal function tests in patients with moderate to severe renal impairment 1, 2
  • Symptom assessment for side effect management 1

Common Side Effects

The most common adverse reactions (>4% and more common than with placebo) are:

• Dizziness 2, 4
• Headache 2, 4
• Constipation 1, 2, 4
• Nausea 2, 4

Special Populations

• Diabetic patients: Ranolazine may provide additional benefit due to favorable effects on glycemic control 1, 4
• Heart failure: May be considered in patients with left ventricular systolic dysfunction (LVEF <40%) 1
• Elderly: Efficacy and tolerability not significantly affected by old age 4

Clinical Efficacy

Ranolazine provides modest but significant improvements in:

• Exercise duration 1, 5
• Reduction in angina frequency 1, 5
• Prevention of less than one angina attack per week when added to ongoing therapy 6

Pitfalls and Caveats

• QT prolongation is dose-dependent but has not been associated with torsades de pointes in clinical trials 5, 7
• Some evidence suggests ranolazine may actually have antiarrhythmic effects 4
• The risk-benefit profile has been questioned by some sources, suggesting the limited efficacy may not outweigh potential risks 6
• Comparative trials with other antianginal agents and long-term mortality data are still needed 5, 7