What is the recommended dosage and treatment approach for Ranolazine (Ranolazine) in patients with chronic angina?

Ranolazine for Chronic Angina Management

Recommended Dosing

Start ranolazine at 500 mg orally twice daily and titrate to 1000 mg twice daily based on clinical symptom response. 1, 2

• The FDA-approved dosing regimen begins with 500 mg twice daily for the first week, followed by escalation to the maximum dose of 1000 mg twice daily if tolerated and needed for symptom control 2
• This titration approach allows assessment of tolerability before reaching the therapeutic target dose 1

Clinical Indications and Patient Selection

Ranolazine should be used as add-on therapy in patients with inadequate angina control despite treatment with beta-blockers and/or calcium channel blockers. 1

Ideal Patient Populations

• Patients with bradycardia or hypotension who cannot tolerate rate-lowering or blood pressure-lowering agents, since ranolazine has a hemodynamically neutral profile with minimal effects on heart rate or blood pressure 1, 3
• Diabetic patients with chronic stable angina, as ranolazine reduces glycated hemoglobin (HbA1c) levels, though it is not indicated as diabetes treatment 3
• Patients with left ventricular hypertrophy, who may experience greater efficacy compared to other antianginal drugs 1, 3

Mechanism of Action

Ranolazine works through concentration-dependent inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia and reduces oxygen demand without significantly affecting heart rate, blood pressure, or myocardial perfusion 1, 3

Expected Clinical Benefits and Limitations

Symptom Improvement

• Ranolazine reduces angina frequency by approximately 0.8-1.2 attacks per week compared to placebo 2
• Nitroglycerin use decreases by approximately 0.9-1.3 doses per week 2
• Exercise duration improves by 24-34 seconds at trough and peak levels 2

Critical Limitation

Ranolazine provides symptom relief only and does not reduce major cardiovascular events (cardiovascular death, myocardial infarction) or improve mortality. 1, 3, 2

• The MERLIN-TIMI 36 trial (n=6,560) demonstrated no benefit on cardiovascular outcomes in acute coronary syndrome patients 2
• This is a symptomatic treatment, not a disease-modifying therapy 1

Gender Considerations

Effects are considerably smaller in women than men, with females experiencing only about 33% of the exercise tolerance improvement seen in males at the 1000 mg dose, and mean reduction in weekly angina attacks of 0.3 for females versus 1.3 for males 2

Absolute Contraindications

Do not use ranolazine in the following situations: 1, 2

• Liver cirrhosis or hepatic impairment (absolute contraindication) 1, 2
• Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir, ritonavir) 2
• CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) 2
• QT-prolonging conditions or pre-existing electrical instability, including R-on-T phenomena 4

Drug Interactions Requiring Dose Adjustments

Moderate CYP3A Inhibitors

Limit ranolazine to 500 mg twice daily when used with diltiazem, verapamil, or erythromycin 2

P-glycoprotein Inhibitors

Ranolazine exposure increases with cyclosporine; titrate based on clinical response 2

Drugs Affected by Ranolazine

• Simvastatin: Limit to 20 mg daily when used with ranolazine 2
• Metformin: Limit to 1700 mg daily when used with ranolazine 1000 mg twice daily 2
• Digoxin: Ranolazine increases digoxin concentration by 40-60%; monitor digoxin levels and reduce dose as needed 3, 2

Safety Monitoring

QTc Prolongation

• Ranolazine causes dose-related QT interval prolongation (mean increase of 2.4 ms), but torsades de pointes has not been observed at therapeutic doses 1, 5
• Avoid in patients with baseline QT prolongation, family history of long QT syndrome, or congenital long QT syndrome 2

Renal Function

Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min); discontinue if acute renal failure develops 2

Common Adverse Effects

The most common side effects (>4% and more common than placebo) are dizziness, headache, constipation, and nausea 2

Long-Term Tolerability

In the ROLE program with mean follow-up of 2.82 years in high-risk patients, 76.7% remained on therapy at 2 years, with only 9.7% discontinuing due to adverse events 5

Clinical Pitfalls to Avoid

• Do not use ranolazine to abort acute angina episodes—it is not effective for acute symptom relief 2
• Do not expect cardiovascular outcome benefits—this is purely symptomatic therapy 1, 2
• Do not overlook drug interactions—ranolazine has extensive CYP3A and P-glycoprotein interactions requiring dose adjustments of multiple medications 2
• Recognize limited efficacy in women—consider alternative antianginal agents if inadequate response 2