What is the appropriate dosing regimen, contraindications, drug interactions, and monitoring recommendations for ranolazine 500 mg in a patient with chronic stable angina?

Ranolazine 500mg: Dosing, Contraindications, Drug Interactions, and Monitoring

Start ranolazine at 500 mg orally twice daily and titrate to 1000 mg twice daily based on symptom response, but only use it as add-on therapy when beta-blockers and/or calcium channel blockers fail to control angina symptoms adequately. 1, 2, 3

Appropriate Clinical Use

Ranolazine is indicated for chronic stable angina as second-line or add-on therapy, not as initial treatment. 1

• Initial therapy: Beta-blockers should be prescribed first for symptom relief in chronic stable angina 1
• Second-line options: Calcium channel blockers or long-acting nitrates when beta-blockers are contraindicated or cause unacceptable side effects 1
• Ranolazine's role: Use ranolazine as a substitute for beta-blockers if they cause unacceptable side effects, are ineffective, or are contraindicated (Class IIa, Level B) 1
• Combination therapy: Ranolazine combined with beta-blockers is useful when initial beta-blocker treatment fails (Class IIa, Level A) 1
• European guidance: Ranolazine should be considered as add-on therapy when symptoms remain inadequately controlled on beta-blockers and/or calcium channel blockers (Class IIa, Level B) 1

Dosing Regimen

Start at 500 mg orally twice daily and increase to 1000 mg twice daily based on clinical symptom response. 2, 3

• The initial dose is 500 mg twice daily 3
• Maximum dose is 1000 mg twice daily 3
• Titration should be based on angina symptom control 2

Absolute Contraindications

Do not use ranolazine in patients with liver cirrhosis, those taking strong CYP3A inhibitors, or those taking CYP3A inducers. 4, 3

• Liver cirrhosis or hepatic impairment: Absolute contraindication 4, 3
• Strong CYP3A inhibitors: Including ketoconazole, clarithromycin, nelfinavir 3
• CYP3A inducers: Including rifampin, phenobarbital, St. John's wort 3
• QT-prolonging conditions: Ranolazine is contraindicated in patients with pre-existing electrical instability or R-on-T phenomena 5

Critical Drug Interactions Requiring Dose Adjustments

Reduce ranolazine to 500 mg twice daily when used with moderate CYP3A inhibitors, and limit simvastatin to 20 mg daily when combined with ranolazine. 3

Interactions Requiring Ranolazine Dose Reduction:

• Moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily 3
• P-glycoprotein inhibitors (cyclosporine): Titrate ranolazine based on clinical response 3

Interactions Requiring Other Drug Dose Reductions:

• Simvastatin: Limit to 20 mg daily when used with ranolazine 3
• Metformin: Limit to 1700 mg daily when used with ranolazine 1000 mg twice daily 3
• Other sensitive CYP3A substrates (lovastatin) and narrow therapeutic range drugs (cyclosporine, tacrolimus, sirolimus): May require dose reduction 3
• P-glycoprotein substrates (digoxin): May require dose reduction; use with caution as ranolazine increases digoxin concentration 2, 3
• CYP2D6 substrates (tricyclic antidepressants): May require dose reduction 3

Safety Monitoring and Warnings

Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCl <60 mL/min), and discontinue if acute renal failure develops. 3

QT Interval Prolongation:

• Ranolazine causes dose-related QT interval prolongation through inhibition of the rapid delayed rectifier potassium current 4, 5, 3
• Torsades de pointes has not been observed at therapeutic doses 2, 4
• Avoid in patients with pre-existing QT prolongation, family history of long QT syndrome, or congenital long QT syndrome 3

Renal Monitoring:

• Monitor renal function after initiation and periodically in patients with CrCl <60 mL/min 3
• Ranolazine plasma levels increase 50-97% as kidney function declines 2
• Discontinue if acute renal failure develops 3

Hepatic Considerations:

• Plasma levels increase 50-60% in patients with moderate hepatic impairment 2
• Absolute contraindication in liver cirrhosis 4, 3

Common Adverse Effects

The most common adverse reactions are dizziness, headache, constipation, and nausea (occurring in >4% of patients). 3

• Dizziness, headache, constipation, and nausea are the most frequently reported adverse effects 3
• These occur more commonly than with placebo 3

Special Patient Populations Where Ranolazine May Be Particularly Useful

Ranolazine is particularly advantageous in diabetic patients with chronic stable angina, patients with bradycardia or hypotension, and those with left ventricular hypertrophy. 2, 4

• Diabetic patients: Ranolazine reduces glycated hemoglobin (HbA1c) levels, fasting glucose, and postprandial glucose while reducing angina 2
• Bradycardia/hypotension: Ranolazine has a hemodynamically neutral profile without significant effects on heart rate or blood pressure 2, 4
• Left ventricular hypertrophy: May experience greater efficacy compared to other antianginal drugs 2
• Atrial fibrillation: Can be added to beta-blockers in patients with both chronic stable angina and atrial fibrillation 2

Critical Limitation on Outcomes

Ranolazine provides symptom relief but does not reduce major cardiovascular events (cardiovascular death, myocardial infarction) or improve mortality. 2, 4

• Ranolazine effectively reduces angina symptoms and improves exercise tolerance 2
• It does not improve outcomes in patients with chronic stable angina regardless of ventricular function 2
• It has not been shown to reduce major cardiovascular events in patients with non-ST-segment elevation acute coronary syndrome 2