What is the recommended dosage and management of Ranexa (Ranolazine) for a patient with chronic angina, particularly those with impaired renal function or intolerance to traditional agents like calcium channel blockers or beta-blockers?

Ranolazine (Ranexa) for Chronic Angina: Dosing and Management

Initial Dosing and Titration

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

• The FDA-approved dosing regimen allows for straightforward titration without complex calculations 1
• Maximum dose is 1000 mg twice daily for most patients 1
• Ranolazine works through inhibition of late sodium current without significantly affecting heart rate or blood pressure, making it useful when hemodynamic agents are not tolerated 2

Critical Contraindications and Restrictions

Renal Impairment

Do NOT prescribe ranolazine when GFR is <30 mL/min/1.73 m² due to risk of drug accumulation and acute renal failure. 3

• Ranolazine undergoes extensive hepatic metabolism but is primarily excreted by the kidney, with plasma levels increasing 50-97% as kidney function declines 3
• For moderate renal impairment (CrCl 30-60 mL/min), limit dose to 500 mg twice daily 3
• Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment 1
• If acute renal failure develops, discontinue ranolazine immediately 1

Hepatic Impairment

Ranolazine is absolutely contraindicated in patients with liver cirrhosis. 1, 2

• This is a black-box level contraindication in the FDA label 1
• Plasma levels increase 50-60% in patients with moderate hepatic impairment 4

Drug Interactions Requiring Dose Adjustment

Limit ranolazine to 500 mg twice daily when used with moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin). 1

• Strong CYP3A inhibitors (ketoconazole, clarithromycin, nelfinavir) are absolute contraindications 1
• CYP3A inducers (rifampin, phenobarbital, St. John's wort) are also contraindicated 1
• When used with P-glycoprotein inhibitors like cyclosporine, titrate ranolazine based on clinical response 1

Place in Therapy for Intolerance to Traditional Agents

When Beta-Blockers or Calcium Channel Blockers Cannot Be Used

Ranolazine may be considered as alternative therapy when patients cannot tolerate beta-blockers or calcium channel blockers, though it carries uncertain safety in heart failure (Class IIb, Level C recommendation). 4

• The European Society of Cardiology gives ranolazine only a IIb recommendation (may be considered) when beta-blockers cannot be tolerated 4
• Ranolazine is particularly useful in cases of bradycardia and/or hypotension due to its neutral hemodynamic profile 2
• For add-on therapy in patients inadequately controlled on beta-blockers and/or calcium channel blockers, ranolazine receives a Class IIa recommendation 2

Specific Clinical Scenarios Favoring Ranolazine

Consider ranolazine preferentially in patients with diabetes and chronic angina, as it reduces HbA1c levels. 2, 5

• Ranolazine demonstrated significant reductions in HbA1c, fasting glucose, and 2-hour postprandial glucose in diabetic patients 5
• Patients with left ventricular hypertrophy may experience greater efficacy with ranolazine 2

Important Safety Monitoring

QT Interval Prolongation

Ranolazine causes dose-dependent QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses. 2

• QT prolongation becomes more pronounced with drug accumulation in renal impairment 3
• Avoid combining ranolazine with other QT-prolonging medications when possible 1
• Little data exists on use in patients with congenital long QT syndrome or family history of long QT 1

Drug Interaction Monitoring

When using ranolazine with digoxin, monitor digoxin levels closely as ranolazine increases digoxin concentration by 40-60%. 2, 5

• Limit simvastatin to 20 mg daily when used with ranolazine 1
• Limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily 1
• Other CYP3A substrates and OCT2 substrates may require dose adjustments 1

Clinical Efficacy and Limitations

Ranolazine effectively reduces angina symptoms and improves exercise tolerance but does NOT reduce major cardiovascular events, cardiovascular death, or myocardial infarction. 2, 1

• In clinical trials, ranolazine reduced angina frequency by approximately 1 attack per week compared to placebo 1
• Exercise duration improved by 24-34 seconds at various doses 1
• The MERLIN-TIMI 36 trial showed no benefit on outcomes in acute coronary syndrome 1
• Gender effects are notable: improvement in exercise tolerance in females was only 33% of that in males 1

Alternative Agents in Renal Impairment

When GFR is <30 mL/min/1.73 m², use calcium channel blockers, nitrates, beta-selective blockers (bisoprolol), or ivabradine instead of ranolazine. 3

• These alternatives have no renal contraindications 3
• Beta-selective blockers or ivabradine can be used for heart rate control without renal dose adjustment concerns 3