What is the recommended use and dosage of Ranolazine (generic name) for chronic angina pectoris?

Ranolazine for Chronic Angina Pectoris

Ranolazine is recommended at an initial dose of 500 mg orally twice daily, which can be escalated as needed to a maximum of 1000 mg twice daily for the treatment of chronic angina that has failed to respond to standard antianginal therapy. 1, 2

Mechanism of Action and Clinical Effects

• Ranolazine primarily works through inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia 3
• Unlike other antianginal medications, ranolazine exerts its effects without significantly reducing heart rate or blood pressure, making it particularly useful in patients with bradycardia or hypotension 1, 3, 4
• Ranolazine promotes glucose oxidation and improves anaerobic metabolism under ischemic conditions, which may provide additional benefit in patients with diabetes 3

Indications and Usage

• Ranolazine is indicated for the treatment of chronic angina pectoris as monotherapy or in combination with amlodipine, beta-blockers, or nitrates when angina is not adequately controlled with standard therapy 1, 2
• It may be particularly beneficial in patients with left ventricular hypertrophy who might experience greater efficacy compared to other antianginal drugs 5
• Patients with diabetes and chronic stable angina may benefit from ranolazine as it has been shown to reduce glycated hemoglobin levels 3, 5

Dosing Recommendations

• Start with 500 mg orally twice daily 1, 2
• Titrate based on clinical response to a maximum of 1000 mg twice daily 1, 2
• For patients with moderate to severe renal impairment (CrCl <60 mL/min), monitor renal function after initiation and periodically thereafter 2
• Limit dose to 500 mg twice daily in patients with severe renal impairment (CrCl <30 mL/min) 6

Contraindications and Precautions

• Contraindicated in patients with:
  • Hepatic impairment or liver cirrhosis 1, 3, 2
  • Concomitant use of strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) 2
  • Concomitant use of CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) 2
• Use with caution in patients with:
  • QT-prolonging conditions, as ranolazine causes dose-dependent QT interval prolongation 6, 2
  • Patients taking digoxin, as ranolazine may increase digoxin concentration by 40-60% through P-glycoprotein inhibition 6, 2

Drug Interactions

• Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily 2
• P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure may increase; titrate based on clinical response 2
• CYP3A substrates:
  • Limit simvastatin to 20 mg when used with ranolazine 2, 4
  • Doses of other sensitive CYP3A substrates may need to be reduced 2
• OCT2 substrates: Limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily 2

Adverse Effects

• Most common adverse effects (>4% and more common than placebo):
  • Dizziness 6, 2
  • Headache 6, 2
  • Constipation 6, 2
  • Nausea 6, 2
• QT interval prolongation is dose-dependent and requires monitoring, especially in patients with risk factors for arrhythmias 6, 2

Clinical Outcomes and Limitations

• While ranolazine effectively reduces angina symptoms, it has not been shown to reduce major cardiovascular events, including cardiovascular death and myocardial infarction 3
• In a large trial (N=6,560) of patients with UA/NSTEMI, ranolazine provided symptom relief but did not significantly reduce the composite of cardiovascular death, MI, or recurrent ischemia 1

Monitoring Recommendations

• ECG monitoring for QT prolongation in high-risk patients, especially when combined with other QT-prolonging drugs 6
• Monitor digoxin levels when co-administered with ranolazine 6, 2
• Monitor renal function in patients with moderate to severe renal impairment 2