Is Ranolazine (Ranexa) ER 1000 mg suitable for managing chronic angina?

Ranolazine ER 1000 mg for Managing Chronic Angina

Ranolazine extended-release 1000 mg twice daily is an effective and appropriate treatment for chronic stable angina, particularly in patients who have inadequate symptom control with first-line agents or cannot tolerate them due to hemodynamic effects. 1, 2, 3

Mechanism of Action and Clinical Benefits

• Ranolazine works primarily through inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia, without significantly affecting heart rate or blood pressure 4, 5
• The extended-release formulation at 500-1000 mg twice daily effectively reduces symptoms of chronic stable angina, similar to other antianginal agents 1, 2
• Ranolazine has a neutral hemodynamic profile, making it particularly useful in cases of bradycardia and/or hypotension where other antianginal agents might worsen these conditions 4, 5
• Clinical trials have demonstrated that ranolazine reduces the frequency of angina episodes and nitroglycerin consumption when compared to standard anti-anginal medications alone 6, 7

Dosing Considerations

• The FDA-approved starting dose is 500 mg twice daily, which can be increased to 1000 mg twice daily based on clinical symptoms 3
• The 1000 mg twice daily dose provides optimal symptom control for many patients while maintaining an acceptable safety profile 1, 2
• Doses above 1000 mg twice daily are poorly tolerated and not recommended 3

Special Populations That May Benefit

• Patients with diabetes and chronic stable angina may benefit particularly from ranolazine treatment, as it reduces glycated hemoglobin (HbA1c) levels 1, 4
• Patients with left ventricular hypertrophy might experience greater efficacy with ranolazine compared to other antianginal drugs 1, 4
• Ranolazine may be especially beneficial for patients who cannot tolerate the hemodynamic effects of traditional antianginal medications 2, 5

Safety Profile and Adverse Effects

• The most common adverse effects (>4% and more common than placebo) include dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%) 3
• Ranolazine causes dose-related QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses 4, 3
• Approximately 6% of patients discontinue treatment due to adverse events, compared to about 3% on placebo 3
• Laboratory abnormalities include mild elevations of serum creatinine (approximately 0.1 mg/dL), which is reversible upon discontinuation and not associated with changes in BUN 3

Contraindications and Precautions

• Ranolazine is contraindicated in patients with:
  • Hepatic impairment or liver cirrhosis 1, 3
  • Concomitant use of strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) 3
  • Concomitant use of CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) 3
• Use with caution in patients taking digoxin, as ranolazine increases digoxin concentration 1, 4
• Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min) 3

Drug Interactions

• Limit ranolazine to 500 mg twice daily when used with moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin) 3
• Adjust doses of CYP3A substrates when used with ranolazine:
  • Limit simvastatin to 20 mg when used with ranolazine 3
  • Doses of other sensitive CYP3A substrates may need to be reduced 3
• Limit metformin to 1700 mg daily when used with ranolazine 1000 mg twice daily 3

Clinical Outcomes

• While ranolazine effectively reduces angina symptoms, it has not been shown to improve cardiovascular outcomes such as mortality or major cardiovascular events in patients with chronic stable angina 1, 4
• It is not effective for treatment of acute coronary syndromes 1, 8

Practical Considerations

• The extended-release formulation allows for twice-daily administration with maintained efficacy 9
• Food has no effect on the rate or extent of absorption from the extended-release formulation 9
• The absolute bioavailability ranges from 35% to 50% 9