Introduction
Ranolazine is an antianginal medication approved for the treatment of chronic angina pectoris. Unlike traditional antianginal agents that primarily reduce myocardial oxygen demand, ranolazine exerts its effects through a unique mechanism involving inhibition of the late sodium current. It represents an important therapeutic option for patients who remain symptomatic despite standard antianginal therapy.
Mechanism of Action
Ranolazine works primarily by inhibiting the late inward sodium current (INa) in cardiac myocytes. This action reduces sodium-dependent calcium overload during myocardial ischemia by decreasing sodium entry into cardiac cells. The reduction in intracellular calcium improves myocardial relaxation and decreases left ventricular diastolic stiffness, thereby reducing myocardial oxygen demand. Additionally, ranolazine may have effects on fatty acid oxidation and cardiac metabolism. Importantly, it does not significantly affect heart rate or blood pressure.
Indications
Ranolazine is FDA-approved for:
- Treatment of chronic angina in combination with amlodipine, beta-blockers, or nitrates in patients who have not achieved an adequate response with other antianginal agents
- As monotherapy when other antianginal agents are not tolerated or are contraindicated
Dosage and Administration
Standard dosing: 500 mg orally twice daily, with or without food Dose titration: May be increased to maximum 1000 mg twice daily based on clinical response Renal impairment:- Moderate impairment (CrCl 30-60 mL/min): Maximum 500 mg twice daily
- Severe impairment (CrCl <30 mL/min): Contraindicated
Pharmacokinetics
Absorption: Well absorbed with approximately 76% bioavailability; food has minimal effect on absorption Distribution: Volume of distribution approximately 90 L; 60-70% plasma protein bound Metabolism: Extensive hepatic metabolism primarily via CYP3A4 and secondarily via CYP2D6 Elimination: Half-life approximately 7 hours; primarily excreted in urine (75%) and feces (25%) Special populations: CYP2D6 poor metabolizers have approximately 1.6-fold higher exposureContraindications
- Severe renal impairment (CrCl <30 mL/min)
- Hepatic cirrhosis
- Concomitant use with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, nelfinavir, etc.)
- Concomitant use with CYP3A4 inducers (rifampin, phenobarbital, St. John's wort, etc.)
- History of QT prolongation or concomitant use with other QT-prolonging drugs
- Hypersensitivity to ranolazine or any component of the formulation
Warnings and Precautions
QT prolongation: Ranolazine dose-dependently prolongs QT interval; monitor ECG periodically Renal impairment: Use contraindicated in severe impairment; dose adjustment required in moderate impairment Hepatic impairment: Use contraindicated in cirrhosis; use with caution in moderate impairment Dizziness and syncope: May occur; caution patients about activities requiring mental alertness Drug interactions: Significant interactions with CYP3A4 inhibitors/inducers and P-gp substrates Elderly: Increased risk of adverse events; monitor closelyDrug Interactions
Strong CYP3A4 inhibitors: Contraindicated (e.g., ketoconazole, clarithromycin, ritonavir) Moderate CYP3A4 inhibitors: Limit ranolazine to 500 mg twice daily (e.g., diltiazem, verapamil, erythromycin) CYP3A4 inducers: Contraindicated (e.g., rifampin, carbamazepine, St. John's wort) Digoxin: May increase digoxin levels; monitor digoxin concentrations Simvastatin: May increase simvastatin exposure; limit simvastatin to 20 mg daily Metformin: May increase metformin exposure; monitor glycemic control Other QT-prolonging drugs: Avoid concomitant useAdverse Effects
Common (≥2%):- Dizziness (6-10%)
- Constipation (5-6%)
- Nausea (4-5%)
- Headache (3-4%)
- Asthenia (2-3%)
- QT prolongation
- Syncope
- Torsades de pointes (rare)
- Acute renal failure
- Hematologic abnormalities
- Vertigo
Monitoring Parameters
- ECG at baseline and periodically during treatment (monitor QT interval)
- Renal function (serum creatinine/CrCl) at baseline and periodically
- Liver function tests at baseline and as clinically indicated
- Signs and symptoms of angina improvement
- Adverse effects (dizziness, constipation, nausea)
- Drug interactions assessment
- Blood pressure and heart rate
Patient Education
- Take exactly as prescribed, usually twice daily with or without food
- Do not crush or chew extended-release tablets
- Report any dizziness, fainting, or palpitations immediately
- Inform all healthcare providers about ranolazine use
- Avoid grapefruit and grapefruit juice during treatment
- Be aware of potential constipation and maintain adequate hydration/fiber intake
- Do not stop taking suddenly without medical supervision
- Keep regular follow-up appointments for monitoring
- Store at room temperature away from moisture and heat
References
1. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113(20):2462-2472. 2. FDA Prescribing Information: Ranexa (ranolazine) extended-release tablets. Revised 2022. 3. Morrow DA, et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297(16):1775-1783. 4. Stone PH, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2013;61(19):2038-2045. 5. European Society of Cardiology Guidelines on the management of stable coronary artery disease. Eur Heart J. 2019;40(2):87-165. 6. Lexicomp Online, Lexi-Drugs. Ranolazine. Wolters Kluwer Clinical Drug Information, Inc. Accessed 2023.