Introduction
Ranexa (ranolazine) is an antianginal medication approved for the treatment of chronic angina pectoris. Unlike traditional antianginal agents that primarily work through hemodynamic mechanisms, ranolazine offers a unique metabolic approach to managing angina symptoms. It is typically used in combination with other antianginal therapies when symptoms are not adequately controlled.
Mechanism of Action
Ranolazine exerts its antianginal effects through inhibition of the late sodium current (INa) in cardiac cells. This action reduces sodium-dependent calcium overload during ischemic conditions, thereby decreasing myocardial tension and oxygen demand. Additionally, ranolazine demonstrates partial inhibition of fatty acid oxidation, shifting myocardial metabolism toward more efficient glucose oxidation. The drug does not significantly affect heart rate or blood pressure at therapeutic doses.
Indications
- Treatment of chronic angina in combination with amlodipine, beta-blockers, or nitrates in patients who have not achieved adequate response with other antianginal agents
- Not indicated for the treatment of acute coronary syndrome
Dosage and Administration
Initial dose: 500 mg twice daily Maximum dose: 1000 mg twice daily Dose titration: Increase to 1000 mg twice daily based on clinical symptoms Administration: Should be taken with or without food consistently Special populations:- Renal impairment: Maximum dose 500 mg twice daily in patients with moderate to severe renal impairment (CrCl <60 mL/min)
- Hepatic impairment: Contraindicated in patients with cirrhosis
- Elderly: No specific dose adjustment required based on age alone
Pharmacokinetics
Absorption: Oral bioavailability approximately 76%, with peak concentrations achieved within 2-5 hours Distribution: Volume of distribution approximately 80 L, protein binding approximately 62% Metabolism: Extensive hepatic metabolism primarily via CYP3A4 and secondarily via CYP2D6 Elimination: Primarily renal excretion (75%) with approximately 25% fecal elimination; elimination half-life approximately 7 hoursContraindications
- Patients with pre-existing QT prolongation
- Concomitant use with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, saquinavir)
- Concomitant use with CYP3A4 inducers
- Patients with hepatic cirrhosis
- History of ventricular tachycardia
Warnings and Precautions
- QT prolongation: Dose-related QT prolongation observed; avoid use in patients with congenital long QT syndrome
- Renal impairment: Requires dose reduction in moderate to severe impairment
- Dizziness and syncope: May occur; patients should avoid driving or operating machinery until drug effects are known
- Hypotension: May occur in volume-depleted patients
- Drug interactions: Significant potential for interactions due to CYP3A4 metabolism
Drug Interactions
Major interactions:- Strong CYP3A4 inhibitors: Contraindicated (increases ranolazine concentrations 3-fold)
- Moderate CYP3A4 inhibitors: Use with caution (diltiazem, verapamil, erythromycin)
- CYP3A4 inducers: Contraindicated (rifampin, carbamazepine, phenobarbital)
- CYP2D6 substrates: Ranolazine may increase concentrations of drugs metabolized by CYP2D6
- Digoxin: Moderate increase in digoxin levels possible
- Simvastatin: May increase simvastatin exposure
Adverse Effects
Common (≥2%):- Dizziness (6-12%)
- Constipation (5-8%)
- Nausea (4-6%)
- Headache (3-6%)
- Asthenia (2-4%)
- QT prolongation
- Syncope
- Torsades de pointes (rare)
- Acute renal failure (rare)
- Vertigo
Monitoring Parameters
- ECG monitoring for QT interval prolongation at baseline and after dose changes
- Renal function assessment (serum creatinine) at baseline and periodically
- Liver function tests at baseline
- Blood pressure monitoring
- Assessment of angina symptom frequency and severity
- Monitoring for signs of dizziness or syncope
Patient Education
- Take medication exactly as prescribed, typically twice daily
- Do not crush or chew extended-release tablets
- Report any dizziness, lightheadedness, or fainting episodes
- Inform all healthcare providers about ranolazine use
- Avoid grapefruit and grapefruit juice during therapy
- Keep a log of angina episodes to discuss with healthcare provider
- Do not discontinue medication without medical supervision
- Be aware that ranolazine is used to reduce angina frequency but not to treat acute attacks
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. Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006;45(5):469-491. 3. FDA Prescribing Information: Ranexa (ranolazine) extended-release tablets. Revised 2022. 4. 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. 5. Stone PH, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43(8):1375-1382. 6. European Society of Cardiology Guidelines on the management of stable coronary artery disease. Eur Heart J. 2019;40(2):87-165.