Ranolazine

• Chronic Stable Angina
• Refractory Angina
• Coronary Artery Disease

Ranolazine is a unique antianginal medication that treats chronic angina through a mechanism distinct from traditional antianginal drugs. It is particularly useful as add-on therapy when other antianginal medications provide incomplete symptom control.

Mechanism of Action

Ranolazine works primarily by inhibiting late sodium current:

• Late INa inhibition: Reduces abnormal late sodium influx into cardiac myocytes
• Decreases intracellular calcium overload: Sodium accumulation normally leads to calcium accumulation via Na+/Ca2+ exchange
• Reduces diastolic tension: Lower calcium improves myocardial relaxation
• Improves coronary blood flow: Reduced wall tension improves diastolic coronary perfusion
• No hemodynamic effects: Does not significantly affect heart rate or blood pressure

This mechanism addresses the metabolic consequences of ischemia rather than altering oxygen supply/demand balance directly.

Available Formulations

Ranolazine is available as extended-release tablets:

• 500 mg tablets
• 1000 mg tablets

Tablets should be swallowed whole; do not crush, break, or chew.

Medical Uses

FDA-Approved Indication:

• Chronic angina

Ranolazine is used when other antianginal drugs (beta-blockers, calcium channel blockers, nitrates) are inadequate or not tolerated.

Dosing Guidelines

Adults:

• Initial: 500 mg twice daily
• May increase to 1000 mg twice daily as needed based on clinical response
• Maximum: 1000 mg twice daily

Administration:

• May be taken with or without food
• Swallow tablets whole

Dose Modifications:

• Limit to 500 mg twice daily with moderate CYP3A4 inhibitors
• Avoid with strong CYP3A4 inhibitors

Important Safety Information

Contraindications:

• Hepatic cirrhosis
• Concomitant use with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, HIV protease inhibitors)
• Concomitant use with CYP3A4 inducers (rifampin, phenytoin, phenobarbital, carbamazepine)

Warnings and Precautions:

• QT prolongation: Dose-dependent QTc prolongation; avoid in patients with QT prolongation, hepatic impairment, or those taking other QT-prolonging drugs
• Renal impairment: Monitor for adverse effects in patients with renal dysfunction (drug levels increase)
• Not for acute angina: Does not provide relief during acute anginal episodes

Drug Interactions

Strong CYP3A4 Inhibitors (ketoconazole, itraconazole, clarithromycin, HIV protease inhibitors):

• Contraindicated; significantly increases ranolazine levels

Moderate CYP3A4 Inhibitors (diltiazem, verapamil, erythromycin):

• Limit ranolazine to 500 mg twice daily

CYP3A4 Inducers (rifampin, phenobarbital, carbamazepine, phenytoin, St. John's Wort):

• Contraindicated; will reduce ranolazine efficacy

P-gp Inhibitors (cyclosporine):

• Limit ranolazine to 500 mg twice daily

Drugs Metabolized by CYP2D6 (TCAs, antipsychotics):

• Ranolazine inhibits CYP2D6; may need to reduce doses of these drugs

QT-Prolonging Drugs:

• Use with caution; additive QTc effects

Special Populations

• Hepatic Impairment: Contraindicated in cirrhosis; avoid in moderate impairment
• Renal Impairment: No adjustment, but monitor closely for adverse reactions (levels increase)
• Elderly: No specific adjustment; start at lower end of dosing range
• Pregnancy: Limited data; use only if benefit outweighs risk
• Lactation: Unknown if excreted in milk