Ranolazine

Approved Indications:

• Chronic Stable Angina (CSA):
• Used as a second-line agent for the treatment of chronic angina.
• Can be used as monotherapy or in combination with beta-blockers, calcium channel blockers, or nitrates.

Clinically Accepted Off-Label Uses:

• Microvascular Angina:
• Used for angina with no obstructive coronary artery disease, especially in women.
• Adjunct in Atrial Fibrillation:
• Investigational off-label use for reducing atrial fibrillation burden or improving rhythm control.
• Diastolic Heart Failure (HFpEF):
• Studied for improvement in diastolic function and exercise capacity in patients with preserved ejection fraction.

Adults:

• Initial dose: 500 mg orally twice daily.
• Maintenance dose: May be increased to 1000 mg twice daily, based on symptoms and tolerance.
• Maximum dose: 1000 mg twice daily.

Administration Route:

• Oral; extended-release tablets only. Swallow whole—do not crush, chew, or split.

Geriatrics:

• No dosage adjustment required, but increased sensitivity may be present; start low and monitor.

Renal Impairment:

• Use with caution in moderate renal impairment (CrCl 30–60 mL/min).
• Avoid in severe renal impairment (CrCl <30 mL/min)—accumulation may increase risk of adverse effects.

Hepatic Impairment:

• Mild impairment: Use with caution.
• Moderate to severe impairment: Contraindicated due to increased plasma levels.

Pediatrics:

• Safety and efficacy not established; not recommended in children or adolescents.

Ranolazine inhibits the late phase of the inward sodium current (INa) in cardiac myocytes during repolarization. This reduces intracellular sodium accumulation and indirectly decreases calcium influx via the sodium-calcium exchanger. As a result, it improves myocardial relaxation and reduces myocardial wall tension and oxygen consumption—thereby alleviating ischemia and angina without significantly altering heart rate or blood pressure. It does not affect coronary blood flow or hemodynamics directly.

• Absorption:
  Oral bioavailability ~35–50%; peak plasma concentration in 2–6 hours.
• Distribution:
  Volume of distribution ~85–180 L; plasma protein binding ~62%.
• Metabolism:
  Extensively metabolized in the liver and intestine via CYP3A4 (major) and CYP2D6 (minor).
• Active Metabolites:
  Several, but less active than parent drug.
• Half-life:
  ~7 hours (immediate-release); ~9–11 hours (extended-release).
• Elimination:
  Primarily renal (73%) and fecal (25%) as metabolites.

• Pregnancy:
  FDA Pregnancy Category C (prior to PLLR removal). Animal studies showed potential fetal toxicity at high doses. Use only if potential benefits justify the risk.
• Lactation:
  Unknown if excreted in human breast milk. Due to potential for adverse effects in nursing infants, consider discontinuing breastfeeding or the drug.

• Primary Class: Antianginal Agent
• Subclass: Late Sodium Current Inhibitor

• Known hypersensitivity to ranolazine or any component of the formulation
• Clinically significant hepatic impairment (Child-Pugh Class B or C)
• Concurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)
• Concurrent use with CYP3A inducers (e.g., rifampin, phenytoin)
• Use with Class Ia or Class III antiarrhythmics (e.g., quinidine, dofetilide) may increase QT interval

• QT Prolongation:
  Ranolazine prolongs the QT interval in a dose-related manner. Avoid in patients with a history of congenital long QT syndrome or those on QT-prolonging medications.
• Hepatic Dysfunction:
  Plasma concentrations significantly increased; contraindicated in moderate to severe hepatic impairment.
• Renal Dysfunction:
  Risk of accumulation; use caution and monitor for adverse effects.
• Drug Interactions:
  Numerous interactions with CYP3A4 and CYP2D6 substrates—dose adjustment or avoidance may be needed.
• Hypotension:
  Rare, but possible in volume-depleted patients despite minimal hemodynamic effect.

Common (≥1%):

• Dizziness
• Headache
• Constipation
• Nausea

Less Common:

• Palpitations
• Peripheral edema
• Bradycardia
• Tinnitus
• Abdominal discomfort

Serious Adverse Effects:

• QT interval prolongation
• Syncope
• Acute renal failure (rare; in predisposed individuals)
• Hallucinations or confusion (rare CNS effects)

Onset:

• Typically within first few days; dose-related.

Dose Dependence:

• Most CNS and cardiac adverse effects are dose-dependent, especially >1000 mg/day.

CYP Enzyme Interactions:

• CYP3A4 Inhibitors (contraindicated):
• Ketoconazole, clarithromycin, ritonavir → increase ranolazine levels → QT prolongation risk.
• CYP3A4 Inducers (contraindicated):
• Rifampin, carbamazepine, phenytoin → reduce ranolazine levels → reduced efficacy.
• CYP2D6 Substrates:
• Inhibits CYP2D6 → may increase plasma levels of tricyclic antidepressants, metoprolol, etc.

Other Major Interactions:

• Digoxin:
  Slight increase in plasma concentrations; monitor if used together.
• Simvastatin:
  Limit simvastatin dose to 20 mg/day when used concurrently.
• Diltiazem/Verapamil:
  Moderate inhibitors of CYP3A4; may increase ranolazine levels—dose adjustment may be required.

• ESC 2019 Guidelines on Chronic Coronary Syndromes:
  Reaffirm ranolazine as a second-line antianginal agent, particularly useful in patients intolerant to beta-blockers or with bradycardia/hypotension.
• FDA Updates:
  No recent safety warnings or label changes as of 2025.
• Ongoing Research:
  Investigational use continues in HFpEF and atrial fibrillation suppression, though not yet guideline-approved.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity & Light Protection:
  Store in a dry place, away from excessive humidity and direct light.
• Handling Precautions:
  Do not crush or split extended-release tablets.
• No Refrigeration Needed