Usage
- Ranolazine is prescribed for the treatment of chronic angina (chest pain) as add-on therapy in patients who experience inadequate symptom relief or are intolerant to first-line antianginal medications like beta-blockers and calcium channel blockers.
- Pharmacological classification: Antianginal agent.
- Ranolazine’s mechanism of action is not fully understood, but it is believed to work by reducing the late sodium current in heart muscle cells. This helps to stabilize the cell membrane and may improve myocardial oxygen supply-demand balance during periods of ischemia.
Alternate Names
- International nonproprietary name (INN): Ranolazine.
- Brand names: Ranexa, Aspruzyo Sprinkle.
How It Works
- Pharmacodynamics: Ranolazine reduces the late sodium current in cardiac myocytes, thereby decreasing intracellular calcium overload and improving diastolic relaxation. This leads to improved myocardial oxygen utilization and reduced angina symptoms.
- Pharmacokinetics:
- Absorption: Ranolazine is absorbed orally, reaching peak plasma concentration in 2-5 hours. Food does not affect absorption.
- Metabolism: Primarily metabolized by CYP3A4 and, to a lesser extent, CYP2D6 enzymes in the liver.
- Elimination: Excreted in urine and feces, with a half-life of approximately 7 hours. Steady-state concentration is achieved within 3 days.
- Mode of Action: Ranolazine inhibits the late sodium current by blocking the influx of sodium ions into cardiac cells during the plateau phase of the action potential. This reduces intracellular calcium overload and improves diastolic relaxation.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Primarily acts by inhibiting late sodium current. It does not significantly affect heart rate, blood pressure, or contractility.
- Elimination Pathways: Primarily hepatic metabolism followed by renal and fecal excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: 500 mg twice daily.
- Titration: Increase to 1000 mg twice daily, as needed, based on clinical symptoms. Maximum dose: 1000 mg twice daily.
- Administration: Administer orally with or without food. Tablets should be swallowed whole and not crushed, broken, or chewed.
Children:
- Safety and efficacy not established in patients under 18 years of age.
Special Cases:
- Elderly Patients: No specific dose adjustments are recommended, but caution is advised due to potential age-related changes in drug metabolism.
- Patients with Renal Impairment: No dose adjustment provided by manufacturer. However, Cmax increases in patients with renal impairment. Close monitoring is advised and discontinuation should be considered if acute renal failure develops.
- Patients with Hepatic Dysfunction: Contraindicated in patients with any degree of hepatic impairment and cirrhosis. Dosage reduction may be considered for patients with moderate or severe hepatic impairment without cirrhosis, starting at 500 mg once daily.
- Patients with Comorbid Conditions: Dose adjustment may be needed for patients with diabetes taking metformin concomitantly. For patients on ranolazine 1000 mg twice daily, the metformin dose should not exceed 1700 mg daily, and blood glucose should be closely monitored.
Clinical Use Cases
Ranolazine is specifically indicated for chronic angina and is not recommended for the following clinical settings:
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations (e.g., status epilepticus, cardiac arrest)
Dosage Adjustments
- Moderate CYP3A4 Inhibitors: Limit the maximum dose to 500 mg twice daily when co-administered with moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, fluconazole).
- P-gp Inhibitors: Titrate dose based on clinical response when used with P-gp inhibitors (e.g., cyclosporine).
Side Effects
Common Side Effects:
- Constipation
- Dizziness
- Headache
- Nausea
- Vomiting
Rare but Serious Side Effects:
- Angioedema
- QT prolongation
- Renal impairment
- Hepatic impairment
Long-Term Effects:
- Potential for QT prolongation with long-term use.
Adverse Drug Reactions (ADR)
- Angioedema
- Torsades de pointes (rare but serious arrhythmia)
Contraindications
- Hypersensitivity to ranolazine.
- Hepatic impairment, especially with cirrhosis.
- Concurrent use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin).
- Pre-existing QT prolongation.
Drug Interactions
- CYP3A4 Inhibitors: Moderate inhibitors (e.g., diltiazem, verapamil, erythromycin) require dose reduction. Strong inhibitors are contraindicated.
- CYP3A4 Inducers: May decrease ranolazine efficacy.
- P-gp Inhibitors: (e.g., cyclosporine) May increase ranolazine concentrations.
- QT Prolonging Drugs: Concurrent use increases the risk of Torsades de pointes.
- Metformin: Ranolazine may increase metformin plasma concentrations, requiring metformin dose adjustment and blood glucose monitoring.
- Grapefruit juice: May increase ranolazine levels and should be avoided.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C.
- Fetal risks are not well-established. Use only if the potential benefit outweighs the potential risk to the fetus.
- It is unknown if ranolazine is excreted in breast milk. Exercise caution if breastfeeding.
Drug Profile Summary
- Mechanism of Action: Inhibits late sodium current in cardiac myocytes.
- Side Effects: Constipation, dizziness, headache, nausea, vomiting, QT prolongation (rare).
- Contraindications: Hepatic impairment with cirrhosis, strong CYP3A4 inhibitors, pre-existing QT prolongation, hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors and inducers, P-gp inhibitors, QT prolonging drugs, metformin.
- Pregnancy & Breastfeeding: Category C; caution advised.
- Dosage: 500-1000 mg twice daily (adults).
- Monitoring Parameters: ECG (for QT prolongation), renal function, hepatic function.
Popular Combinations
- Beta-blockers
- Nitrates
- Calcium channel blockers
Precautions
- Monitor for QT prolongation.
- Assess renal and hepatic function.
- Caution in patients with pre-existing heart conditions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ranolazine?
A: Initial dose: 500 mg twice daily, titrated up to 1000 mg twice daily as needed based on clinical response. Maximum dose is 1000 mg twice daily.
Q2: How does Ranolazine work?
A: Ranolazine inhibits the late sodium current in cardiac myocytes, reducing calcium overload and improving myocardial oxygen balance.
Q3: What are the common side effects of Ranolazine?
A: Constipation, dizziness, headache, nausea, and vomiting are common side effects.
Q4: What are the serious side effects of Ranolazine?
A: QT interval prolongation, angioedema, renal impairment, and hepatic impairment.
Q5: What are the contraindications for Ranolazine?
A: Hepatic impairment with cirrhosis, strong CYP3A4 inhibitors, pre-existing QT prolongation, and hypersensitivity.
Q6: What are the important drug interactions of Ranolazine?
A: CYP3A4 inhibitors and inducers, P-gp inhibitors, QT prolonging agents, and metformin.
Q7: Can Ranolazine be used in pregnancy?
A: Pregnancy Category C. Use with caution only if potential benefit outweighs the risk.
Q8: Can Ranolazine be used during breastfeeding?
A: It is unknown if ranolazine is excreted in breast milk. Exercise caution if breastfeeding.
Q9: How should Ranolazine tablets be administered?
A: Swallow whole; do not crush, break, or chew. May be taken with or without food.
Q10: What should be monitored in patients taking Ranolazine?
A: ECG for QT prolongation, renal function, and hepatic function.
