RANOLAZINE

Dosing Information

Adult: In Angina pectoris, chronic, initial, 500 mg orally twice daily; increase to the maximum recommended dose of 1000 mg orally twice daily as needed based on clinical symptoms.

Pediatric: Safety and efficacy not established in pediatric patients.

Contraindications

• Concurrent use of potent and moderately potent CYP3A inhibitors, including diltiazem, verapamil, macrolide antibiotics, HIV protease inhibitors, ketoconazole and other azole antifungals, and grapefruit juice or grapefruit-containing products; increased ranolazine levels and QTc prolongation.

• Concurrent use of QT prolonging drugs (such as Class Ia and Class III antiarrhythmics, and certain antipsychotic).

• Hepatic impairment, Child-Pugh Classes A, B or C; QTc prolongation is increased approximately 3-fold.

• QT prolongation, pre-existing, including congenital long QT syndrome and uncorrected hypokalemia.

Precautions

• Concurrent use of CYP3A and P-glycoprotein inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentin, St John’s Wort) should be avoided; decreased ranolazine concentrations.

• Doses greater than 1,000 mg twice daily should be avoided; increased risk of QTc interval prolongation.

• QTc interval prolongation; dose-related prolongation may occur, possibly leading to torsades de pointes-type arrhythmias and sudden death.

• Renal impairment, severe; increases blood pressure by approximately 15 mmHg.

• Ventricular tachycardia, history.

Adverse Effects

• Prolonged QT interval

• Serum blood urea nitrogen raised

• Syncope

Pharmacokinetics

Onset and Duration of action: Initial Response in stable angina, Oral: 2.5 hours (single doses; reflects time of efficacy measurements after dosing).

Drug Concentration Levels

A) Therapeutic Drug Concentration: In stable Angina Pectoris 500 ng/mL suggested in single-dose study.

B) Peak Concentration

1) Oral, extended-release: 2569 ng/mL.

2) Steady state peak and trough plasma concentrations for ranolazine and its metabolites were generally higher in renally impaired subjects compared to healthy subjects. Patients received a ranolazine extended-release loading dose of 875 mg orally, followed by 500 mg every 12 hours for a total of 4 maintenance doses.

C) Time to Peak Concentration: Oral, extended-release: 2 to 5 hours.

Mechanism of Action

1) Ranolazine is a piperazine derivative and the mechanism of action of its anti-anginal and anti-ischemic effect is unknown. The anti-anginal and anti-ischemic action of ranolazine is not dependent upon heart rate or blood pressure reduction and does not increase myocardial workload. At therapeutic levels, ranolazine can inhibit the inactivating component of the sodium current (I(Na)) although its relationship to angina symptoms is uncertain. It also inhibits the rapid inward rectifying current (I(Kr)), thereby prolonging the ventricular action potential.

2) Ranolazine has also been postulated to modulate myocardial metabolism by partially inhibiting fatty acid oxidation, thereby increasing glucose oxidation and generating more adenosine triphosphate (ATP) per molecule of oxygen consumed (i.e., cardiac muscle cell substrate utilization is shifted towards carbohydrates and away from fatty acids). The anti-anginal and anti-ischemic action of ranolazine is not dependent upon heart rate or blood pressure reduction and does not increase myocardial workload.

3) Action unlike beta-blockers and calcium antagonists, ranolazine lacks effects on hemodynamics, contractile/ conduction parameters.

4) Ranolazine has renal transplant preservation potential.

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