Ranolazine 375 mg (ER) · Tablets

The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (I Na). However, the relationship of this inhibition to angina symptoms is uncertain.

The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of I Kr, which prolongs the ventricular action potential.

Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1,000 mg twice daily, the mean steady-state C maxwas 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine extended-release tablets. At steady state over the dose range of 500 to 1,000 mg twice daily, C maxand AUC 0-τincrease slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.

Absorption and Distribution — After oral administration of ranolazine extended-release tablets, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from ranolazine extended-release tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.

Food (high-fat breakfast) has no important effect on the C maxand AUC of ranolazine. Therefore, ranolazine extended-release tablets may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins.

Metabolism and Excretion — Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent half-lives ranging from 6 to 22 hours.

Effect of Other Drugs on ranolazine — In vitro data indicate that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is also a substrate of P-glycoprotein.

Strong CYP3A Inhibitors — Plasma levels of ranolazine with ranolazine extended-release tablets 1,000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see Contraindications (4)].

Moderate CYP3A Inhibitors — Plasma levels of ranolazine with ranolazine extended-release tablets 1,000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with ranolazine extended-release tablets 750 mg twice daily are increased by 100% by verapamil 120 mg three times daily [see Drug Interactions (7.1)].

Weak CYP3A Inhibitors — The weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.

CYP3A Inducers — Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1,000 mg twice daily) by approximately 95% [see Contraindications (4)].

CYP2D6 Inhibitors — Paroxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving ranolazine extended-release tablets 1,000 mg twice daily. No dose adjustment of ranolazine extended-release tablets is required in patients treated with CYP2D6 inhibitors.

Digoxin — Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily.

Effect of ranolazine on Other Drugs — In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2.